Methods of treating cancer and / or chemotherapy related conditions using non-naturally occurring melanocortin analogs

Abstract

Provided herein are methods of treating, preventing, or reducing conditions and / or side effects associated with anti-cancer agents (e.g., chemotherapeutic agents) via administration of a non-naturally occurring melanocortin analog prior to, during, and / or after administration of the anti-cancer agents. The methods reduce adverse effects associated with the anti-cancer agent, such as anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite, thereby enhancing tolerance of the anti-cancer agents and survival of the subject having cancer or having a disease or condition that is not cancer but is treated, reduced, or prevented by administration of an anti-cancer agent.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application 63 / 618587 filed January 8, 2024, which is incorporated herein by reference in its entirety. SEQUENCE LISTING INCORPORATED BY REFERENCE

[0002] This application contains an ST.26 compliant Sequence Listing, which is submitted concurrently in .xml format via Patent Center and is hereby incorporated by reference in its entirety. The .xml copy, created on February 16, 2024, is named 146316_8019_WO00_SL.xml and is 1,552,278 bytes in size. BACKGROUND

[0003] The use of anti-cancer agents, including chemotherapeutic agents, to treat patients is often restricted because the patient suffers from certain conditions such as anorexia, emesis, weight loss, fat and muscle wasting, and fatigue. These conditions may be caused by the subject’s cancer or may be side effects of the anti-cancer agents. Restrictions on anti-cancer agent use may include limited duration and dose of cancer treatment due to subject’s suffering from one or more of these conditions. Accordingly, these conditions limit treatment tolerance of a subject to an anti-cancer agent thereby reducing the overall treatment efficacy, reducing quality of life in cancer patients, and increasing risk that treatments are not as effective as they otherwise could be.

[0004] Despite recent advances in cancer treatment, there is a demand for novel approaches to make anti-cancer agents and associated cancer therapeutic methods more tolerable for patients, including reduced adverse side effects compared to conventional methods, yet retaining or increasing robust therapeutic activity.

[0005] Body weight of rats will be recorded before any doses of TCMCB07 and / or cisplatin are administered, between TCMCB07 and / or cisplatin doses, and after all doses of TCMCB07 and / or cisplatin are administered. SUMMARY

[0001] In some embodiments, the present technology comprises a method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0002] In some embodiments, the present technology comprises a method of maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

[0003] In some embodiments, the present technology comprises a method of maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anticancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0004] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog to treat, prevent, or reduce one or more side effects associated with an anti-cancer agent in a subject, the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite, wherein the non-naturally occurring melanocortin analog is administered to the subject prior to, during, and / or after administration of the anti-cancer agent.

[0005] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog to maintain or increase weight in a subject prior to, during, and / or after administration of an anti-cancer agent, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

[0006] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog to maintain or increase weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0007] In some embodiments, the subject experiences an increase in weight by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% compared to baseline or a control.

[0008] In some embodiments, the present technology comprises a method of maintaining or increasing muscle mass, fat mass, or cardiac mass in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0009] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog to maintain or increase muscle mass, fat mass, or cardiac mass in a subject prior to, during, and / or after administration of an anti-cancer agent.

[0010] In some embodiments, the subject experiences an increase in muscle mass, fat mass, or cardiac mass by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

[0011] In some embodiments, the present technology comprises a method of maintaining or increasing bone density in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0012] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog to maintain or increase bone density in a subject prior to, during, and / or after administration of an anti-cancer agent.

[0013] In some embodiments, the subject experiences an increase in bone density by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline ora control.

[0014] In some embodiments, the present technology comprises a method of increasing or maintaining a Functional Assessment of Anorexia / Cachexia Therapy (FAACT) score in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0015] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog to maintain or increase a Functional Assessment of Anorexia / Cachexia Therapy (FAACT) score in a subject prior to, during, and / or after administration of an anti-cancer agent.

[0016] In some embodiments, the subject experiences an increase in the FAACT score compared to baseline or control by at least 1, 2, 3, 4, or 5 points.

[0017] In some embodiments, the present technology comprises a method of stimulating appetite or reducing loss of appetite induced by an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent.

[0018] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog to stimulate appetite or reduce loss of appetite induced by an anti-cancer agent in a subject.

[0019] In some embodiments, the subject experiences an increase in appetite as measured by an increased food intake by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, or more calories compared to baseline a control.

[0020] In some embodiments, the present technology comprises a method of preventing, reducing, or restoring weight loss induced by an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent.

[0021] In some embodiments, the present technology comprises a method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0022] In some embodiments, the present technology comprises a method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0023] In some embodiments, the present technology comprises a method of preventing or reducing an anti-cancer agent induced side effect in a subject having cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0024] In some embodiments, the present technology comprises a method of treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in a subject having cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0025] In some embodiments, the present technology comprises a method of preventing reduction of, maintaining, or improving Eastern Cooperative Oncology Group (ECOG) and / or Karnofsky performance status (KPS) score of a subject having cancer relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0026] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog for preventing, reducing, or restoring weight loss induced by an anti-cancer agent in a subject.

[0027] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0028] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0029] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog for preventing or reducing an anti-cancer agent induced side effect in a subject having cancer.

[0030] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in a subject having cancer.

[0031] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog prior to, during, and / or after administration of an anti-cancer agent for preventing reduction of, maintaining, or improving ECOG and / or KPS score of a subject having cancer relative to a baseline or a control.

[0032] In some embodiments, the subject experiences a reduction in ECOG performance score by about 1,2, or 3 compared to baseline or control.

[0033] In some embodiments, the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to baseline or control.

[0034] In some embodiments, the present technology comprises a method of preventing reduction of, maintaining, or improving overall survival (OS) or progression free survival (PFS) in a subject having cancer relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0035] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog prior to, during, and / or after administration of an anti-cancer agent for preventing reduction of, maintaining, or improving OS or PFS in a subject having cancer relative to a baseline or a control.

[0036] In some embodiments, the subject experiences an increase in OS or an increase in PFS compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

[0037] In some embodiments, the present technology comprises a method of reducing time to cancer treatment failure in a subject having cancer relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0038] In some embodiments, the present technology comprises a method of increasing or maintaining body mass index (BMI) in a subject relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0039] In some embodiments, the present technology comprises a use of a non-naturally occurring analog for reducing time to cancer treatment failure in a subject having cancer relative to a baseline or a control, prior to, during, and / or after administration of an anti-cancer agent.

[0040] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog for increasing or maintaining BMI in a subject relative to a baseline or a control, prior to, during, and / or after administration of an anticancer agent.

[0041] In some embodiments, the subject experiences an increase in BMI compared to baseline or control by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, or 35 points.

[0042] In some embodiments, the subject experiences in an increase in BMI durability compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

[0043] In some embodiments, the present technology comprises a method of reducing a proinflammatory transcript or protein level in a subject having cancer relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0044] In some embodiments, the present technology comprises a use of a non-naturally occurring melanocortin analog for reducing a proinflammatory transcript or protein level in a subject having cancer relative to a baseline or a control, prior to, during, and / or after administration of an anti-cancer agent.

[0045] In some embodiments, the subject experiences a reduction in an inflammatory transcript level compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

[0046] In some embodiments, the subject experiences a reduction in an inflammatory protein level compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

[0047] In some embodiments, the proinflammatory transcript is a transcript selected from the group consisting of an IL1 transcript, an IL6 transcript, an IL1R1 transcript, a TNFa transcript, a Selectin P transcript, a cytokine transcript, and a chemokine transcript.

[0048] In some embodiments, the proinflammatory protein is a protein selected from the group consisting of an IL1 protein, an IL6 protein, an IL1R1 protein, a TNFa protein, a Selectin P protein, a cytokine protein, and a chemokine protein.

[0049] In some embodiments, the method or the use maintains or increases lean body mass, fat body mass, and / or weight of the subject relative to a baseline or a control.

[0050] In some embodiments, the method or the use maintains or increases lean body mass, fat body mass, and / or body weight of the subject relative to a baseline or a control.

[0051] In some embodiments, the failure to respond to an antiemetic treatment further comprises clinically and / or therapeutically insufficient weight gain, muscle mass gain, fat mass gain, increased appetite, and / or increased food intake in the subject.

[0052] In some embodiments, the nutritional intervention further comprises nutritional supplementation.

[0053] In some embodiments, the iatrogenic injury is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0054] In some embodiments, the improvement, maintenance, or prevented reduction of ECOG and / or KPS score occurs by inhibiting or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

[0055] In some embodiments, the subject has a cancer.

[0056] In some embodiments, the anti-cancer agent comprises a chemotherapy.

[0057] In some embodiments, the method or the use reduces chemotherapy induced mass loss and / or wasting in the subject and increases lean body mass and body weight of the subject relative to a baseline or a control.

[0058] In some embodiments, the method or the use maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and wherein the method reduces mass loss and / or wasting in the subject relative to a baseline or a control.

[0059] In some embodiments, the anorexia is associated with weight loss.

[0060] In some embodiments, the subject has not previously received an anticancer agent.

[0061] In some embodiments, the subject has previously received an anti-cancer agent.

[0062] In some embodiments, the subject is receiving an anti-cancer agent.

[0063] In some embodiments, the administration of the non-naturally occurring melanocortin analog enhances tolerability of the anti-cancer agent.

[0064] In some embodiments, the enhanced tolerability results in a greater dosage, an increased frequency of administration, and / or an increased duration of administration of the anti-cancer agent, relative to a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0065] In some embodiments, the anti-cancer agent comprises a chemotherapy comprising at least two chemotherapeutic agents, and wherein the enhanced tolerability results in a second chemotherapeutic agent being administered to the subject during or after administration of a first chemotherapeutic agent.

[0066] In some embodiments, the administration of the non-naturally occurring melanocortin analog prevents or reduces a downward titration in dosing regimen of the anti-cancer agent relative to a baseline or a control.

[0067] In some embodiments, the downward titration comprises a decreased dosage, a decreased frequency of administration, and / or a decreased duration of administration, compared to a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0068] In some embodiments, the subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss prior to the administration of the non-naturally occurring melanocortin analog.

[0069] In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by cancer.

[0070] In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the anti-cancer agent.

[0071] In some embodiments, the subject is receiving or has received an antiemetic.

[0072] In some embodiments, the antiemetic is marijuana, megestrol, somatropin, or dronabinol.

[0073] In some embodiments, the non-naturally occurring melanocortin analog and the anti-cancer agent are administered concurrently.

[0074] In some embodiments, the non-naturally occurring melanocortin analog is administered before and / or after the anti-cancer agent.

[0075] In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents or reduces the one or more side effects associated with an anti-cancer agent in a subject.

[0076] In some embodiments, administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

[0077] In some embodiments, administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing one or more side effects selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0078] In some embodiments, administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anticancer agent in the subject relative to a baseline or a control.

[0079] In some embodiments, administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores weight loss induced by an anticancer agent in the subject relative to a baseline or a control.

[0080] In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and / or therapeutically to an antiemetic treatment, relative to a baseline or a control.

[0081] In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and / or therapeutically to nutritional intervention, relative to a baseline or a control.

[0082] In some embodiments, administration of the non-naturally occurring melanocortin analog prevents or reduces the anti-cancer agent induced side effect in the subject, relative to a baseline or a control.

[0083] In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the iatrogenic injury caused by an anticancer agent in the subject, relative to a baseline or a control.

[0084] In some embodiments, administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves ECOG and / or KPS score of the subject, relative to a baseline or a control.

[0085] In some embodiments, the subject’s mass and / or weight is not more than 5% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0086] In some embodiments, the subject’s mass and / or weight is not more than 10% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0087] In some embodiments, the subject has an ECOG score of 1 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anticancer agent.

[0088] In some embodiments, the subject has an ECOG score of 2 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anticancer agent.

[0089] In some embodiments, the method lowers the ECOG scale of the subject, relative to a baseline or a control.

[0090] In some embodiments, the subject has a KPS score not more than 70 prior to administration of the non-naturally occurring melanocortin analog and / or the anticancer agent.

[0091] In some embodiments, the subject has a KPS score not more than 50 prior to administration of the non-naturally occurring melanocortin analog and / or the anticancer agent.

[0092] In some embodiments, the method or the use increases the subject’s cumulative mass relative to a baseline or control.

[0093] In some embodiments, the method or the use reduces the subject’s rate of loss of cumulative mass relative to a baseline or control.

[0094] In some embodiments, the method or the use increases a net weight gain in the subject relative to a baseline or control.

[0095] In some embodiments, the net weight gain is the change in weight between two or more time points.

[0096] In some embodiments, the net weight gain is the change in weight between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

[0097] In some embodiments, the two or more time points comprises an intermediate time point.

[0098] In some embodiments, the method or the use increases the subject’s cumulative food intake relative to a baseline or control.

[0099] In some embodiments, the cumulative food intake is the total food intake between two or more time points.

[0100] In some embodiments, the cumulative food intake is the total in food intake between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

[0101] In some embodiments, the two or more time points comprises an intermediate time point.

[0102] In some embodiments, the method or the use increases the subject’s BMI relative to a baseline or control.

[0103] In some embodiments, the increase in BMI is the change in BMI between two or more time points.

[0104] In some embodiments, the increase in BMI is a change in BMI between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

[0105] In some embodiments, the two or more time points comprises an intermediate time point.

[0106] In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject based on the subject’s BMI at the time of administration.

[0107] In some embodiments, the subject is administered the non-naturally occurring melanocortin analog at two or more doses based on the subject’s BMI at the time of each administration.

[0108] In some embodiments, the two or more doses are inversely titrated based on the subject’s BMI at the time of each administration. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I), X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8 (I) wherein: R1 is absent or is selected from the group consisting of cysteine, norleucine (Nie), acetylated norleucine (Ac-Nle), trans-4-guanidinyl-proline (fransPro(guan)), c / s-4-guanidinyl-proline (c / sPro(guan)), acetylated frans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated c / s-4-guanidinyl-proline (Ac-c / sPro(guan)), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid; R2 is absent or is selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), YansPro(guan), c / sPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, norleucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine; R3 is absent or is selected from the group consisting of histidine, L-proline, transPro(guan), c / sPro(guan), D-valine, glutamic acid, tryptylarginine (Trp-Arg), glycine, D-leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-( 1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6- tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1-amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), and indoline-2-carboxylic acid (loc), R4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CP3)dPhe); R5 is absent or is selected from the group consisting of arginine, homoarginine, proline, transPro(guan), c / sPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(l)dPhe; R6 is absent or is selected from the group consisting of L-tryptophan, D-phenylalanine, D-Nal(2’), L-Nal(2'), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(T), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine; R7 is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, ornithine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8 is absent or is lysine; R9.R20 are absent; X1 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, p-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X2 is absent or is D-proline; X3 is absent; Y1 is absent or is selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline; Y2 is absent or is selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine; Y3 is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine; Y4 is absent or is D-aspartic acid or aspartic acid; Y5-Y8 are absent; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 and R7 when R1 is cysteine and R7 is cysteine; a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid; a side-chain lactam bridge between R1 or R2 and R7 when R1 or R2 is glutamic acid or aspartic acid, and R7 is lysine, Dap, or ornithine; a side-chain lactam bridge between R2 and R7 when R2 is lysine, and R7 is glutamic acid or aspartic acid; a side-chain lactam bridge between R1 or R2 and R8 when R1 or R2 is glutamic acid or aspartic acid, R8 is lysine, and R7 is proline, glycine or tryptophan; provided that: when R2 is dAsp, then R7 is not dLys; when R2-R4 is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7 is not Arg-Trp-Lys; when Y1 is dPro, Y2 is dVal, and Y3-Y8 are absent, then R4 is not dNal(2’) or R4 is dNal(2’) and the C-terminus is not modified; when R3 is Aba, Ata, or Aia, R6 is Aia, or R7 is Orn, then R4 is not dNal(2’), or R4 is dNal(2’) and R5 is not Arg; when R4 is p(CI)dPhe, then R3 is not Pro or His; when R4 is p(l)dPhe then the non-naturally occurring melanocortin analog is cyclized through a side-chain lactam bridge between R1 and R7 and at least one of R2 and R3 is Pro; when Y2-Y4 are absent, then Y1 is absent or is norleucine; when R2 is Pro or Y2 is Hyp, then R3 is not Pro; when R3, R5, or R6 is absent, then the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1 and R7 or X1-X2 are present and are Ac-dVal-dPro; when R2-R7 is Asp-Pro-dNal(2’)-Arg-Trp-Lys (SEQ ID NO: 526) or Cys-Pro-dNal(2’)-Arg-Trp-Cys (SEQ ID NO: 527), then R1 is not Ac-Nie or Y1-Y2 is not dVal-dPro, dVal-dVal, dPro-dPro; and when the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2 and R8, then R3 is not His or Y1 is not dVal.

[0109] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2.

[0110] In some embodiments, the chemotherapy comprises at least one chemotherapeutic agent.

[0111] In some embodiments, the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of a platinum-coordination complex, an antimetabolite, a tubulin binding agent or a plant alkaloid, an alkylating antineoplastic agent, and a cytotoxic antibiotic.

[0112] In some embodiments, the at least one chemotherapeutic agent comprises a platinum-coordination complex.

[0113] In some embodiments, the at least one chemotherapeutic agent comprises an antimetabolite.

[0114] In some embodiments, the at least one chemotherapeutic agent comprises a tubulin binding agent or a plant alkaloid.

[0115] In some embodiments, the at least one chemotherapeutic agent comprises an alkylating antineoplastic agent.

[0116] In some embodiments, the at least one chemotherapeutic agent comprises a cytotoxic antibiotic.

[0117] In some embodiments, the platinum-coordination complex is carboplatin and / or cisplatin.

[0118] In some embodiments, the antimetabolite is at least one selected from the group consisting of 5-fluorouracil (5-FU), 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil.

[0119] In some embodiments, the tubulin binding agent or the plant alkaloid is at least one selected from the group consisting of vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and Topotecan.

[0120] In some embodiments, the alkylating antineoplastic agent is at least one selected from the group consisting of altretamine, busulfan, carmustine, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.

[0121] In some embodiments, the cytotoxic antibiotic is at least one selected from the group consisting of daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, and valrubicin.

[0122] In some embodiments, the platinum-coordination complex is cisplatin.

[0123] In some embodiments, the antimetabolite is 5-fluorouracil (5-FU).

[0124] In some embodiments, the tubulin binding agent or the plant alkaloid is vincristine.

[0125] In some embodiments, the alkylating antineoplastic agent is cyclophosphamide.

[0126] In some embodiments, the cancer is at least one selected from the group consisting of bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, colorectal cancer, oral cancer, skin cancer, and melanoma.

[0127] In some embodiments, the cancer is at least one selected from the group consisting of bone cancer, lung cancer, testicular cancer, breast cancer, prostate cancer, colorectal cancer, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer.

[0128] In some embodiments, the cancer is breast cancer, and wherein the anticancer agent is at least one selected from the group consisting of an anthracycline, cyclophosphamide, epirubicin, fluorouracil, methotrexate, ataxane, and docetaxel.

[0129] In some embodiments, the anthracycline is doxorubicin.

[0130] In some embodiments, the taxane is paclitaxel.

[0131] In some embodiments, the cancer is lung cancer, and the anti-cancer agent is at least one selected from the group consisting of cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide, and pemetrexed.

[0132] In some embodiments, the cancer is prostate cancer, and the anti-cancer agent is at least one selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, and estramustine.

[0133] In some embodiments, the cancer is colorectal cancer, and the anti-cancer agent is at least one selected from the group consisting of 5-FU, capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

[0134] In some embodiments, the cancer is colorectal cancer, the subject is receiving radiation therapy, and wherein the chemotherapy is at least one selected from the group consisting of cisplatin, cisplatin plus 5-FU, and mitomycin plus 5-FU.

[0135] In some embodiments, the cancer is colorectal cancer, the subject is not receiving radiation therapy, and wherein the chemotherapy is at least one selected from the group consisting of gemcitabine plus cisplatin, methotrexate, vinblastine, doxorubicin, plus cisplatin, cisplatin, methotrexate, plus vinblastine, and gemcitabine plus paclitaxel.

[0136] In some embodiments, the cancer is melanoma, and the anti-cancer agent is dacarbazine and / or temozolomide.

[0137] In some embodiments, the cancer is non-Hodgkin's lymphoma, and the anti-cancer agent is at least one selected from the group consisting of cyclophosphamide, chlorambucil, bendamustine, ifosfamide, prednisone, dexamethasone, cisplatin, carboplatin, oxaliplatin, fludarabine, pentostatin, cladribine (2-CdA), cytarabine (ara-C), gemcitabine, methotrexate, pralatrexate, doxorubicin, liposomal doxorubicin, hydroxydaunorubicin, vincristine, mitoxantrone, etoposide, and bleomycin.

[0138] In some embodiments, the method or the use does not reduce efficacy of the anti-cancer agent.

[0139] In some embodiments, the subject with a cancer has previously undergone a treatment with the anti-cancer agent.

[0140] In some embodiments, the subject has previously experienced one or more adverse side effects when treated with the anti-cancer agent, wherein the adverse side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, and appetite reduction or loss of appetite.

[0141] In some embodiments, the subject is a human.

[0142] In some embodiments, the subject is an animal.

[0143] In some embodiments, the muscle mass loss is cardiac muscle mass loss, skeletal muscle mass loss, or both.

[0144] In some embodiments, the cardiac muscle mass loss is determined by measuring change in heart weight.

[0145] In some embodiments, the skeletal muscle mass loss is determined by measuring change in gastrocnemius tissue weight.

[0146] In some embodiments, anorexia is determined by daily food intake, daily food consumption, and / or weekly food intake.

[0147] In some embodiments, the daily food intake is determined by total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 day.

[0148] In some embodiments, the daily food consumption is determined by the daily food intake normalized to daily body weight of the subject.

[0149] In some embodiments, the weekly food intake is determined total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 week.

[0150] In some embodiments, the weight loss is determined by daily body weight, and / or daily body weight gain.

[0151] In some embodiments, the fat mass of the subject treated with the method is at least 10% to 100% greater than a baseline or control, and the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0152] In some embodiments, the heart weight of the subject treated with the method is at least 0.1% to 10% greater than a baseline or control, and the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0153] In some embodiments, the gastrocnemius tissue weight of the subject treated with the method is at least 0.1 % to 10% greater than a baseline or control, and the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0154] In some embodiments, the daily food intake of the subject treated with the method is at least 5% to 50% greater than a baseline or control, and the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0155] In some embodiments, appetite of the subject is increased by at least 10% to 200% after the administration of the non-naturally occurring melanocortin analog.

[0156] In some embodiments, appetite of the subject is increased by at least 25% to 100% after the administration of the non-naturally occurring melanocortin analog.

[0157] In some embodiments, appetite is increased for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years during the administration.

[0158] In some embodiments, appetite is increased for at least 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days during the administration.

[0159] In some embodiments, the increased appetite is maintained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after the administration is stopped.

[0160] In some embodiments, the appetite is assessed by a scale for measuring desire to eat, feeling of hunger, and / or level of satiety.

[0161] In some embodiments, the appetite is assessed between meals.

[0162] In some embodiments, the subject comprises two or more subjects, and wherein the appetite is an average appetite of the two or more subjects.

[0163] In some embodiments, anorexia is determined by food consumption.

[0164] In some embodiments, the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.

[0165] In some embodiments, the pharmaceutical composition further comprises a pharmaceutical salt.

[0166] In some embodiments, the pharmaceutical composition further comprises a pharmaceutical carrier.

[0167] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the pharmaceutical composition.

[0168] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the pharmaceutical composition.

[0169] In some embodiments, the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

[0170] In some embodiments, the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally.

[0171] In some embodiments, the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

[0172] In some embodiments, the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

[0173] In some embodiments, the pharmaceutical carrier comprises water.

[0174] In some embodiments, the non-naturally occurring melanocortin analog is administered to a subject prior to or after a meal.

[0175] In some embodiments, the non-naturally occurring melanocortin analog is administered to a subject with a meal.

[0176] In some embodiments, a therapeutically effective amount of the non-naturally occurring melanocortin analog is administered, and wherein the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

[0177] In some embodiments, the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.5 mg / kg to 10 mg / kg per body weight of the subject.

[0178] In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

[0179] In some embodiments, the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg per body weight of the subject.

[0180] In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

[0181] In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

[0182] In some embodiments, the anti-cancer agent and the non-naturally occurring melanocortin analog are administered simultaneously as a single composition.

[0183] In some embodiments, the non-naturally occurring melanocortin analog is present in the single composition in a concentration of 0.1 mg / mLto 500 mg / mL, relative to a total volume of the single composition.

[0184] In some embodiments, the non-naturally occurring melanocortin analog is present in the single composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the single composition.

[0185] In some embodiments, the non-naturally occurring melanocortin analog is present in the single composition in a concentration of about 50 mg / mL, relative to a total volume of the single composition.

[0186] In some embodiments, the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

[0187] In some embodiments, the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

[0188] In some embodiments, the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

[0189] In some embodiments, the administration is performed once per day.

[0190] In some embodiments, the anti-cancer agent is present in a first pharmaceutical composition; and the non-naturally occurring melanocortin analog is present in a second pharmaceutical composition.

[0191] In  some embodiments,  the first and  the second  pharmaceutical compositions are different and are administered sequentially.

[0192] In  some embodiments,  the first and  the second  pharmaceutical compositions are different and are administered simultaneously but separately.

[0193] In some embodiments, the second pharmaceutical composition is administered subcutaneously.

[0194] In some embodiments, anti-cancer agent comprises a chemotherapy, and the chemotherapy is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0195] In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the second pharmaceutical composition.

[0196] In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the second pharmaceutical composition.

[0197] In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the second pharmaceutical composition.

[0198] In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

[0199] In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

[0200] In some embodiments, the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day. BRIEF DESCRIPTION OF THE DRAWINGS

[0201] FIG. 1A is a graph depicting daily food intake of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the daily food intakes in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0202] FIG. 1B is a graph depicting daily food consumption of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the daily food consumptions (i.e., daily food intake normalized to daily body weight) in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0203] FIG. 1C is a graph depicting daily body weight of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the daily body weights in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0204] FIG. 1D is a graph depicting daily body weight gain of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the daily body weight gains (% initial) in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0205] FIG. 2A is a graph depicting locomotor activity in dark phase of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the locomotor activities in dark phase in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. The locomotor activities in dark phase are monitored from 5 days prior to the administration until 21 days after administration of the initial dose. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0206] FIG. 2B is a graph depicting locomotor activity in light phase of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the locomotor activities in light phase in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. The locomotor activities in light phase are monitored from 5 days prior to the administration until 21 days after administration of the initial dose. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0207] FIG. 2C is a graph depicting locomotor activity (% of baseline) in dark phase of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the locomotor activities (% of baseline) in dark phase in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. The locomotor activities in dark phase are monitored from 5 days prior to the administration until 21 days after administration of the initial dose. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0208] FIG. 2D is a graph depicting locomotor activity (% of baseline) in light phase of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the locomotor activities (% of baseline) in light phase in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. The locomotor activities in light phase are monitored from 5 days prior to the administration until 21 days after administration of the initial dose. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0209] FIG. 3 is a bar graph depicting fat mass, lean mass, and total water changes of Sprague Dawley rats after a chemotherapy dose-response study. The graph compares the changes in fat mass, lean mass, and total water of the rats after administration with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days.

[0210] FIG. 4 is a bar graph depicting serum GDF-15 (growth differentiation factor-15) concentration of Sprague Dawley rats after a chemotherapy dose-response study. The graph compares the serum GDF-15 concentrations of the rats after administration with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days.

[0211] FIG. 5 is a graph depicting the design of studies using one or more compositions of the present technology.

[0212] FIG. 6A is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.O5, **<.01, ***<.001 ****<.0001.

[0213] FIG. 6B is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.O5, **<.01, ***<.001 ****<.0001.

[0214] FIG. 6C is a graph depicting daily food consumption of Sprague Dawley rats in a combination therapy study. The graph compares the daily food consumptions (i.e., daily food intake normalized to daily body weight) in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are* (or#, &)<.O5, **<.01, ***<.001 ****<.0001.

[0215] FIG. 6D is a graph depicting daily food consumption of Sprague Dawley rats in a combination therapy study. The graph compares the daily food consumptions (i.e., daily food intake normalized to daily body weight) in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are* (or#, &)<05, **<.01, ***<.001 ****<.0001.

[0216] FIG. 7A is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)< 05, **< 01, ***<.001 ****<.0001.

[0217] FIG. 7B is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for21 days. The cutoffs for significance are* (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0218] FIG. 7C is a graph depicting weekly food intake of Sprague Dawley rats in a combination therapy study. The graph compares the weekly food intakes in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0219] FIG. 7D is a graph depicting weekly food intake of Sprague Dawley rats in a combination therapy study. The graph compares the weekly food intakes in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for21 days.

[0220] FIG. 8A is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline, (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.O5, **<.01, ***<.001 ****<.0001. [0221 ] FIG. 8B is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline, (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.O5, **<.01, ***<.001 ****<.0001.

[0222] FIG. 9A is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline, (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are* (or#, &)< 05, **<.01, ***<001 ****<.0001.

[0223] FIG. 9B is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline, (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.05, **<.01, ***<.001 ****<.0001.

[0224] FIG. 10A is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered cisplatin, saline, and IgG (Group 1), cisplatin plus saline plus an anti-GDF-15 monoclonal antibody (mAb) comprising a human ponsegromab Fab region (“ponsegromab”; Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<.O5, **<.01, ***<.001 ****<.0001.

[0225] FIG. 10B is a graph depicting weekly food intake of Sprague Dawley rats in a combination therapy study. The graph compares the weekly food intakes in the rats administered cisplatin plus saline plus IgG (IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus GDF15 the anti-GDF-15 mAb (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or#, &)<05, **< 01, ***< 001 ****<.0001.

[0226] FIG. 10C is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or#, &)<.O5, **<.01, ***<.001 ****<.0001.

[0227] FIG. 10D is a graph depicting total food intake of Sprague Dawley rats in a combination therapy study over 21 days. The graph compares total food intakes in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<.O5, **<.01, ***<.001 ****<.0001.

[0228] FIG. 11A is a graph depicting daily body weight of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weights in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.O5, **<.01, ***<.001 ****<.0001.

[0229] FIG. 11B is a graph depicting daily body weight of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weights in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<05, **<.01, ***< 001 ****< 0001.

[0230] FIG. 11C is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% initial) in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<05, **<.01, ***< 001 ****<.0001.

[0231] FIG. 11D is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% initial) in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or#, &)<.O5, **<01, ***<.001 ****<.0001.

[0232] FIG. 11E is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% of day 0) in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively. Daily body weight gains are shown from day -10 to day 21, where day 0 signifies initiation of cisplatin administration. The cutoffs for significance are* (or#, &)<05, **<.01, ***<001 ****<.0001.

[0233] FIG. 12A is a graph depicting cumulative body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative body weight gains (% of initial) in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0234] FIG. 12B is a graph depicting cumulative body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative body weight gains (% of initial) in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0235] FIG. 13A is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains in the rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.O5, **<.01, ***<.001 ****<.0001.

[0236] FIG. 13B is a graph depicting daily body weight change of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% of initial) in the rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)< 05, **<01, ***<.001 ****<.0001.

[0237] FIG. 14A is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gain in the rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 65 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are* (or#, &)<.05, **<01, ***<.001 ****<.0001.

[0238] FIG. 14B is a graph depicting daily body weight change of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% of initial) in the rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 65 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.O5, **<.01, ***<.001 ****<.0001.

[0239] FIG. 15A is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gain in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb of FIG. 10 (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 the anti-GDF-15 mAb of FIG. 10 (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<.O5, **<01, ***<.001 ****<.0001.

[0240] FIG. 15B is a graph depicting cumulative body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the body weight change (% of initial) in the rats administered cisplatin plus saline plus (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb of FIG. 10 (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb of FIG. 10 (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are* (or#, &)<05, **<.01, ***<.001 ****<.0001.

[0241] FIG. 15C is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight change (% of initial) in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb of FIG. 10 (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb of FIG. 10 (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are* (or#, &)<.O5, **<.01, ***<.001 ****<.0001.

[0242] FIG. 15D is a graph depicting total body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the net body weight gain (% of baseline) in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb of FIG. 10 (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb of FIG. 10 (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are* (or#, &)<.O5, **<.01, ***<.001 ****<.0001.

[0243] FIG. 16A is a graph depicting daily body weight of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight in the rats administered 2 mg / kg / week doxorubicin plus saline (Group 1), 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<05, **<01, ***<.001 ****<.0001.

[0244] FIG. 16B is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gain (% of initial) in the rats administered 2 mg / kg / week doxorubicin plus saline (Group 1), 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)< 05, **<.01, ***<.001 ****<.0001.

[0245] FIG. 16C is a graph depicting daily body weight of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight in the rats administered 2 mg / kg / week doxorubicin plus saline (Group 1), 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 63 days. Administration occurred on days 0, 7, 14, 21,28, and 35.

[0246] FIG. 16D is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gain (% of initial) in the rats administered 2 mg / kg / week doxorubicin plus saline (Group 1), 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 63 days. Administration occurred on days 0, 7, 14, 21, 28, and 35.

[0247] FIG. 17A is a bar graph depicting heart weight of Sprague Dawley rats after combination therapy. The graph compares the heart weights of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0248] FIG. 17B is a bar graph depicting heart weight of Sprague Dawley rats after combination therapy. The graph compares the heart weights of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0249] FIG. 17C is a bar graph depicting gastrocnemius weight of Sprague Dawley rats after combination therapy. The graph compares the gastrocnemius weights of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0250] FIG. 17D is a bar graph depicting gastrocnemius weight of Sprague Dawley rats after combination therapy. The graph compares the gastrocnemius weights of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0251] FIG. 17E is a bar graph depicting spleen weight of Sprague Dawley rats after combination therapy. The graph compares the spleen weights of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0252] FIG. 17F is a bar graph depicting spleen weight of Sprague Dawley rats after combination therapy. The graph compares the spleen weights of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0253] FIG. 18A is a bar graph depicting heart weight of Sprague Dawley rats after combination therapy. The graph compares heart weights of rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or#, &)<.O5, **<.01, ***<.001 ****<.0001.

[0254] FIG. 18B is a bar graph depicting gastrocnemius weight of Sprague Dawley rats after combination therapy. The graph compares gastrocnemius weights of rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.O5, **<.01, ***<.001 ****<.0001.

[0255] FIG. 19A is a bar graph depicting heart weight of Sprague Dawley rats after combination therapy. The graph compares heart weights of rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or#, &)<.O5, **<.01, ***<.001 ****<.0001.

[0256] FIG. 19B is a bar graph depicting gastrocnemius weight of Sprague Dawley rats after combination therapy. The graph compares gastrocnemius weights of rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are* (or#, &)<05, **<.01, ***<001 ****< 0001.

[0257] FIG. 20A is a bar graph depicting fat mass gain of Sprague Dawley rats after combination therapy. The graph compares the fat mass gains of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0258] FIG. 20B is a bar graph depicting fat mass gain of Sprague Dawley rats after combination therapy. The graph compares the fat mass gains of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0259] FIG. 20C is a bar graph depicting lean mass gain of Sprague Dawley rats after combination therapy. The graph compares the lean mass gains of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0260] FIG. 20D is a bar graph depicting lean mass gain of Sprague Dawley rats after combination therapy. The graph compares the lean mass gains of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0261] FIG. 21A is a bar graph depicting fat mass of Sprague Dawley rats after combination therapy. The graph compares the fat mass of the rats before and after administration with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or#, &)<.O5, **<.01, ***<.001 ****<.0001.

[0262] FIG. 21B is a bar graph depicting fat mass gain of Sprague Dawley rats after combination therapy. The graph compares the fat mass gain (% of initial) of the rats after administration with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<05, **<.01, ***< 001 ****< 0001.

[0263] FIG. 21C is a bar graph depicting lean mass of Sprague Dawley rats after combination therapy. The graph compares the lean mass of the rats before and after administration with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)< 05, **<.01, ***< 001 ****< 0001.

[0264] FIG. 21D is a bar graph depicting lean mass gain of Sprague Dawley rats after combination therapy. The graph compares the lean mass gain (% of initial) of the rats after administration with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<.O5, **<.01, ***<.001 ****<.0001.

[0265] FIG. 22A is a bar graph depicting fat mass of Sprague Dawley rats after combination therapy. The graph compares the fat mass of the rats before and after administration with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are* (or#, &)<05, **<.01, ***<001 ****<.0001.

[0266] FIG. 22B is a bar graph depicting fat mass gain of Sprague Dawley rats after combination therapy. The graph compares the fat mass gain (% of initial) of the rats after administration with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are* (or#, &)<.O5, **<.01, ***<.001 ****<.0001.

[0267] FIG. 22C is a bar graph depicting lean mass of Sprague Dawley rats after combination therapy. The graph compares the lean mass of the rats before and after administration with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are* (or#, &)<05, **<.01, ***<001 ****<.0001.

[0268] FIG. 22D is a bar graph depicting lean mass gain of Sprague Dawley rats after combination therapy. The graph compares the lean mass gain (% of initial) of the rats after administration with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are* (or#, &)<05, **<.01, ***<.001 ****<.0001.

[0269] FIG. 23A is a graph depicting locomotor activity in dark phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities in dark phase in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0270] FIG. 23B is a graph depicting locomotor activity in dark phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities in dark phase in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0271] FIG. 23C is a graph depicting locomotor activity (% of baseline) in dark phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities (% of baseline) in dark phase in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), and 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0272] FIG. 23D is a graph depicting locomotor activity (% of baseline) in dark phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities (% of baseline) in dark phase in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), and 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0273] FIG. 24A is a graph depicting locomotor activity in light phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities in light phase in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The locomotor activities in light phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0274] FIG. 24B is a graph depicting locomotor activity in light phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities in dark phase in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0275] FIG. 24C is a graph depicting locomotor activity (% of baseline) in light phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities (% of baseline) in light phase in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), and 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), respectively, for 21 days. The locomotor activities in light phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0276] FIG. 24D is a graph depicting locomotor activity (% of baseline) in light phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities (% of baseline) in light phase in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), and 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), respectively, for 21 days. The locomotor activities in light phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0277] FIG. 25A is a bar graph depicting leukocyte counts (total leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) of Sprague Dawley rats after combination therapy. The graph compares the leukocyte counts (total leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0278] FIG. 25B is a bar graph depicting leukocyte counts (total leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) of Sprague Dawley rats after combination therapy. The graph compares the leukocyte counts (total leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0279] FIG. 25C is a bar graph depicting leukocyte ratios of neutrophils, lymphocytes, monocytes, eosinophils, and basophils of Sprague Dawley rats after combination therapy. The graph compares the leukocyte ratios of neutrophils, lymphocytes, monocytes, eosinophils, and basophils of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0280] FIG. 25D is a bar graph depicting leukocyte ratios of neutrophils, lymphocytes, monocytes, eosinophils, and basophils of Sprague Dawley rats after combination therapy. The graph compares the leukocyte ratios of neutrophils, lymphocytes, monocytes, eosinophils, and basophils of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. [0281 ] FIG. 26A is a bar graph depicting erythrocytes (RBC, Hb, HCT, MCV, MCH, and MCHC) of Sprague Dawley rats after combination therapy. The graph compares the erythrocytes (RBC, Hb, HCT, MCV, MCH, and MCHC) of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0282] FIG. 26B is a bar graph depicting erythrocytes (RBC, Hb, HCT, MCV, MCH, and MCHC) of Sprague Dawley rats after combination therapy. The graph compares the erythrocytes (RBC, Hb, HCT, MCV, MCH, and MCHC) of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0283] FIG. 26C is a bar graph depicting concentration of thrombocytes of Sprague Dawley rats after combination therapy. The graph compares the concentrations of thrombocytes of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0284] FIG. 26D is a bar graph depicting concentration of thrombocytes of Sprague Dawley rats after combination therapy. The graph compares the concentrations of thrombocytes of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0285] FIG. 27A is a bar graph depicting total body weight change (as a percentage of baseline) after combination therapy for 7 days in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the total body weight gains (as a percentage of baseline) of the rats after administration with saline vehicle (Group 1) 2 mg / kg / week doxorubicin (DOX) plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 7 days. N=10, 16, and 12 rats for Group 1, Group 2, and Group 3, respectively. DOX was administered by intraperitoneal injection and TCMCB07 was administered by subcutaneous injection. The cutoffs for significance are * <.05, **<.01, ***< 001 ****<.0001.

[0286] FIG. 27B is a bar graph depicting total body weight change (as a percentage of baseline) after combination therapy for 14 days in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the total body weight gains (as a percentage of baseline) of the rats after administration with saline vehicle (Group 1) 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 14 days. N=10, 16, and 12 rats for Group 1, Group 2, and Group 3, respectively. DOX was administered by intraperitoneal injection and TCMCB07 was administered by subcutaneous injection. The cutoffs for significance are * < 05, **<.01, ***< 001 ****< 0001.

[0287] FIG. 27C is a bar graph depicting total body weight change (as a percentage of baseline) after combination therapy for 21 days in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the total body weight gains (as a percentage of baseline) of the rats after administration with saline vehicle (Group 1) 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 21 days. N=10, 16, and 12 rats for Group 1, Group 2, and Group 3, respectively. DOX was administered by intraperitoneal injection and TCMCB07 was administered by subcutaneous injection.

[0288] FIG. 27D is a bar graph depicting total body weight change (as a percentage of baseline) after combination therapy for 28 days in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the total body weight gains (as a % of baseline) of the rats after administration with saline vehicle (Group 1) 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 28 days. N=10, 16, and 12 rats for Group 1, Group 2, and Group 3, respectively. DOX was administered by intraperitoneal injection and TCMCB07 was administered by subcutaneous injection. The cutoffs for significance are * <.05, **<.01, ***<.001 ****<.0001.

[0289] FIG. 28A is a graph depicting daily body weight after combination therapy in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the daily body weights in the rats administered with saline vehicle (Group 1) 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 17 days.

[0290] FIG. 28B is a graph depicting daily body weight after combination therapy in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the daily body weights in the rats administered with saline vehicle (Group 1), 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 26 days. N = 12 rats per group. TCMCB07 was administered subcutaneously.

[0291] FIGS. 29A-C are graphs from a post treatment study (TCMCB07 post treatment after cisplatin administration) in a Sprague Dawley rat model. Rats were administered with cisplatin plus TCMCB07 followed by saline vehicle (Group 1), cisplatin plus TCMCB07 followed by TCMCB07 post treatment (Group 2), cisplatin followed by saline vehicle (Group 3), and cisplatin followed by TCMCB07 post treatment (Group 4) respectively. N = 10 rats per group. FIG. 29A depicts daily body weight. FIG. 29B depicts body weight gain (% of initial). FIG. 29C depicts daily cumulative food intake (g). TCMCB07 was administered subcutaneously.

[0292] FIGS. 30A-YY illustrate percent activation of the melanocortin 3 receptor (MC3R) following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non-naturally occurring melanocortin analogs included HS024(TFA) (FIG. 30A; SEQ ID NO: 525), E1 (FIG. 30B; SEQ ID NO: 15), E2 (FIG. 30C; SEQ ID NO: 16), E3 (FIG. 30D; SEQ ID NO: 17), E4 (FIG. 30E; SEQ ID NO: 18), E5 (FIG. 30F; SEQ ID NO: 19), E6 (FIG. 30G; SEQ ID NO: 20), E7 (FIG. 30H; SEQ ID NO: 21), E8 (FIG. 30I; SEQ ID NO: 22), E9 (FIG. 30J; SEQ ID NO: 23), E10 (FIG. 30K; SEQ ID NO: 24), E11 (FIG. 30L; SEQ ID NO: 25), E12 (FIG. 30M; SEQ ID NO: 26), E13 (FIG. 30N; SEQ ID NO: 27), E14 (FIG. 300; SEQ ID NO: 28), E15 (FIG. 30P; SEQ ID NO: 29), E16 (FIG. 30Q; SEQ ID NO: 30), E17 (FIG. 30R; SEQ ID NO: 31), E18 (FIG. 30S; SEQ ID NO: 32), E19 (FIG. 30T; SEQ ID NO: 35), E20 (FIG. 30U; SEQ ID NO: 36), E21 (FIG. 30V; SEQ ID NO: 37), F1 (FIG. 30W; SEQ ID NO: 40), F2 (FIG. 30X; SEQ ID NO: 41), F3 (FIG. 30Y; SEQ ID NO: 42), F4 (FIG. 30Z; SEQ ID NO: 43), F5 (FIG. 30AA; SEQ ID NO: 44), F6 (FIG. 30BB; SEQ ID NO: 50), F7 (FIG. 30CC; SEQ ID NO: 51), F8 (FIG. 30DD; SEQ ID NO: 52), F9 (FIG. 30EE; SEQ ID NO: 53), F10 (FIG. 30FF; SEQ ID NO: 54), F11 (FIG. 30GG; SEQ ID NO: 55), F12 (FIG. 30HH; SEQ ID NO: 56), F13 (FIG. 30II; SEQ ID NO: 57), F14 (FIG. 3DJJ; SEQ ID NO: 58), F15 (FIG. 30KK; SEQ ID NO: 59), F16 (FIG. 30LL; SEQ ID NO: 60), F17 (FIG. 30MM; SEQ ID NO: 61), F18 (FIG. 30NN; SEQ ID NO: 62), F19 (FIG. 3000; SEQ ID NO: 63), F20 (FIG. 30PP; SEQ ID NO: 64), F21 (FIG. 30QQ; SEQ ID NO: 65), F22 (FIG. 30RR; SEQ ID NO: 45), F23 (FIG. 30SS; SEQ ID NO: 46), F24 (FIG. 30TT; SEQ ID NO: 47), F25 (FIG. 30UU; SEQ ID NO: 48), F26 (FIG. 30W; SEQ ID NO: 49), F28 (FIG. 30WW; SEQ ID NO: 67), F29 (FIG. 30XX; SEQ ID NO: 68), and F30 (FIG. 30YY; SEQ ID NO: 69).

[0293] FIGS. 31A-00 illustrate percent activation of the MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non-naturally occurring melanocortin analogs included Example non-naturally occurring melanocortin analogs included G5 (FIG. 31 A; SEQ ID NO: 77), G6 (FIG. 31B; SEQ ID NO: 78), G7 (FIG. 31C; SEQ ID NO: 75), G8 (FIG. 31D; SEQ ID NO: 74), G9 (FIG. 31E; SEQ ID NO: 79), G10 (FIG. 31F; SEQ ID NO: 80), G11 (FIG. 31G; SEQ ID NO: 81), G12 (FIG. 31H; SEQ ID NO: 82), G13 (FIG. 311; SEQ ID NO: 83), G15 (FIG. 31J; SEQ ID NO: 85), G17 (FIG. 31K; SEQ ID NO: 211), G18 (FIG. 31L; SEQ ID NO: 212), G19 (FIG. 31M; SEQ ID NO: 213), G 20 (FIG. 31N; SEQ ID NO: 214), H1 (FIG. 310; SEQ ID NO: 97), H2 (FIG. 31P; SEQ ID NO: 98), H3 (FIG. 31Q; SEQ ID NO: 99), H4 (FIG. 31 R; SEQ ID NO: 100), H5 (FIG. 31S; SEQ ID NO: 101), H6 (FIG. 31T; SEQ ID NO: 102), H7 (FIG. 31U; SEQ ID NO: 103), H8 (FIG. 31V; SEQ ID NO: 104), H9 (FIG. 31W; SEQ ID NO: 105), H10 (FIG. 31X; SEQ ID NO: 106), H11 (FIG. 31Y; SEQ ID NO: 107), H12 (FIG. 31Z; SEQ ID NO: 108), H13 (FIG. 31AA; SEQ ID NO: 109), H14 (FIG. 31BB; SEQ ID NO: 110), H15 (FIG. 31CC; SEQ ID NO: 111), 11 (FIG. 31DD; SEQ ID NO: 112), I2 (FIG. 31 EE; SEQ ID NO: 113), I3 (FIG. 31FF; SEQ ID NO: 119), I4 (FIG. 31GG; SEQ ID NO: 115), I5 (FIG. 31HH; SEQ ID NO: 120), I6 (FIG. 3111; SEQ ID NO: 121), I7 (FIG. 31JJ; SEQ ID NO: 116), I8 (FIG. 31KK; SEQ ID NO: 117), I9 (FIG. 31LL; SEQ ID NO: 122), 110 (FIG. 31MM; SEQ ID NO: 123), 111 (FIG. 31NN; SEQ ID NO: 118), and 112 (FIG. 3100; SEQ ID NO: 124).

[0294] FIGS. 32A-ZZ illustrate percent inhibition of the MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non-naturally occurring melanocortin analogs included Example non-naturally occurring melanocortin analogs included J1 (FIG. 32A; SEQ ID NO: 126), J4 (FIG. 32B; SEQ ID NO: 129), J5 (FIG. 32C; SEQ ID NO: 130), J6 (FIG. 32D; SEQ ID NO: 131), J7 (FIG. 32E; SEQ ID NO: 132), J8 (FIG. 32F; SEQ ID NO: 133), J9 (FIG. 32G; SEQ ID NO: 134), J10 (FIG. 32H; SEQ ID NO: 135), J11 (FIG. 32I; SEQ ID NO: 136), J12 (FIG. 32J; SEQ ID NO: 137), J13 (FIG. 32K; SEQ ID NO: 138), J14 (FIG. 32L; SEQ ID NO: 139), J15 (FIG. 32M; SEQ ID NO: 140), J16 (FIG. 32N; SEQ ID NO: 141), J17 (FIG. 320; SEQ ID NO: 142), J18 (FIG. 32P; SEQ ID NO: 143), J19 (FIG. 32Q; SEQ ID NO: 144), J20 (FIG. 32R; SEQ ID NO: 145), J21 (FIG. 32S; SEQ ID NO: 146), J22 (FIG. 32T; SEQ ID NO: 147), J23 (FIG. 32U; SEQ ID NO: 148), J24 (FIG. 32V; SEQ ID NO: 149), J25 (FIG. 32W; SEQ ID NO: 150), J26 (FIG. 32X; SEQ ID NO: 151), J27 (FIG. 32Y; SEQ ID NO: 152), J28 (FIG. 32Z; SEQ ID NO: 153), J29 (FIG. 32AA; SEQ ID NO: 154), J30 (FIG. 32BB; SEQ ID NO: 155), J31 (FIG. 32CC; SEQ ID NO: 156), J32 (FIG. 32DD; SEQ ID NO: 157), J33 (FIG. 32EE; SEQ ID NO: 158), J34 (FIG. 32FF; SEQ ID NO: 159), J35 (FIG. 32GG; SEQ ID NO: 160), J36 (FIG. 32HH; SEQ ID NO: 161), J37 (FIG. 32II; SEQ ID NO: 162), J38 (FIG. 32JJ; SEQ ID NO: 163), J39 (FIG. 32KK; SEQ ID NO: 164), J40 (FIG. 32LL; SEQ ID NO: 165), J41 (FIG. 32MM; SEQ ID NO: 166), J42 (FIG. 32NN; SEQ ID NO: 167), J43 (FIG. 3200; SEQ ID NO: 168), J44 (FIG. 32PP; SEQ ID NO: 169), J45 (FIG. 32QQ; SEQ ID NO: 170), J46 (FIG. 32RR; SEQ ID NO: 171), J47 (FIG. 32SS; SEQ ID NO: 172), J48 (FIG. 32TT; SEQ ID NO: 173), J49 (FIG. 32UU; SEQ ID NO: 174), J60 (FIG. 32W; SEQ ID NO: 185), J63 (FIG. 32WW; SEQ ID NO: 188), J65 (FIG. 32XX; SEQ ID NO: 190), J68 (FIG. 32YY; SEQ ID NO: 193), and J69 (FIG. 32ZZ; SEQ ID NO: 194).

[0295] FIGS. 33A-SS illustrate percent inhibition of the MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non-naturally occurring melanocortin analogs included Example non-naturally occurring melanocortin analogs included K2 (FIG. 33A; SEQ ID NO: 394), K3 (FIG. 33B; SEQ ID NO: 396), K4 (FIG. 33C; SEQ ID NO: 398), K5 (FIG. 33D; SEQ ID NO: 399), K6 (FIG. 33E; SEQ ID NO: 392), K7 (FIG. 33F; SEQ ID NO: 393), K8 (FIG. 33G; SEQ ID NO: 395), K9 (FIG. 33H; SEQ ID NO: 397), K10 (FIG. 33I; SEQ ID NO: 400), K13 (FIG. 33J; SEQ ID NO: 403), K16 (FIG. 33K; SEQ ID NO: 376), K17 (FIG. 33L; SEQ ID NO: 377), K18 (FIG. 33M; SEQ ID NO: 378), K20 (FIG. 33N; SEQ ID NO: 380), K23 (FIG. 330; SEQ ID NO: 388), L4 (FIG. 33P; SEQ ID NO: 217), M1 (FIG. 33Q; SEQ ID NO: 225), M2 (FIG. 33R; SEQ ID NO: 234), M3 (FIG. 33S; SEQ ID NO: 226), M4 (FIG. 33T; SEQ ID NO: 235), M5 (FIG. 33U; SEQ ID NO: 227), M6 (FIG. 33V; SEQ ID NO: 228), M7 (FIG. 33W; SEQ ID NO: 229), M8 (FIG. 33X; SEQ ID NO: 230), M9 (FIG. 33Y; SEQ ID NO: 231), M11 (FIG. 33Z; SEQ ID NO: 233), N1 (FIG. AA; SEQ ID NO: 236), N2 (FIG. 33BB; SEQ ID NO: 237), N3 (FIG. 33CC; SEQ ID NO: 240), N4 (FIG. 33DD; SEQ ID NO: 241), N5 (FIG. 33EE; SEQ ID NO: 242), N6 (FIG. 33FF; SEQ ID NO: 243), N7 (FIG. 33GG; SEQ ID NO: 244), N8 (FIG. 33HH; SEQ ID NO: 245), 01 (FIG. 33II; SEQ ID NO: 246), 02 (FIG. 33JJ; SEQ ID NO: 247), 03 (FIG. 33KK; SEQ ID NO: 248), 04 (FIG. 33LL; SEQ ID NO: 249), 05 (FIG. 33MM; SEQ ID NO: 250), 06 (FIG. 33NN; SEQ ID NO: 255), 07 (FIG. 3300; SEQ ID NO: 256), 09 (FIG. 33PP; SEQ ID NO: 258), 01O (FIG. 33QQ; SEQ ID NO: 259), 011 (FIG. 33RR; SEQ ID NO: 260), and TCMCB07 (FIG. 33SS; SEQ ID NO: 3).

[0296] FIGS. 34A-DDD illustrate percent activation of the melanocortin 4 receptor (MC4R) following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non-naturally occurring melanocortin analogs included HS024(TFA) (FIG. 34A; SEQ ID NO: 525), E1 (FIG. 34B; SEQ ID NO: 15), E2 (FIG. 340; SEQ ID NO: 16), E3 (FIG. 34D; SEQ ID NO: 17), E4 (FIG. 34E; SEQ ID NO: 18), E5 (FIG. 34F; SEQ ID NO: 19), E6 (FIG. 34G; SEQ ID NO: 20), E7 (FIG. 34H; SEQ ID NO: 21), E8 (FIG. 34I; SEQ ID NO: 22), E9 (FIG. 34J; SEQ ID NO: 23), E10 (FIG. 34K; SEQ ID NO: 24), E11 (FIG. 34L; SEQ ID NO: 25), E12 (FIG. 34M; SEQ ID NO: 26), E13 (FIG. 34N; SEQ ID NO: 27), E14 (FIG. 340; SEQ ID NO: 28), E15 (FIG. 34P; SEQ ID NO: 29), E16 (FIG. 34Q; SEQ ID NO: 30), E17 (FIG. 34R; SEQ ID NO: 31), E18 (FIG. 34S; SEQ ID NO: 32), E20 (FIG. 34T; SEQ ID NO: 36), E21 (FIG. 34U; SEQ ID NO: 37), E22 (FIG. 34V; SEQ ID NO: 195), E23 (FIG. 34W; SEQ ID NO: 196), E24 (FIG. 34X; SEQ ID NO: 197), F1 (FIG. 34Y; SEQ ID NO: 40), F2 (FIG. 34Z; SEQ ID NO: 41), F3 (FIG. 34AA; SEQ ID NO: 42), F4 (FIG. 34BB; SEQ ID NO: 43), F5 (FIG. 34CC; SEQ ID NO: 44), F6 (FIG. 34DD; SEQ ID NO: 50), F7 (FIG. 34EE; SEQ ID NO: 51), F8 (FIG. 34FF; SEQ ID NO: 52), F9 (FIG. 34GG; SEQ ID NO: 53), F10 (FIG. 34HH; SEQ ID NO: 54), F11 (FIG. 34II; SEQ ID NO: 55), F12 (FIG. 34JJ; SEQ ID NO: 56), F13 (FIG. 34KK; SEQ ID NO: 57), F14 (FIG. 34LL; SEQ ID NO: 58), F15 (FIG. 34MM; SEQ ID NO: 59), F16 (FIG. 34NN; SEQ ID NO: 60), F17 (FIG. 3400; SEQ ID NO: 61), F18 (FIG. 34PP; SEQ ID NO: 62), F19 (FIG. 34QQ; SEQ ID NO: 63), F20 (FIG. 34RR; SEQ ID NO: 64), F21 (FIG. 34SS; SEQ ID NO: 65), F22 (FIG. 34TT; SEQ ID NO: 45), F23 (FIG. 34UU; SEQ ID NO: 46), F24 (FIG. 34W; SEQ ID NO: 47), F25 (FIG. 34WW; SEQ ID NO: 48), F26 (FIG. 34XX; SEQ ID NO: 49), F27 (FIG. 34YY; SEQ ID NO: 66), F28 (FIG. 34ZZ; SEQ ID NO: 67), F29 (FIG. 34AAA; SEQ ID NO: 68), F30 (FIG. 34BBB; SEQ ID NO: 69), F31 (FIG. 34CCC; SEQ ID NO: 201), and F32 (FIG. 34DDD; SEQ ID NO: 205).

[0297] FIGS. 35A-ZZ illustrate percent activation of the MC4R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non-naturally occurring melanocortin analogs included G1 (FIG. 35A; SEQ ID NO: 71), G2 (FIG. 35B; SEQ ID NO: 72), G3 (FIG. 35C; SEQ ID NO: 73), G4 (FIG. 35D; SEQ ID NO: 76), G5 (FIG. 35E; SEQ ID NO: 77), G6 (FIG. 35F; SEQ ID NO: 78), G7 (FIG. 35G; SEQ ID NO: 75), G8 (FIG. 35H; SEQ ID NO: 74), G9 (FIG. 35I; SEQ ID NO: 79), G10 (FIG. 35J; SEQ ID NO: 80), G11 (FIG. 35K; SEQ ID NO: 81), G12 (FIG. 35L; SEQ ID NO: 82), G13 (FIG. 35M; SEQ ID NO: 83), G14 (FIG. 35N; SEQ ID NO: 84), G15 (FIG. 350; SEQ ID NO: 85), G16 (FIG. 35P; SEQ ID NO: 86), G17 (FIG. 35Q; SEQ ID NO: 211), G18 (FIG. 35R; SEQ ID NO: 212), G19 (FIG. 35S; SEQ ID NO: 213), G20 (FIG. 35T; SEQ ID NO: 214), G21 (FIG. 35U; SEQ ID NO: 215), G22 (FIG. 35V; SEQ ID NO: 202), G23 (FIG. 35W; SEQ ID NO: 203), G24 (FIG. 35X; SEQ ID NO: 204), H1 (FIG. 35Y; SEQ ID NO: 97), H2 (FIG. 35Z; SEQ ID NO: 98), H3 (FIG. 35AA; SEQ ID NO: 99), H4 (FIG. 35BB; SEQ ID NO: 100), H5 (FIG. 35CC; SEQ ID NO: 101), H6 (FIG. 35DD; SEQ ID NO: 102), H7 (FIG. 35EE; SEQ ID NO: 103), H8 (FIG. 35FF; SEQ ID NO: 104), H9 (FIG. 35GG; SEQ ID NO: 105), H10 (FIG. 35HH; SEQ ID NO: 106), H11 (FIG. 35II; SEQ ID NO: 107), H12 (FIG. 35JJ; SEQ ID NO: 108), H13 (FIG. 35KK; SEQ ID NO: 109), H14 (FIG. 35LL; SEQ ID NO: 110), H15 (FIG. 35MM; SEQ ID NO: 111), 11 (FIG. 35NN; SEQ ID NO: 112), I2 (FIG. 3500; SEQ ID NO: 113), I3 (FIG. 35PP; SEQ ID NO: 119), I4 (FIG. 35QQ; SEQ ID NO: 115), I5 (FIG. 35RR; SEQ ID NO: 120), I6 (FIG. 35SS; SEQ ID NO: 121), I7 (FIG. 35TT; SEQ ID NO: 116), I8 (FIG. 35UU; SEQ ID NO: 117), I9 (FIG. 35W; SEQ ID NO: 122), 110 (FIG. 35WW; SEQ ID NO: 123), 111 (FIG. 35XX; SEQ ID NO: 118), 112 (FIG. 35YY; SEQ ID NO: 124), and 113 (FIG. 35ZZ; SEQ ID NO: 200).

[0298] FIGS. 36A-RRR illustrate percent inhibition of the MC4R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non- naturally occurring melanocortin analogs included J1 (FIG. 36A; SEQ ID NO: 126), J2 (FIG. 36B; SEQ ID NO: 127), J3 (FIG. 36C; SEQ ID NO: 128), J4 (FIG. 36D; SEQ ID NO: 129), J5 (FIG. 36E; SEQ ID NO: 130), J6 (FIG. 36F; SEQ ID NO: 131), J7 (FIG. 36G; SEQ ID NO: 132), J8 (FIG. 36H; SEQ ID NO: 133), J9 (FIG. 36I; SEQ ID NO: 136), J10 (FIG. 36J; SEQ ID NO: 135), J11 (FIG. 36K; SEQ ID NO: 136), J12 (FIG. 36L; SEQ ID NO: 137), J13 (FIG. 36M; SEQ ID NO: 138), J14 (FIG. 36N; SEQ ID NO: 139), J15 (FIG. 360; SEQ ID NO: 140), J16 (FIG. 36P; SEQ ID NO: 141), J17 (FIG. 36Q; SEQ ID NO: 142), J18 (FIG. 36R; SEQ ID NO: 143), J19 (FIG. 36S; SEQ ID NO: 144), J20 (FIG. 36T; SEQ ID NO: 145), J21 (FIG. 36U; SEQ ID NO: 146), J22 (FIG. 36V; SEQ ID NO: 147), J23 (FIG. 36W; SEQ ID NO: 148), J24 (FIG. 36X; SEQ ID NO: 149), J25 (FIG. 36Y; SEQ ID NO: 150), J26 (FIG. 36Z; SEQ ID NO: 151), J27 (FIG. 36AA; SEQ ID NO: 152), J28 (FIG. 36BB; SEQ ID NO: 153), J29 (FIG. 36CC; SEQ ID NO: 154), J30 (FIG. 36DD; SEQ ID NO: 155), J31 (FIG. 36EE; SEQ ID NO: 156), J32 (FIG. 36FF; SEQ ID NO: 157), J33 (FIG. 36GG; SEQ ID NO: 158), J34 (FIG. 36HH; SEQ ID NO: 159), J35 (FIG. 36II; SEQ ID NO: 160), J36 (FIG. 36JJ; SEQ ID NO: 161), J37 (FIG. 36KK; SEQ ID NO: 126; SEQ ID NO: 162), J38 (FIG. 36LL; SEQ ID NO: 163), J39 (FIG. 36MM; SEQ ID NO: 164), J40 (FIG. 36NN; SEQ ID NO: 165), J41 (FIG. 3600; SEQ ID NO: 166), J42 (FIG. 36PP; SEQ ID NO: 167), J43 (FIG. 36QQ; SEQ ID NO: 168), J44 (FIG. 36RR; SEQ ID NO: 169), J45 (FIG. 36SS; SEQ ID NO: 170), J46 (FIG. 36TT; SEQ ID NO: 171), J47 (FIG. 36UU; SEQ ID NO: 172), J48 (FIG. 36VV; SEQ ID NO: 173), J49 (FIG. 36WW; SEQ ID NO: 174), J50 (FIG. 36XX; SEQ ID NO: 175), J51 (FIG. 36YY; SEQ ID NO: 176), J52 (FIG. 36ZZ; SEQ ID NO: 177), J53 (FIG. 36AAA; SEQ ID NO: 178), J54 (FIG. 36BBB; SEQ ID NO: 179), J55 (FIG. 36CCC; SEQ ID NO: 180), J56 (FIG. 36DDD; SEQ ID NO: 181), J57 (FIG. 36EEE; SEQ ID NO: 182), J58 (FIG. 36FFF; SEQ ID NO: 183), J59 (FIG. 36GGG; SEQ ID NO: 184), J60 (FIG. 36HHH; SEQ ID NO: 185), J61 (FIG. 36III; SEQ ID NO: 186), J62 (FIG. 36JJJ; SEQ ID NO: 187), J63 (FIG. 36KKK; SEQ ID NO: 188), J64 (FIG. 36LLL; SEQ ID NO: 189), J65 (FIG. 36MMM; SEQ ID NO: 190), J66 (FIG. 36NNN; SEQ ID NO: 191), J67 (FIG. 36000; SEQ ID NO: 192), J68 (FIG. 36PPP; SEQ ID NO: 193), J69 (FIG. 36QQQ; SEQ ID NO: 194), and J70 (FIG. 36RRR; SEQ ID NO: 206).

[0299] FIGS. 37A-GGG illustrate percent inhibition of the MC4R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Example non- naturally occurring melanocortin analogs included Example non-naturally occurring melanocortin analogs included K1 (FIG. 37A; SEQ ID NO: 391), K2 (FIG. 37B; SEQ ID NO: 394), K3 (FIG. 37C; SEQ ID NO: 396), K4 (FIG. 37D; SEQ ID NO: 398), K5 (FIG. 37E; SEQ ID NO: 399), K6 (FIG. 37F; SEQ ID NO: 392), K7 (FIG. 37G; SEQ ID NO: 393), K8 (FIG. 37H; SEQ ID NO: 395), K9 (FIG. 37I; SEQ ID NO: 397), K10 (FIG. 37J; SEQ ID NO: 400), K11 (FIG. 37K; SEQ ID NO: 401), K12 (FIG. 37L; SEQ ID NO: 402), K13 (FIG. 37M; SEQ ID NO: 403), K14 (FIG. 37N; SEQ ID NO: 406), K15 (FIG. 370; SEQ ID NO: 375), K16 (FIG. 37P; SEQ ID NO: 376), K17 (FIG. 37Q; SEQ ID NO: 377), K18 (FIG. 37R; SEQ ID NO: 378), K19 (FIG. 37S; SEQ ID NO: 379), K20 (FIG. 37T; SEQ ID NO: 380), K21 (FIG. 37U; SEQ ID NO: 381), K22 (FIG. 37V; SEQ ID NO: 125), K23 (FIG. 37W; SEQ ID NO: 388), L1 (FIG. 37X; SEQ ID NO: 198), L2 (FIG. 37Y; SEQ ID NO: 199), L3 (FIG. 37Z; SEQ ID NO: 216), L4 (FIG. 37AA; SEQ ID NO: 217), L5 (FIG. 37BB; SEQ ID NO: 220), M1 (FIG. 37CC; SEQ ID NO: 225), M2 (FIG. 37DD; SEQ ID NO: 234), M3 (FIG. 37EE; SEQ ID NO: 226), M4 (FIG. 37FF; SEQ ID NO: 237), M5 (FIG. 37GG; SEQ ID NO: 227), M6 (FIG. 37HH; SEQ ID NO: 228), M7 (FIG. 37II; SEQ ID NO: 229), M8 (FIG. 37JJ; SEQ ID NO: 230), M9 (FIG. 37KK; SEQ ID NO: 231), M10 (FIG. 37LL; SEQ ID NO: 232), M11 (FIG. 37MM; SEQ ID NO: 233), N1 (FIG. 37NN; SEQ ID NO: 236), N2 (FIG. 3700; SEQ ID NO: 237), N3 (FIG. 37PP; SEQ ID NO: 239), N4 (FIG. 37QQ; SEQ ID NO: 241), N5 (FIG. 37RR; SEQ ID NO: 242), N6 (FIG. 37SS; SEQ ID NO: 243), N7 (FIG. 37TT; SEQ ID NO: 244), N8 (FIG. 37UU; SEQ ID NO: 245), 01 (FIG. 37W; SEQ ID NO: 246), 02 (FIG. 37WW; SEQ ID NO: 247), 03 (FIG. 37XX; SEQ ID NO: 248), 04 (FIG. 37YY; SEQ ID NO: 249), 05 (FIG. 37ZZ; SEQ ID NO: 250), 06 (FIG. 37AAA; SEQ ID NO: 255), 07 (FIG. 37BBB; SEQ ID NO: 256), 08 (FIG. 37CCC; SEQ ID NO: 257), 09 (FIG. 37DDD; SEQ ID NO: 258), 010 (FIG. 37EEE; SEQ ID NO: 259), 011 (FIG. 37FFF; SEQ ID NO: 260), and TCMCB07 (FIG. 37GGG; SEQ ID NO: 3).

[0300] FIG. 38 illustrates proinflammatory gene expression in the hypothalamus of cancer cachectic rats administered either TCMCB07 or saline control as measured by mRNA levels.

[0301] FIGS. 39A-C illustrate changes in cAMP levels following activation of the human (FIG. 39A), rat (FIG. 39B), and dog (FIG. 39C) melanocortin 1 receptor (MC1R) under various concentrations of TCMCB07.

[0302] FIG. 40 illustrates a dosing schema for administering TCMCB07 in a chronic kidney disease model.

[0303] FIG. 41 illustrates daily body weight measurements in rats having chronic kidney disease induced cachexia (G2) and control rats (G1) administered TCMCB07 under 3 different dosing schemas (G3, G4, and G5).

[0304] FIGS. 42A-G illustrate that subcutaneous administration of the non-naturally occurring melanocortin analogs of the present technology ameliorate anorexia, body weight loss, and lean mass loss in rats with chronic kidney disease (CKD) cachexia. FIG. 42A is a graph depicting design of an in vivo renal failure model (5 / 6 nephrectomy model) in rats using one or more non-naturally occurring melanocortin analogs of the present technology. FIG. 42B is a graph comparing the daily body weights in rats who received the nephrectomy according to the in vivo renal failure model of FIG. 42A administered with saline (Neph / saline) or TCMCB07 (Neph / TCMCB07), respectively, and rat on sham operation administered with saline (Sham / saline), for 28 days. FIG. 42C is a graph comparing the daily food intakes in rats who received the nephrectomy according to the in vivo renal failure model of FIG. 42A administered with saline (Neph / saline) or TCMCB07 (Neph / TCMCB07), respectively, and rat on sham operation administered with saline (Sham / saline), for 28 days. FIG. 42D is a bar graph depicting fat mass gain in rats who received the nephrectomy according to the in vivo renal failure model of FIG. 42A administered with saline (Neph / saline) orTCMCB07 (Neph / TCMCB07), respectively, and rat on sham operation administered with saline (Sham / saline), for 28 days. FIG. 42E is a graph showing body weight gain (%, net gain normalized to baseline) post-nephrectomy and post-treatment. FIG. 42F is a graph showing cumulative food intake post-treatment. FIG. 42G is a graph showing lean mass were determined by MR pre- (day 14) and post- (day 28) treatment, and gain (%) was calculated (net gain normalized to baseline). All data are expressed as mean ± SEM for each group. Two-way ANOVA in (42B-42E), Unpaired Student’s t-Test in (42D & 42G), * & # p < 0.05, ## p < 0.01, *”& ### p < 0.001 and ““ p < 0.0001. Stars in (42B & 42C): Neph / saline group versus Sham / saline group, and red pounds in (42B & 42C): Neph / TCMCB07 group versus Neph / saline group

[0305] FIGS. 43A-F illustrate effects of continued treatment with TCMCB07 in CKD model after the rat meets the equivalence point, where the weight of the rat treated with TCMCB07 is no different from a sham rat. FIG. 43A shows a schematic diagram of the experimental method. FIG. 43B shows daily body weight of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 43C shows daily body weight gain compared to day 1 of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 43D shows body weight gain, measured as % of initial weight compared to day 1 of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 43E shows body weight gain, measured as % of initial weight compared to day 14 of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 43F shows the cumulative food intake of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point.

[0306] FIGS. 44A-F illustrate body compositions of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 44A illustrates fat mass; FIG. 44B illustrates lean mass; FIG. 44C illustrates fluid mass; FIG. 44D illustrates fat mass gained; FIG. 44E illustrates lean mass gained; and FIG. 44F illustrates fluid mass gained.

[0307] FIGS. 45A-D illustrates tissue weight and length of the rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 45A illustrates heart weight; FIG. 45B illustrates gastrocnemii weight; FIG. 45C illustrates spleen weight; and FIG. 45D illustrates body length.

[0308] FIGS. 46A and 46B illustrate serum creatinine and urea in rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 46A illustrates serum creatinine and FIG. 46B illustrates serum blood urea nitrogen (BUN). DETAILED DESCRIPTION

[0309] Described herein are methods of treating, preventing, or reducing one or more conditions, including but not limited to side effects and iatrogenic injury, associated with an anti-cancer agent (e.g., chemotherapy agent) in a subject in need thereof using non-naturally occurring melanocortin analogs, as well as methods of treating subjects with having one or more such conditions. In some embodiments, the present technology includes methods for preventing or reducing one or more of the conditions associated with an anti-cancer agent by administering a non-naturally occurring melanocortin analog to the subject in need thereof prior to administration of the anti-cancer agent. In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject after an anti-cancer agent In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject concurrently with an anti-cancer agent or during an anti-cancer agent dosing regimen. In any of the embodiments of the present technology, the subject has cancer, or the subject has another condition (e.g., not cancer) which may be treated with an anticancer agent such as, but not limited to, a chemotherapy agent.

[0310] Some of the non-naturally occurring melanocortin analogs may bind only the MC3R or MC4R. Other non-naturally occurring melanocortin analogs may bind the MC3R with greater affinity than the MC4R, whereas other non-naturally occurring melanocortin analogs may bind the MC4R with greater affinity than the MC3R. some non-naturally occurring melanocortin analogs may bind the MC3R with the same or generally similar affinity as the MC4R. [0311 ] Each of the non-naturally occurring melanocortin analogs may have one or more beta hairpin (P-hairpin) and / or beta turn (P-turn) structures. The presence of amino acids that are structurally rigid, such as, for example, Aia, Aba, Ata, Hyp, D-Hyp, Pro, D-Pro, transPro(guan), and c / sPro(guan), may lead to formation of p-hairpin and / or P-turn structures in the peptide. Additionally, D-Met and disulfide bridges (cyclization via a disulfide bridge) may induce and / or stabilize beta-turn structures of the non-naturally occurring melanocortin analogs. Pro-Gly and Gly-Gly linkers may also induce and / or stabilize beta-turns. In general, cyclization may stabilize beta-turns, and D-amino acids may induce and / or stabilize beta-turns. The non-naturally occurring melanocortin analogs include D-valine-D-proline (dV-dP) or D-proline-D-valine (dP-dV) chain as their C-terminus, which may provide enhanced transport and resistance to degradation. The non-naturally occurring melanocortin analogs may be linear or optionally cyclized via a disulfide bridge or a lactam bond at various positions of the peptide chain. Each of the non-naturally occurring melanocortin analogs may include one or more of the foregoing features.

[0312] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. It should be understood that throughout the drawings, corresponding reference numerals indicate like or corresponding parts and features. The description of specific examples indicated in various embodiments of the present technology are intended for purposes of illustration only and are not intended to limit the scope of the present technology described herein. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features or other embodiments incorporating different combinations of the stated features.

[0313] Furthermore, the detailed description of various embodiments herein makes reference to the accompanying drawing / FIGS, which show various embodiments by way of illustration. While the embodiments are described in sufficient detail to enable those skilled in the art to practice the present technology, it should be understood that other embodiments may be realized and that logical and mechanical changes may be made without departing from the spirit and scope of the present technology. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, steps or functions recited in descriptions, any method, system, or process, may be executed in any order and are not limited to the order presented. Moreover, any of the step or functions thereof may be outsourced to or performed by one or more third parties. Definitions

[0314] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present technology belongs. For the purposes of the present technology, the following terms are defined below.

[0315] The articles “a” and “an” are used herein to refer to one or to more than one (Le., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0316] The term “about” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by acceptable levels in the art. In some embodiments, such variation may be as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.

[0317] “Melanocortin analogs,” “non-naturally occurring melanocortin analogs,” “melanocortin peptides,” “melanocortin receptor peptides,” or“melanocortins,” are used interchangeably and refer to melanocortin-receptor ligands, which are macromolecules containing at least one melanocortin pharmacophore. Melanocortin analogs are typically peptides that bind melanocortin receptors under physiological conditions. Melanocortin analogs include naturally occurring non-naturally occurring melanocortin analogs (i.e., “synthetic peptides” or “synthetic analogs”) and truncated and / or modified versions of melanocortin full-length protein or peptides. For example, the full-length pro-opiomelanocortin protein (POMC), prior to proteolytic cleavage of “sub-peptides,” consists of 241 amino acids. Tissue-specific proteolytic cleavage of POMC yields peptides ranging in size from 13 amino acids to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, vol. 3, 257-265, Academic Press (2000). Synthesized, non-naturally occurring melanocortin analogs having increased melanocortin receptor activity as discussed herein are approximately 7-12 amino acids in size. Melanocortin analogs exhibit binding functionality with melanocortin receptors. The binding to the melanocortin receptor is inhibitory (antagonist). In addition to peptides, the non-naturally occurring melanocortin analogs include small molecule analogs of melanocortin or portions thereof comprised of organic compounds, inorganic compounds, or combinations of peptide and small molecule—i.e., peptide mimetics, or various combinations thereof. “Non-naturally occurring melanocortin analogs” may be structurally similar and / or functionally similar to biological melanocortin proteins in their ability to bind melanocortin receptors. Further, the non-naturally occurring melanocortin analogs generally contain the pharmacophore: His-Phe-Arg-Trp (SEQ ID NO: 1) or a modified version thereof, or a structural or functional peptide mimetic thereof.

[0318] A “pharmacophore” is the minimum set of amino acid residues necessary to achieve a physiological effect; or a small molecule that is (with respect to a receptor) a structural mimic of the amino acid residues required for binding to and activation of a receptor. His-Phe-Arg-Trp (SEQ ID NO: 1) and their analogs are the pharmacophore of melanocortin for the regulated physiological effect. Therefore, non-naturally occurring melanocortin pharmacophore analogs may be small peptides or organic molecules designed to mimic the appearance or function (including activation or deactivation of receptor activity) of the melanocortin pharmacophore core sequence peptide.

[0319] “Potentiated therapeutic activity” refers to an increase in melanocortin activity in a non-naturally occurring melanocortin analog that has undergone derivatization at the N- and / or C-terminus. Such derivatizations do not necessarily involve the pharmacophore but do imply a relative increase in in vivo biological half-life.

[0320] A melanocortin receptor “antagonist” is a naturally occurring substance or manufactured drug substance or composition that opposes the melanocortin receptor-associated responses normally induced by a melanocortin receptor agonist agent.

[0321] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like.

[0322] The “peptides” described herein may be (a) naturally-occurring, (b) produced by chemical synthesis, (c) produced by recombinant DNA technology, (d) produced by biochemical or enzymatic fragmentation of larger molecules, (e) produced by methods resulting from a combination of methods (a) through (d) listed above, or (f) produced by any other means for producing peptides.

[0323] The term “peptide” as used herein includes any structure comprised of two or more amino acids, including chemical modifications and derivatives of amino acids. The amino acids forming all or a part of a peptide may be naturally occurring amino acids, stereoisomers and modifications of such amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically modified amino acids, constructs or structures designed to mimic amino acids, and the like, so that the term “peptide” includes pseudopeptides and peptidomimetics, including structures which have a non-peptidic backbone. The term “peptide” also includes dimers or multimers of peptides. A “manufactured” peptide includes a peptide produced by chemical synthesis, recombinant DNA technology, biochemical, or enzymatic fragmentation of larger molecules, combinations of the foregoing or, in general, made by any other method. The term “peptide” includes peptides containing a variable number of amino acid residues, optionally with non-amino acid residue groups at the N- and C-termini, such groups including acyl, acetyl, alkenyl, alkyl, N-alkyl, amine, or amide groups, among others.

[0324] By employing chemical synthesis, a useful means of production, it is possible to introduce various amino acids which do not naturally occur along the chain, modify the N- or C-terminus, and the like, thereby providing for improved stability and formulation, resistance to protease degradation, and the like.

[0325] “Amino acids” are molecules containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen and have the generic formula H2N—CHR—COOH, wherein R represents a side chain group. The various a-amino acids differ in the side-chain moiety that is attached to the a-carbon. The “amino acids” of the present technology include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Non-naturally occurring melanocortin analogs: A User’s Guide, G. A. Grant, editor, W.H. Freeman & Co., New York (1992), the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24. As set forth above, the term “amino acid” also includes stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are described generally in Non-naturally occurring melanocortin analogs: A User’s Guide, supra; Hruby et al., Biochem. J. 268:249-262 (1990); and Toniolo, Int. J. Peptide Protein Res. 35:287-300 (1990); the teachings of all of which are incorporated herein by reference.

[0326] The phrase “amino acid side chain moiety” used herein, including as used in the specification and claims, includes any side chain of any amino acid, as the term “amino acid” is defined herein. This thus includes the side chain moiety present in naturally occurring amino acids. It further includes side chain moieties in modified naturally occurring amino acids, such as glycosylated amino acids. It further includes side chain moieties in stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids, and the like. For example, the side chain moiety of any amino acid described herein is included within the definition. A “derivative” of an amino acid side chain moiety is included within the definition of an amino acid side chain moiety.

[0327] The “derivative” of an amino acid side chain moiety includes any modification to or variation in any amino acid side chain moieties, including a modification of naturally occurring amino acid side chain moieties. By way of example, derivatives of amino acid side chain moieties include straight chain or branched, cyclic or noncyclic, substituted or unsubstituted, saturated or unsaturated, alkyl, aryl or aralkyl moieties.

[0328] In the peptides described herein, conventional amino acid residues have their conventional meaning as given in Chapter 2400, of the Manual of Patent Examining Procedure, 8th Ed. Thus, “Ala” is alanine; “Arg” is arginine; “Asn” is asparagine; “Asp” is aspartic acid; “Cys” is cysteine; “Gin” is glutamine; “Glu” is glutamic acid; “His” is histidine; “He” is isoleucine; “Leu” is leucine; “Lys” is lysine; “Met” is methionine; The” is phenylalanine; “Pro” is proline; “Ser” is serine; “Thr” is threonine; “Trp” is tryptophan; “Tyr” is tryosine; and “Vai” is valine. Unless otherwise indicated, all amino acids abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof may be used. Thus, for example, “L-Phe” or “IPhe” is L-phenylalanine; “D-Phe” or“dPhe” is D-phenylalanine; dVal is D-valine; dPro is D-proline; “D- / L-Phe” or “d / IPhe” is D-phenylalanine, L-phenylalanine, or combinations thereof; The” is also D-phenylalanine, L-phenylalanine, or combinations thereof, and so on. Non-standard amino acids are “Nie” is norleucine; “Nai” is naphthylalanine; “D-Nal” is D-naphthylalanine; D-Nal(2') or DNal(2’) is D-2'-naphthylalanine; L-Nal(2') or LNal(2’) is L-2'-naphthylalanine; L-Nal(1') is L-1'-naphthylalanine; D-Nal(T) or DNal(1’) is D-T-naphthylalanine; Tie is tert-Leucine; Nva is norvaline; Orn is ornithine; and so on.

[0329] An alpha (a)-amino acid has the generic formula H2N—CaHR—COOH, where R is a side chain moiety and the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (i.e., the a-carbon). Other types of amino acids exist when the amino group is attached to a different carbon atom. For example, 253 (P)-amino acids, the carbon atom to which the amino group is attached is separated from the carboxylate group by one carbon atom, Cp. For example, a-alanine has the formula H2N—CaH(CH3)—COOH. In contrast, P-alanine has the general formula H2N— CpH2—CaH2—COOH (i.e., 3-aminopropanoic acid).

[0330] When p-amino acids are incorporated into peptides, two main types of p-peptides exist: those with the side chain residue, R, on the carbon next to the amine are called p3 peptides and those with the side chain residue on the carbon next to the carbonyl group are called p2 amino acids. As a non-limiting example, “P-valine” may refer to: —NH—CpH2—CaH(CH3)2—CO—, i.e., p2-valine (R on carboxy side); —NH—CpH(CHs)2—CaH2—CO—, i.e., p3-valine (R on amino side); or —NH—CpH(CH3)2—CaH(CH3)2—CO—, i.e., p23-valine (R at both positions).

[0331] Further, p-amino acids may adopt L- or D- stereochemistry. Unless otherwise indicated, all P-amino acid abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or a combination thereof.

[0332] Gamma (y)-amino acids are amino acids with the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms. For example, y-amino butyric acid has the formula, H2N—CVH2—CpH2—CaH?—COOH.

[0333] For additional modified and unusual amino acids, see §2422 of the MPEP, particularly Table 4 at 2400-24. Additionally, “Ac” indicates N-acetyl and “cyclo” refers to a cyclic structure, which is also shown in the literature as “c” or referred to as a “lactam.” “NH2” indicates an amine group, typically added on the C-terminus of a polypeptide. Accordingly, as used herein, an —NH2 moiety on the C-terminus of a peptide indicates an amidated C-terminus. In addition, the following abbreviations are used herein: Harg is Homo arginine; Hlys is Homo lysine.

[0334] Additional abbreviations are used as follows: tBu is tert-butyl; Hyp(Bzl) is benzyl-L-hydroxy-proline; glutaric acid linker is CO—(CH2)3—CO; Pen is L-Penicillamine; Aib is 2-Aminoisobutyric acid; Aba is 4-amino-1,2,4,5-tetra-hydro-2-benzazepin-3-one; Pip is piperidine-2-carboxylic acid; Nip is piperidine-3-carboxylic acid; Tic is tetrahydroquinoline-3-carboxylic acid; Bip is biphenylalanine; Phg is a-Phenyl-glycine; Sar is Sarcosine; Azt is 3'-azido-3'-deoxythymidine; Oic is Octohydroindole-2-carboxylic acid; Ata is 7-amino-7,8-dihydro4H-(1,2,3)triazolo(1,5-a)(1,4)diazepin-6(5H)-one; Aia is 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one; Mamb is 3-aminomethylbenzoic acid; Ate is 2-Aminotetraline-2-carboxylic acid; APC is 1-Amino-4-phenylcyclohexane-carboxylic acid; ACC is 4- Aminophenylpiperidine-4-carboxylic acid (APPC); Acpc is 1-aminocyclo-propane-1 -carboxylic acid; Aic is 2-aminoindone-2-carboxylic acid; p(CI)Phe is para-chloro-phenylalanine (I - iodo, Br- bromo, F- fluoro, CF3 - trifluoromethyl); and p(CI)dPhe is para-chloro-D-phenylalanine (I - iodo, Br- bromo, F-fluoro, CF3 - trifluoromethyl).

[0335] The term "alkene” includes unsaturated hydrocarbons that contain one or more double carbon-carbon bonds. Examples of such alkene groups include ethylene, propene, and the like.

[0336] The term “alkenyl” includes a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing at least one double bond; examples thereof include ethenyl, 2-propenyl, and the like.

[0337] The “alkyl” groups specified herein include those alkyl radicals of the designated length in either a straight or branched configuration. Examples of such alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.

[0338] The term “alkynyl” includes a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing at least one triple bond; examples thereof include ethynyl, propynyl, butynyl, and the like.

[0339] The term “aryl” includes a monovalent or bicyclic aromatic hydrocarbon radical of 6-to-12 ring atoms, and optionally substituted independently with one or more substituents selected from alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, or alkoxy-carbonyl. Examples of an aryl group include phenyl, biphenyl, naphthyl, 1-naphthyl, and 2-naphthyl, derivatives thereof, and the like.

[0340] The term “aliphatic” includes compounds with hydrocarbon chains, such as for example alkanes, alkenes, alkynes, and derivatives thereof.

[0341] The term “acyl” includes a group RCO—, where R is an organic group. An example is the acetyl group CH3CO—, referred to herein as “Ac.”

[0342] The term “fatty acid” describes a carboxylic acid with an aliphatic chain, which may be fully saturated or partially unsaturated, and optionally attached to a functional group such as a hydroxyl group or a carboxyl group. The aliphatic chain may contain e.g., from 6 to 26 carbon atoms and hydrogen atoms.

[0343] A peptide or aliphatic moiety is “acylated” when an alkyl or substituted alkyl group as defined above is bonded through one or more carbonyl {—(C=O)—} groups. A peptide is most usually acylated at the N-terminus.

[0344] An “omega amino derivative” includes an aliphatic moiety with a terminal amino group. Examples of omega amino derivatives include aminoheptanoyl and the amino acid side chain moieties of ornithine and lysine.

[0345] The term “heteroaryl” includes mono- and bicyclic aromatic rings containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. Five- or sixmembered heteroaryl are monocyclic heteroaromatic rings; examples thereof include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like. Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazole, indole, benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzothiazole, quinoline, benzotriazole, benzoxazole, isoquinoline, purine, furopyridine, and thienopyridine.

[0346] An “amine” includes compounds that contain an amine group (—NH2).

[0347] An “amide” includes compounds that have a trivalent nitrogen attached to a carbonyl group (i.e., —CO—NH2), such as for example methylamide, ethylamide, propylamide, and the like. A peptide is most usually amidated at the C-terminus by the addition of an amine (—NH2) moiety to the C-terminal carboxyl group.

[0348] An “imine” includes compounds that have a carbon-nitrogen double bond, with the nitrogen also attached to a hydrogen (NH=CH—R).

[0349] An “imide” includes compounds containing an imido group (—OC—NH— CO—).

[0350] A “nitrile” includes compounds that are carboxylic acid derivatives and contain a (—CN) group bound to an organic group.

[0351] The term “halogen” is intended to include the halogen atoms fluorine, chlorine, bromine and iodine, and groups including one or more halogen atoms, such as —CF3 and the like.

[0352] Amino acids, including stereoisomers and modifications of naturally occurring amino acids, protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids (peptide mimetics), and the like, including all of the foregoing, are sometimes referred to herein as “residues.”

[0353] A peptide or amino acid “mimetic” is a non-amino acid molecule that mimics a peptide (a chain of amino acids) or one amino acid residue.

[0354] “Substantial degradation” refers to the degradation of the N-terminal extension, the C-terminal extension, both N- and C-terminal degradation or degradation to other regions of the non-naturally occurring melanocortin analog by physiological enzymes and other factors, in such a manner or to a degree that side effects appear. According to one aspect, a non-naturally occurring melanocortin analog having a C-terminal extension that resists substantial degradation is one where no more than 50% of the administered peptide causes side effects and / or displays a low half-life. In some aspects, no more than 25% of the administered peptide causes side effects and / or displays a low half-life. More preferably, in some aspects, less than 10% of the administered peptide causes side effects and / or displays a low half-life, as compared to a non-naturally occurring melanocortin analog that lacks a C-terminal extension.

[0355] The terms “administering” or “administer” include delivery of therapies (e.g., combination therapies, non-naturally occurring melanocortin analogs (also referred to herein as peptides), anti-cancer agents) of the present technology to a subject either by local or systemic administration. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer), intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.

[0356] The terms “active ingredient” and “active compound” refer to a biologically active substance, whether naturally or non-naturally occurring, that is the main component of the pharmaceutical composition which elicits the intended effect of an administered therapeutic. This may be any component that drives the pharmacological activity or direct effect in the diagnosis, cure, mitigation, treatment, or prevention of the conditions associated with the present technology, such as but not limited to, reduced appetite and weight loss.

[0357] As used herein, a “composition” or a “pharmaceutical composition” refers to a mixture of the active ingredient with other chemical components, such as pharmaceutically acceptable carriers and / or excipients.

[0358] As used herein, a “pharmaceutically acceptable carrier” of the first or the second pharmaceutical composition refers to a carrier or diluent that does not cause significant irritation to an organism, does not abrogate the biological activity and properties of the administered active ingredient, and / or does not interact in a deleterious manner with the other components of the composition in which it is contained. The term “carrier” encompasses any excipient, binder, diluent, filler, salt, buffer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety). Some examples of physiologically acceptable carriers include antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN® (ICI, Inc.; Bridgewater, N.J.), polyethylene glycol (PEG), and PLURONICS™ (BASF; Florham Park, N.J.). An “excipient” of the first or the second pharmaceutical composition refers to an inert substance added to a composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0359] As used herein, “a side effect associated with the anti-cancer agent”, “an adverse side-effect associated with the anti-cancer agent”, or “a side effect induced by the anti-cancer agent”, refers to any unwanted, undesirable, or deleterious biological activity occurs during or after independent use of the anti-cancer agent. Examples of such side effects include, but are not limited to, anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. Such anti-cancer agents may also be administered to subjects for therapeutic uses besides cancer, for example, to treat, reduce, or prevent a condition or disease in a subject not having cancer.

[0360] The terms “treat,” “treatment,” and “treating” refer to a manner of providing a pharmaceutical composition and / or melanocortin analog to alleviate disease outcomes. This includes utilizing administration techniques as described in the context of the present technology. Efficacy of treatment may be determined by various assessment methods as described in the context of the present technology (e g., assessment of appetite, food consumption, body weight, muscle mass, fat mass, and measurement of biomarkers). The term “biomarker” refers to a biological output that is used as a measure of cellular response, whether that be to assess response to therapeutics, disease status, such as cachexia, or as a predictor of clinical outcomes. Biomarkers evaluated in the context of cells, tissue, or whole organisms. The term “disease” herein refers to any disorder adversely affecting biological status. This includes weight-related disorders, such as cachexia. Disease also may be in the context of human and animal health. [0361 ] The terms “treat”, “treatment”, and “treating” may also refer to the reduction or inhibition of the progression and / or duration of a disease (e.g., cancer), the reduction or amelioration of the severity of the disease, and / or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies. Specifically, these terms may refer to: (1) a stabilization, reduction (e.g. by more than 10%, 20%, 30%, 40%, 50%, or more than 60% of the population of cancer cells and / or tumor size before administration), or elimination of the cancer cells, (2) inhibiting cancerous cell division and / or cancerous cell proliferation, (3) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with a pathology related to or caused in part by unregulated or aberrant cellular division, (4) an increase in disease-free, relapse-free, progression-free, and / or overall survival, duration, or rate, (5) a decrease in hospitalization rate, (6) a decrease in hospitalization length, (7) eradication, removal, or control of primary, regional and / or metastatic cancer, (8) a stabilization or reduction (e.g. by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or at least 80% relative to the initial growth rate) in the growth of a tumor or neoplasm, (9) an impairment in the formation of a tumor, (10) a reduction in mortality, (11) an increase in the response rate, the durability of response, or number of patients who respond or are in remission, (12) the size of the tumor is maintained and does not increase or increases by less than 10%, less than 5%, less than 4%, or less than 2%, (13) a decrease in the need for surgery (e g. colectomy, mastectomy), (14) preventing or reducing the metastasis of cancer cells, and (15) promoting mass gain and / or mass maintenance by the subject or otherwise preventing mass loss or reducing mass loss by the subject prior to, during, or after administration of an anti-cancer agent. The terms “treat”, “treatment”, and “treating” include prophylactic and / or therapeutic treatments. If it is administered prior to clinical manifestation of a condition, the treatment is considered prophylactic. Therapeutic treatment includes, e.g., ameliorating or reducing the severity of a disease, or shortening the length or frequency of the disease.

[0362] As used herein, the terms “effective amount” or “therapeutically effective amount”, refer to that amount of the active ingredient being administered which will relieve to some extent one or more of the symptoms of the disease being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate “effective amount” may differ from one individual to another. An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study.

[0363] The term “after administration” refers to any duration of time after the non-naturally occurring melanocortin analog or pharmaceutical composition thereof, and / or the anti-cancer agent has been administered to a subject. “After administration” may also refer to the duration of time after one dose has been completed or after more than one dose has been completed, such as two doses, three doses, four doses, and the like. In some embodiments, “after administration” refers to completion of dosing regimen that includes one or more doses. Likewise, the term “prior to” refers to any duration of time before the non-naturally occurring melanocortin analog or pharmaceutical composition thereof, and / or the anti-cancer agent has been administered to a subject. Unless otherwise specified, durations of time encompassed by “after administration” or “prior to administration” may include seconds, minutes, hours, days, weeks, months, and years.

[0364] “Appetite” in a subject and / or patient is typically assessed by their desire to eat and / or the amount of food they consume. As used herein, appetite may be assessed through a daily questionnaire given at specified or random times of the day. In the questionnaire, subjects or patients rate their hunger and / or desire to eat greater varieties of food using scales ranging from 0 (not at all) to 100 (extremely).

[0365] “Cachexia” refers to a state of general ill health and malnutrition characterized by loss of body mass including loss of weight, loss of muscle mass (skeletal, smooth, and / or cardiac muscle), loss of fat mass, or a combination thereof, and wasting. It is often associated with and induced by certain diseases or conditions such as, but not limited to, cancer, cystic fibrosis, or AIDS. The term “cancer cachexia” refers to cachexia induced by cancer. Diagnostic criterion for cachexia may include (i) weight loss of greater than 5% over past 6 months; (ii) weight loss of greater than 2% in patients with a body mass index (BMI) less than 20 kg / m2; or (iii) weight loss of greater than 2% in patients with sarcopenia (or appendicular skeletal muscle index consistent with sarcopenia). See Fearon K, et al., Lancet Oncol. 12(5):489-95 (2011). Cachexia may be used interchangeably with the term “Protein-Energy Wasting” (i.e., PEW).

[0366] “Anorexia” refers to a loss of appetite, whether brought on by medical, physiological, or psychological factors. Anorexia is often closely associated with, and generally contributes to, cachexia seen in patients with advanced cancers and other conditions.

[0367] The term “Body Mass Index” or “BMI” refers to a value derived from an individual’s body weight and height. Specifically, BMI is determined by body weight (kilograms) divided by the square of height (m2) and is expressed in units of “kg / m2”. “Normal” BMI ranges are known to a person of ordinary skill in the art and consider factors such as patient sex, age, height, race, and body type. Typically, a normal BMI range is about 18.5 kg / m2 to about 25 kg / m2.

[0368] The terms “subject” and “patient” refer to anyone being evaluated for disease or condition or being administered a therapeutic or pharmaceutical composition. This includes people without diagnosed or confirmed disease or condition. This also includes people with diagnosed or confirmed disease or condition, such as cancer, loss of appetite, nausea, emesis, anorexia, or cachexia.

[0369] The term “control,” as used herein, refers to any basis for comparison to the subject (e.g., test subject). A control includes, but is not limited to, a given measurement at baseline in a subject, any subject who has not been administered the therapeutic or pharmaceutical composition (e.g., the non-naturally occurring melanocortin analog, a therapeutically effective amount of the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof) or administered a placebo. A control may reference to a measurement from the same subject as the subject being treated (e.g., a measurement at baseline or an intermediate timepoint), or from a different subject (e.g., a subject not having the same treatment or condition as the subject being treated).

[0370] The disclosure of all publications, patents, and published patent applications listed herein are hereby incorporated by reference in their entireties, including but not limited to U.S. Patent Nos. 8,541,545 and 9,534,018. Non-naturally Occurring Melanocortin Analogs

[0371] The present technology provides non-naturally occurring melanocortin analogs that may be administered to a subject in need thereof. The present technology also provides methods of treating, preventing, or reducing unwanted side effects induced by anti-cancer agents (e.g., chemotherapeutic agents) as well as symptoms associated with cancer via administration of a non-naturally occurring melanocortin analog, which may be the non-naturally occurring melanocortin analog as described herein in any of its embodiments.

[0372] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I), X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5YsY7Y8 (I) wherein: R1 is absent or is selected from the group consisting of cysteine, norleucine (Nie), acetylated norleucine (Ac-Nle), acetylated frans-4-guanidinyl-proline (Ac-fransPro(guan)), acetylated c / s-4-guanidinyl-proline (Ac-c / sPro(guan)), trans-4- guanidinyl-proline (fransPro(guan)), c / s-4-guanidinyl-proline (c / sPro(guan)), acetylated cysteine, methylated D-phenylalanine, succinic acid, o-phthalic acid, tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, CO-cis-CH=CH—CO, an n-pentanoyl group, an n-hexanoyl group, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Ac-Tle), acetylated D-tert-leucine (Ac-dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R2 is absent or is selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), hydroxyproline (Hyp), fransPro(guan), c / sPro(guan), D-aspartic acid, aspartic acid, D-glutamic acid, glutamic acid, glycine, lysine, alanine, D-alanine, tryptophan, cysteine, D-cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH=CH—CO, an n-pentanoyl group, an n-hexanoyl group, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); R3 is absent or is selected from the group consisting of histidine, histidine methylated at positions 1 or 3, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), fransPro(guan), c / sPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-phenylalanine, succinic acid, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (p-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2 / - / )-one (Aia), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (loc), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe); R4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), (o-Phe)Phe, aspartic acid, biphenylalanine (Bip), dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe); R5 is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, transPro(guan), c / sPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-asparticacid, glutamic acid, D-glutamic acid, cysteine, and p(l)dPhe; R6 is absent or is selected from the group consisting of D-tryptophan, L-tryptophan, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, histidine, D-histidine, cysteine, Nal(T), D-Nal(T), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, Pen, dPen, alanine, and D-alanine; R7 is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), ornithine, D-ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8 is absent or is lysine or arginine; R9 is absent or is tryptophan; R10 is absent or is lysine; R11-R20 are each independently absent or selected from the group consisting of cysteine, norleucine, tyrosine, aspartic acid, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, arginine, histidine, hydroxyproline, D-hydroxyproline, D-proline, prolylglycine (Pro-Gly), D-Nal(2'), L-Nal(2'), Bip, ornithine, and tryptophan; wherein if R2 is an n-pentanoyl group or an n-hexanoyl group, then R1, X1, X2 and X3 are absent; X1 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, P-homo proline, D-alanine, L-alanine, P-alanine, D-arginine, L-arginine, D-valine, L-valine, p-valine, D-leucine, L-leucine, p-leucine, D- isoleucine, L-isoleucine, p-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X2 is absent or is selected from the group consisting of D-threonine, D-proline, L-proline, p-homo proline, D-alanine, L-alanine, p-alanine, D-valine, L-valine, p-valine, D-leucine, L-leucine, p-leucine, D-isoleucine, L-isoleucine, p-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; X3 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, p-homo proline, D-alanine, L-alanine, D-valine, L-valine, p-valine, D-leucine, L-leucine, p-leucine, D-isoleucine, L-isoleucine, p-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; Y1 is selected from the group consisting of D-alanine, L-alanine, p-alanine, D-threonine, L-threonine, p-threonine, D-valine, L-valine, p-valine, (3-methyl)-p-valine, D-leucine, L-leucine, p-leucine, D-isoleucine, L-isoleucine, p-isoleucine, D-tert-leucine, L-tert-leucine, norleucine, L-proline, D-proline, P-homo proline, a piperazin-2-one ring, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, L-arginine, D-arginine, L-asparagine, D-asparagine, L-lysine, D-lysine, and L-tryptophan; Y2 is absent or is selected from the group consisting of D-proline, L-proline, p-homo proline, a piperazin-2-one ring, D-threonine, L-threonine, p-threonine, D-valine, L-valine, P-valine, (3-methyl)-P-valine, D-leucine, L-leucine, P-leucine, D-isoleucine, L-isoleucine, p-isoleucine, D-tert-leucine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, p-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine; Y3 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, L-threonine, D-alanine, L-alanine, D-lysine, L-lysine, D-proline, L-proline, D-valine, L-valine, P-valine, (3-methyl)-P-valine, D-leucine, L-leucine, P-leucine, D-isoleucine, L-isoleucine, p-isoleucine, and a piperazin-2-one ring; Y4 is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine; Y5 is absent or is D-proline or D-valine; Y6 is absent or is D-proline or D-valine; Y7 is absent or is D-proline or D-valine; Y8 is absent or is D-proline or D-valine; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 orX1 when R1 or R2 is cysteine and R7 or X1 is cysteine; a disulfide bond between R2 and any one of R5-R20 when R2 and the any one of R5.R20 are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen; a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid; a side-chain lactam bridge between R1 or R2 and R7 when R1 or R2 is glutamic acid, aspartic acid, or CO-cis-CH=CH—CO, and R7 is lysine, D-lysine, Dap, D-ornithine, or ornithine; a side-chain lactam bridge between R2 and R7 when R2 is lysine, and R7 is glutamic acid or aspartic acid; a side-chain lactam bridge between R1 or R2 and R8 when R1 or R2 is glutamic acid or aspartic acid, R8 is lysine, and R7 is glycine, proline or tryptophan; a side-chain lactam bridge between R2 or R4 and R10 when R2 is glutamic acid or aspartic acid and R10 is lysine; a lactam closure between R1 and R7 when R1 is succinic acid or o-phthalic acid and R7 is lysine; and a lactam closure between R2 and R7 when R2 is succinic acid and R7 is 2,3-diamino-propionic acid; X1X2X3 represents an optionally present N-terminus; and yiY2Y3Y4Y5Y6Y7Y8 represents a C-terminus.

[0373] In some embodiments of Formula (I): R1 is absent or is selected from the group consisting of cysteine, norleucine (Nie), acetylated norleucine (Ac-Nle), trans-4-guanidinyl-proline (t / 'ansPro(guan)), c / s-4-guanidinyl-proline (c / sPro(guan)), acetylated trans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated c / s-4-guanidinyl-proline (Ac-cfsPro(guan)), acetylated cysteine, methylated D-phenylalanine, succinic acid, o-phthalic acid, tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, CO-cis-CH=CH—CO, an n-pentanoyl group, an n-hexanoyl group, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tie), acetylated D-tert-leucine (dTle), acetylated norvaline (Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R2 is absent or is selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), hydroxyproline (Hyp), fransPro(guan), c / sPro(guan), D-asprtic acid, aspartic acid, D-glutamic acid, glutamic acid, glycine, lysine, alanine, D-alanine, tryptophan, D-cysteine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH=CH—CO, an n-pentanoyl group, an n-hexanoyl group, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); R3 is absent or is selected from the group consisting of histidine, histidine methylated at positions 1 or 3, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), fransPro(guan), c / sPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-phenylalanine, succinic acid, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (p-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2 / - / )-one (Aia), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3- carboxylic acid (Tic), indoline-2-carboxylic acid (loc), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentane carboxylic (Cpe); R4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), (o-Phe)Phe, aspartic acid, biphenylalanine (Bip), dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5 is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, transPro(guan), c / sPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-asparticacid, glutamic acid, D-glutamic acid, cysteine, and p(l)dPhe; R6 is absent or is selected from the group consisting of D-tryptophan, L-tryptophan, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, histidine, D-histidine, cysteine, Nal(T), D-Nal(T), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, Pen, dPen, alanine, and D-alanine; R7 is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), ornithine, D-ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8 is absent or is lysine or arginine; R9 is absent or is tryptophan; R10 is absent or is lysine; R11-R20 are each independently absent or selected from the group consisting of cysteine, norleucine, tyrosine, aspartic acid, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, arginine, histidine, hydroxyproline, D-hydroxyproline, D-proline, prolylglycine (Pro-Gly), D-Nal(2'), L-Nal(2'), Bip, ornithine, and tryptophan; wherein if R2 is an n-pentanoyl group or an n-hexanoyl group, then R1, X1, X2 and X3 are absent; X1 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, p-homo proline, D-alanine, L-alanine, p-alanine, D-arginine, L-arginine, D-valine, L-valine, p-valine, D-leucine, L-leucine, p-leucine, D-isoleucine, L-isoleucine, p-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X2 is absent or is selected from the group consisting of D-threonine, D-proline, L-proline, p-homo proline, D-alanine, L-alanine, p-alanine, D-valine, L-valine, p-valine, D-leucine, L-leucine, P-leucine, D-isoleucine, L-isoleucine, P-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; X3 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, p-homo proline, D-alanine, L-alanine, D-valine, L-valine, P-valine, D-leucine, L-leucine, P-leucine, D-isoleucine, L-isoleucine, p-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; Y1 is selected from the group consisting of D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, D-tert-leucine, L-tert-leucine, norleucine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; Y2 is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine; Y3 is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine; Y4 is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine; Y5 is absent or is D-proline or D-valine; Y6 is absent or is D-proline or D-valine; Y7 is absent or is D-proline or D-valine; Y8 is absent or is D-proline or D-valine; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 orX1 when R1 or R2 is cysteine and R7 or X1 is cysteine; a disulfide bond between R2 and any one of R5-R20 when R2 and the any one of r5-r20 are selected from the group consisting of D-cysteine, cysteine, Dap, Pen, and dPen; a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid; a side-chain lactam bridge between R1 or R2 and R7 when R1 or R2 is glutamic acid, aspartic acid, or CO-cis-CH=CH—CO, and R7 is lysine, D-lysine, D-ornithine, or ornithine; a side-chain lactam bridge between R2 and R7 when R2 is lysine, and R7 is glutamic acid or aspartic acid; a side-chain lactam bridge between R1 or R2 and R8 when R1 or R2 is glutamic acid or aspartic acid, R8 is lysine, and R7 is proline, glycine or tryptophan; a side-chain lactam bridge between R2 or R4 and R10 when R2 is glutamic acid or aspartic acid and R10 is lysine; a lactam closure between R1 and R7 when R1 is succinic acid or o-phthalic acid and R7 is lysine; and a lactam closure between R2 and R7 when R2 is succinic acid and R7 is 2,3-diamino-propionic acid; X1X2X3 represents an optionally present N-terminus; and Y1y2y3Y4Y5Y6Y7Y8 represents a C-terminus.

[0374] In some embodiments of Formula (I): R1 is absent or is selected from the group consisting of cysteine, norleucine (Nie), acetylated norleucine (Ac-Nle), frans-4-guanidinyl-proline (transProtguan)), c / s-4-guanidinyl-proline (c / sPro(guan)), acetylated frans-4-guanidinyl-proline (Ac- fransPro(guan)), acetylated c / s-4-guanidinyl-proline (Ac-c / sPro(guan)), acetylated cysteine, tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tie), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R2 is absent or is selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), hydroxyproline (Hyp), fransPro(guan), c / sPro(guan), D-aspartic acid, aspartic acid, D-glutamic acid, glutamic acid, glycine, lysine, alanine, D-alanine, tryptophan, D-cysteine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH=CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); R3 is absent or is selected from the group consisting of histidine, D-proline, L-proline, hydroxy proline (Hyp), D-hydroxyproline (dHyp), fransPro(guan), c / sPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-phenylalanine, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (p-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2 / - / )-one (Aia), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (loc), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentane carboxylic (Cpe); R4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe); R5 is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, transPro(guan), c / sPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-asparticacid, glutamic acid, D-glutamic acid, cysteine, and p(l)dPhe; R6 is absent or is selected from the group consisting of L-tryptophan, D-Nal(2’), L-Nal(2'), Tic, Bip, arginine, histidine, D-histidine, cysteine, Nal(T), D-Nal(T), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, Pen, dPen, alanine, and D-alanine; R7 is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), ornithine, D-ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8 is absent or is lysine or arginine; R9 is absent or is tryptophan; R10 is absent or is lysine; R11-R20 are absent; X1 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, P-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X2 is absent or is selected from the group consisting of D-threonine, D-proline, L-proline, D-alanine, L-alanine, P-alanine, D-valine, L-valine, P-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; X3 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; Y1 is absent or is selected from the group consisting of D-alanine, L-alanine, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; Y2 is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine; Y3 is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine; Y4 is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine; Y5 is absent or is D-proline or D-valine; Y6 is absent or is D-proline or D-valine; Y7 is absent or is D-proline or D-valine; Y8 is absent or is D-proline or D-valine; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 orX1 when R1 or R2 is cysteine and R7 or X1 is cysteine; a disulfide bond between R2 and any one of R5-R20 when R2 and the any one of R5-R20 are selected from the group consisting of D-cysteine, cysteine, Dap, Pen, and dPen; a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid; a side-chain lactam bridge between R1 or R2 and R7 when R1 or R2 is glutamic acid, aspartic acid, or CO-cis-CH=CH—CO, and R7 is lysine, D-lysine, D-ornithine, or ornithine; a side-chain lactam bridge between R2 and R7 when R2 is lysine, and R7 is glutamic acid or aspartic acid; a side-chain lactam bridge between R1 or R2 and R8 when R1 or R2 is glutamic acid or aspartic acid, R8 is lysine, and R7 is proline, glycine or tryptophan; a side-chain lactam bridge between R2 or R4 and R10 when R2 is glutamic acid or aspartic acid and R10 is lysine; provided that: when R2 is dAsp, then R7 is not dLys; when R2-R4 is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7 is not Arg-Trp-Lys; and when Y1 is dPro, Y2 is dVal, Y3-Y8 are absent, then R4 is not dNal(2’) or R4 is dNal(2’) and the C-terminus is not modified.

[0375] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein: R1 is absent or is selected from the group consisting of cysteine, norleucine (Nie), acetylated norleucine (Ac-Nle), frans-4-guanidinyl-proline (transPro(guan)), c / s-4-guanidinyl-proline (c / sPro(guan)), acetylated frans-4-guanidinyl-proline (Ac-fransPro(guan)), acetylated c / s-4-guanidinyl-proline (Ac-c / sPro(guan)), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid; R2 is absent or is selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), transPro(guan), c / sPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, norleucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine; R3 is absent or is selected from the group consisting of histidine, L-proline, fransPro(guan), c / sPro(guan), D-valine, glutamic acid, tryptylarginine (Trp-Arg), glycine, D-leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2 / - / )-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), and indoline-2-carboxylic acid (loc), R4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CP3)dPhe); R5 is absent or is selected from the group consisting of arginine, homoarginine, proline, transPro(guan), c / sPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), D-histidine, D-alanine, D-aspartic acid, D-glutamicacid, cysteine, and p(l)dPhe; R6 is absent or is selected from the group consisting of L-tryptophan, D-phenylalanine, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1’), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine; R7 is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8 is absent or is lysine; R9-R20 are absent; X1 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, P-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X2 is absent or is D-proline; X3 is absent; Y1 is absent or is selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline; Y2 is absent or is selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine; Y3 is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine; Y4 is absent or is D-aspartic acid or aspartic acid; Y5-Y8 are absent; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 and R7 when R1 is cysteine and R7 is cysteine; a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid; a side-chain lactam bridge between R1 or R2 and R7 when R1 or R2 is glutamic acid or aspartic acid, and R7 is lysine or Dap; a side-chain lactam bridge between R2 and R7 when R2 is lysine, and R7 is glutamic acid or aspartic acid; a side-chain lactam bridge between R1 or R2 and R8 when R1 or R2 is glutamic acid or aspartic acid, R8 is lysine, and R7 is proline, glycine or tryptophan; provided that: when R2 is dAsp, then R7 is not dLys; when R2-R4 is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7 is not Arg-Trp-Lys; when Y1 is dPro, Y2 is dVal, and Y3-Y8 are absent, then R4 is not dNal(2’) or R4 is dNal(2’) and the C-terminus is not modified; when R3 is Aba, Ata, or Aia, R6 is Aia, then R4 is not dNal(2’), or R4 is dNal(2’) and R5 is not Arg; when R4 is p(CI)dPhe, then R3 is not Pro or His; when R4 is p(l)dPhe then the non-naturally occurring melanocortin analog is cyclized through a side-chain lactam bridge between R1 and R7 and at least one of R2 and R3 is Pro; when Y2-Y4 are absent, then Y1 is absent or is norleucine; when R2 is Pro or Y2 is Hyp, then R3 is not Pro; when R3, R5, or R6 is absent, then the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1 and R7 orX1-X2 are present and are Ac-dVal-dPro; when R2-R7 is Asp-Pro-dNal(2’)-Arg-Trp-Lys (SEQ ID NO: 526) or Cys-Pro-dNal(2’)-Arg-Trp-Cys (SEQ ID NO: 527), then R1 is not Ac-Nle or Y1-Y2 is not dVal-dPro, dVal-dVal, dPro-dPro; and when the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2 and R8, then R3 is not His or Y1 is not dVal.

[0376] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein: R1 is absent or is selected from the group consisting of cysteine, norleucine (Nie), acetylated norleucine (Ac-Nle), frans-4-guanidinyl-proline (transPro(guan)), c / s-4-guanidinyl-proline (c / sPro(guan)), acetylated frans-4-guanidinyl-proline (Ac-fransPro(guan)), acetylated c / s-4-guanidinyl-proline (Ac-c / sPro(guan)), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid; R2 is absent or is selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), fransPro(guan), c / sPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, norleucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine; R3 is absent or is selected from the group consisting of histidine, L-proline, fransPro(guan), c / sPro(guan), D-valine, glutamic acid, tryptylarginine (Trp-Arg), glycine, D-leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-( 1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), and indoline-2-carboxylic acid (loc), R4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CFs)dPhe); R5 is absent or is selected from the group consisting of arginine, homoarginine, proline, ZransPro(guan), c / sPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), D-histidine, D-alanine, D-aspartic acid, D-glutamicacid, cysteine, and p(l)dPhe; R6 is absent or is selected from the group consisting of L-tryptophan, D-phenylalanine, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1’), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine; R7 is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), and tetrahydro-isoquinoline-3-carboxylic acid (Tic); R8 is absent or is lysine; R9.R20 are absent; X1 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, P-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine; X2 is absent or is D-proline; X3 is absent; Y1 is absent or is selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline; Y2 is absent or is selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine; Y3 is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine; Y4 is absent or is D-aspartic acid or aspartic acid; Y5-Y8 are absent; the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 and R7 when R1 is cysteine and R7 is cysteine; a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid; a side-chain lactam bridge between R1 or R2 and R7 when R1 or R2 is glutamic acid or aspartic acid, and R7 is lysine or Dap; a side-chain lactam bridge between R2 and R7 when R2 is lysine, and R7 is glutamic acid or aspartic acid; a side-chain lactam bridge between R1 or R2 and R8 when R1 or R2 is glutamic acid or aspartic acid, R8 is lysine, and R7 is proline, glycine or tryptophan; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-NH2 (SEQ ID NO: 139); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-NH2 (SEQ ID NO: 140); Ac-Nle-c(Asp-Aba-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 207); Ac-Nle-c(Asp-Aia-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 208); Ac-Nle-c(Asp-Ata-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 209), Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 192); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 193); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dPro-NH2 (SEQ ID NO: 190); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-dPro-NH2 (SEQ ID NO: 191); Ac-Nle-c(Asp-Pro-p(CI)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 391); Ac-Nle-c(Asp-His-p(CI)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 396); Ac-Nle-c(Asp-His-Arg-p(l)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2 (SEQ ID NO: 376); Ac-Nle-c(Asp-Pro-p(l)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 392); Ac-Nle-c(Asp-His-p(l)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 397); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-NH2 (SEQ ID NO: 137); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dPro-NH2 (SEQ ID NO: 138); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-OH (SEQ ID NO: 127); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 129); Ac-Nle-c(Asp-Pro-dNal(2>Arg-Trp-Lys)-Val-Hyp-NH2 (SEQ ID NO: 131); Ac-Nle-c(Asp-Pro-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 198); Ac-Nle-c(Asp-Pro-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 401); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Aia-Lys)-dVal-dPro-NH2 (SEQ ID NO: 114); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3; B07); Ac-Nle-Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2 (SEQ ID NO: 13; A1); Ac-Nle-c(Asp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-Nle-c(Cys-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c(Asp-Pro-dNal(2’)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Lys)-dVal-dPro-NH2 (SEQ ID NO: 112); Ac-Nle-c(Asp-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 5; D1); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 8; D2); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 286); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 287); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 288); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 289); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 291); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 292); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 293); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 420); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 421); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 424); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 425); and Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 426).

[0377] In some embodiments, the non-naturally occurring melanocortin analog has one or more beta hairpin (P-hairpin) and / or beta turn (P-turn) structures. In some embodiments, R3 of the sequence according to Formula (I), which may be D-proline, L-proline, hydroxyproline, D-hydroxyproline, D-alanine, D-methionine, D-valine, prolylglycine (Pro-Gly), glycine, transPro(guan), cisPro(guan), provides the P-hairpin and / or p-turn structures of the non-naturally occurring melanocortin analog. In some embodiments, the disulfide bond of the sequence according to Formula (I), if present, provides the P-hairpin and / or P-turn structures of the non-naturally occurring melanocortin analog.

[0378] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by a functional group selected from the group consisting of an acyl group, an imine group, an amide group, a urea group, a carbamate group, a sulfonamide group, and an alkylamine group.

[0379] In some embodiments, the N-terminus of the melanocortin analog, if present, is modified by an acyl group. 0 11 ^peptide the acyl group is acetyl group (e.g.,                         ). 0 ^peptide the acyl group is formyl group (e.g., W     NH          y non-naturally occurring In some embodiments, In some embodiments,

[0380] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an imine group.

[0381] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an amide group. In some embodiments, the amide group is a pyroglutamyl (pGlu) group (e.g.,

[0382] Other examples of the N-terminal modifications include, but are not limited (carbamate group), / < / / S. ^peptide / / $                (sulfonamide group), H3C^ peptide CW3 and ^peptide H3a NH (alkylamine group).

[0383] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is not modified.

[0384] As discussed above, y1Y2Y3Y4Y5Y6Y7Y8 represents a C-terminus of the non-naturally occurring melanocortin analog. In some embodiments, Y1-Y8 are absent. In some embodiments, Y1 is present and Y2-Y8 are absent.

[0385] In some embodiments, Y1 and Y2 are present and Y3-Y8 are absent. In some embodiments, Y3-Y8 are absent, and Y1 is D-valine and Y2 is D-proline, or Y1 is D-proline and Y2 is D-valine.

[0386] In some embodiments, Y3 is present and Y4-Y8 are absent. In some embodiments, Y3 is present and Y4-Y8 are absent, and (i) Y1 is D-valine or D-proline, (ii) Y2 is D-valine or D-proline, and / or (iii) Y3 is D-valine or D-proline. In some embodiments, Y3 is present and Y4-Y8 are absent, and (i) Y1 is D-valine, Y2 is D-valine, and Y3 is D-proline, (ii) Y1 is D-proline, Y2 is D-valine, and Y3 is D-valine, or (iii) Y1 is D-valine, Y2 is D-proline, and Y3 is D-valine.

[0387] In some embodiments, Y3 and Y4 are present, and Y5-Y8 are absent. In some embodiments, Y3 and Y4 are present, and Y5-Y8 are absent, and (i) Y1 is D-valine or D-proline, (ii) Y2 is D-valine or D-proline, (iii) Y3 is D-valine or D-proline, and / or (iv) Y4 is D-valine or D-proline. In some embodiments, Y3 and Y4 are present, and Y5-Y8 are absent, and (i) Y1 is D-valine, Y2 is D-valine, Y3 is D-valine, and Y4 is D-proline, (ii) Y1 is D-proline, Y2 is D-valine, Y3 is D-valine, and Y4 is D-valine, (iii) Y1 is D-valine, Y2 is D-proline, Y3 is D-valine, and Y4 is D-valine, or (iv) Y1 is D-valine, Y2 is D-valine, Y3 is D-proline, and Y4 is D-valine.

[0388] In some embodiments, the C-terminus includes additional derivatives to extend the length of C-terminus of the non-naturally occurring melanocortin analog. Exemplary additional C-terminus include, but are not limited to, y1Y2Y3Y4Y5Y6Y7Y8Y9, yi Y2y3y4y5y6y7y8y9yio y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11 y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y1 1Y12 yi y2Y3Y4Y5Y6Y7Y8y9 Y10 Y11Y1 3 Y^3              Y1 Y2 Y3 Y4Y5Y6Y7Y8 Y9 Y1 °Y11Y12 Y13Y14 y1 Y2Y3Y4y5Y6Y7Y8y9y10 y11 y12y13y14y15 y1 y2 y3y4y5 Y6y7y8Y9y1 Oy 11 y12 y13y14y15y16 y 1 y2y3Y4Y5Y6Y7Y8Y9Y1 Oy 11 yi 2yl 3yl 4yl 5yl 6yl 7 y 1 Y2Y3y4y5Y6Y7Y8Y9y10y11 y12y13y14y15y16y17y18 y1 Y2Y3y4y5Y6y 7y8y9y10 y11 y12y13y14y15y16y17y18y19 y1 Y2Y3y4y5Y6y 7y8y9 y10 y11 y 12y13y14 y15y16y17y18y19y20 y 1 Y2Y3Y4y5Y6Y7Y8Y9y10 y11 y12y13y14y15y16y17y18y19y20y21 y 1 Y2Y3y4y5Y6y 7y8y9yl Oyl 1 yi 2yl 3yl 4yl 5yl 6yl 7yl 8yl 9y20y2l y22 y 1 Y2Y3y4Y5Y6Y7Y8y9y10 y11 y12y13y14y15y16y17y18y19y20y21 y22 y23                and yiY2Y3y4Y5Y6y7y8y9yioyi 1 Yi2yi3yi4yi5yi6yi7yI8yi9y2oy2iy22y23y24 qJq wherein Y9-Y24, if present, are each independently D-proline or D-valine.

[0389] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by a functional group selected from the group consisting of an amide group, an ester group, and an aldehyde group.

[0390] In some embodiments, the C-terminus of the non-naturally occurring O Peptide melanocortin analog is modified by an amide group (e.g., NW, ). In the sequence of Formula (I), a non-naturally occurring melanocortin analog with a C- terminus modified by an amide may be represented by a terminal -NH2, such as, for example, in the sequence Ac-Nle-c(Asp-Pro-ID NO: 126). In some embodiments, the ami 0 o Peptide Peptide—NH~\ NH-GH3               ch3 embodiments, the N-aryl amide grc p \     / /   xx    V \   /   \ . ) or 0 A JU A Pepj&U A--'

[0391] In some embodiments, the dNal(2')-Arg-Trp-Lys)-Val-Pro-NH2 (SEQ de group is an N-alkyl amide group (e.g., or an N-aryl amide group. In some is p-nitroanilide group (pNA) (e.g., 7-amino-4-methylcoumarin (AMC) (e.g., melanocortin analog is modified by an o—ch3)

[0392] In some embodiments, the C-terminus of the non-naturally occurring O Peptide— O— CH ester group (e.g.,                          3, C-terminus of the non-naturally occurring O Peptide melanocortin analog is modified by an aldehyde (e.g.,              w).

[0393] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of Formula (I), a non-naturally occurring melanocortin analog with an unmodified C-terminus may be represented by -OH, such as, for example, in the sequence Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-OH (SEQ ID NO: 127) or by the absence of a C-terminal group, such as, for example, in the sequence Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro (SEQ ID NO: 2; B07a). In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified, and the sequence of Formula (I) is Ac-Nle-c(Asp-Pro-dNal2'-Arg-Trp-Lys)-dVal-dPro (SEQ ID NO: 2).

[0394] In some embodiments, R1 is absent, and R2 is D-aspartic acid. In some embodiments, R1 is acetylated norleucine, and R2 is D-aspartic acid.

[0395] In some embodiments, X1, X2, and X3 are absent. In some embodiments, X1 is present and X2 and X3 are absent.

[0396] In some embodiments, R4 is not D-phenylalanine. In some embodiments, R4 is D-Nal(2'). When R4 is D-Nal(2'), the non-naturally occurring melanocortin analog described herein may act as a melanocortin receptor antagonist.

[0397] In some embodiments, the non-naturally occurring melanocortin analog described herein is cyclized. For example, the non-naturally occurring melanocortin analog may be cyclized through a moiety selected from the group consisting of: a disulfide bond between R1 or R2 and R7 or X1 when R1 or R2 is cysteine and R7 or X1 is cysteine; a disulfide bond between R2 and any one of R5-R20 when R2 and the any one of R5-R20 are selected from the group consisting of cysteine, Pen, and dPen; a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid; a side-chain lactam bridge between R1 and any of R5'8 when R1 is aspartic acid and any of R5-8 are lysine; a side-chain lactam bridge between R2 and R7 when R2 is lysine and R7 is aspartic acid; a side-chain lactam bridge between R2 and R7 when R2 is glutamic acid, aspartic acid, or CO-cis-CH=CH—CO, and R7 is lysine, Dap, or ornithine; a side-chain lactam bridge between R2 and R8 when R2 is glutamic acid or aspartic acid, R8 is lysine, and R7 is glycine, proline, or tryptophan; a side-chain lactam bridge between R2 or R4 and R10 when R2 or R4 is glutamic acid or aspartic acid and R10 is lysine; a lactam closure between R1 and R7 when R1 is succinic acid or o-phthalic acid and R7 is lysine; and / or a lactam closure between R2 and R7 when R2 is succinic acid and R7 is 2,3- diamino-propionic acid. Cyclization may also occur from any of the X residues (optional stabilizing N-terminus residues). For example, X2 may be an aspartic acid that may be used for cyclization.

[0398] In some embodiments, R1, R2, and R7 are present and R8-R20 are absent, and the sequence of Formula (I) is cyclized through R2 and R7 via a lactam bond. In some embodiments, R1 is acetylated norleucine, R2 is aspartic acid, R3 is selected from the group consisting of proline, hydroxyproline, and D-hydroxyproline, R4 is D-Nal(2'), R5 is arginine, R6 is D-tryptophan or L-tryptophan, R7 is lysine, Y1 is D-valine, and / or Y2 is D-proline.

[0399] In some embodiments, the sequence of Formula (I) is: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3; B07) or Ac-Nle-c(Asp-Hyp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 4; D3), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0400] In some embodiments, R1, R2, R7, and R8 are present and R9-R20 are absent, and the sequence of Formula (I) is cyclized through R2 and R8 via a lactam bond. In some embodiments, R1 is acetylated norleucine, R2 is aspartic acid, R3 is selected from the group consisting of proline, hydroxyproline, D-hydroxyproline, phenylalanine, and histidine, R4 is histidine or dNal(2'), R5 is dNal(2') or arginine, R6 is selected from the group consisting of arginine, D-tryptophan, and L-tryptophan, R7 is tryptophan or proline, R8 is lysine, Y1 is selected from the group consisting of D-valine, D-leucine, and D-isoleucine, and / or Y2 is D-proline.

[0401] In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 5; D1); Ac-Nle-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 6; D1y); Ac-Nle-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dTle-dPro-NH2 (SEQ ID NO: 7; D18); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 8; D2); Ac-Nle-c(Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 9; D4); and Ac-Nle-c(Asp-Pro-His-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 10; D5), wherein c represents cyclization through R2 and R8 via a lactam bond.

[0402] In some embodiments, R1-R2 and R7-R10 are present and R11-R20 are absent, and the sequence of Formula (I) is cyclized through R2 and R10 via a lactam bond. In some embodiments, the sequence of Formula (I) is Ac-Nle-c(Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 11; D1a), wherein c represents cyclization through R2 and R10 via a lactam bond.

[0403] In some embodiments, R1-R2 and R7-R10 are present and R11-R20 are absent, and the sequence of Formula (I) is cyclized through R4 and R10 via a lactam bond. In some embodiments, the sequence of Formula (I) is Ac-Nle-Phe-Phe-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 12; Dip), wherein c represents cyclization through R4 and R10 via a lactam bond.

[0404] In some embodiments, the sequence of Formula (I) is linear. In some embodiments, the sequence of Formula (I) is Ac-Nle-Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2 (SEQ ID NO: 13; A1). In some embodiments, the sequence of Formula (I) is Ac-Nle-Pro-DNal(2’)-Arg-Trp-dVal-dPro-NH2 (SEQ ID NO: 14; A2).

[0405] In some embodiments of the sequence of Formula (I), R1 is acetylated norleucine. Alternatively, in some embodiments, R1 is an acetylated amino acid other than acetylated norleucine. In some embodiments, R1 is a non-acetylated amino acid. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-dArg-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-dMet-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dlle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-dLeu-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 18); Ac-dVal-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 19); Ac-dAla-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 20); Ac-Ala-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 21); Ac-Tle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-dTle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 23); Ac-dNle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 24); Ac-Nva-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 25); Ac-Gly-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 26); Ac-dPro-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 27); Ac-dCys-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 28); Ac-dPhe-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 29); AodTyr-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 30); Ac-dGln-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 31); Ac-dAsn-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 32); Ac- / ransPro(guan)-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 33); Ac-c / sPro(guan)-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 34); dTyr-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 35); Tyr-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 36); Dmt-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 37); Ac-Glu-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 38); and Ac-Asn-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 39), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0406] In some embodiments, when the sequence of Formula (I) is cyclized through R2 and R7, then R2 is Asp and R7 is Lys. Alternatively, in some embodiments, when the sequence of Formula (I) is cyclized through R2 and R7, then R2 is an amino acid capable of forming a linkage to the residue at R7 other than Asp and R7 is an amino acid capable of forming a linkage to the residue at R2 other than Lys. For example, when R2 is an amino acid other than Arg and R7 is an amino acid other than Lys, the residue at R2 may be capable of forming a linkage such as a lactam bond or a disulfide bond with the residue at R7. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(dAsp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 40); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 41); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 42); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 46); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 47); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 50); Ac-Nle-c(dCys-Pra-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 51); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 52); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 54); Ac-Nle-c(dPen-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Nle-c(dPen-Pro-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 59); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 60); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c(dPen-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c(dPen-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 65); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-dOrn)-dVal-dPro-NH2 (SEQ ID NO: 67); Ac-Nle-c(Glu-Pro-dNal(2’)-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c(Glu-Pro-dNal(2’)-Arg-Trp-dOrn)-dVal-dPro-NH2 (SEQ ID NO: 69); and Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 70), wherein c represents cyclization through R2 and R6 or R7 via a lactam bond or a disulfide bond.

[0407] In some embodiments of the sequence of Formula (I), R3 is Pro. Alternatively, in some embodiments, R3 is absent or an amino acid other than Pro. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-Nle-c(Asp-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Nle-c(Asp-dPro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Nle-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-Nle-c(Asp-dMet-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-Nle-c(Asp-Pro-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 76); Ac-Nle-c(Asp-Gly-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Nle-c(Asp-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c(Asp-Leu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c(Asp-lle-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c(Asp-Val-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 81); Ac-Nle-c(Asp-dLeu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c(Asp-dlle-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 83); Ac-Nle-c(Asp-dVal-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-c(Asp-Trp-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-c(Asp-dTrp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Nle-c(Asp-fransPro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 87); Ac-Nle-c(Asp-c / sPro(guan)-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 88); Ac-Nle-c(Asp-Val-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 89); Ac-Nle-c(Asp-lle-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 90); Ac-Nle-c(Asp-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 91); Ac-Nle-c(Asp-Glu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 92); Ac-Nle-c(Asp-Arg-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c(Asp-dLeu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 95); and Ac-Nle-c(Asp-dMet-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 96), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0408] In some embodiments of the sequence of Formula (I), R5 is Arg. Alternatively, in some embodiments, R5 is absent or an amino acid other than Arg. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-Nle-c(Asp-Pro-dNal(2’)-Lys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 98); Ac-Nle-c(Asp-Pro-dNal(2’)-dLys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-Nle-c(Asp-Pro-dNal(2’)-dArg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c(Asp-Pro-dNal(2’)-Orn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 101); Ac-Nle-c(Asp-Pro-dNal(2’)-dOrn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-Nle-c(Asp-Pro-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 103); Ac-Nle-c(Asp-Pro-dNal(2’)-Ala-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle-c(Asp-Pro-dNal(2’)-Gly-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 105); Ac-Nle-c(Asp-Pro-dNal(2’)-Asp-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 106); Ac-Nle-c(Asp-Pro-dNal(2’)-Glu-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 107); Ac-Nle-c(Asp-Pro-dNal(2’)-dHis-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 108); Ac-Nle-c(Asp-Pro-dNal(2’)-dAla-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 109); Ac-Nle-c(Asp-Pro-dNal(2’)-dAsp-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 110); and Ac-Nle-c(Asp-Pro-dNal(2’)-dGlu-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 111), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0409] In some embodiments of the sequence of Formula (I), R6 is Trp. Alternatively, in some embodiments, R6 is absent or an amino acid other than Trp. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Lys)-dVal-dPro-NH2 (SEQ ID NO: 112); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Nal(T)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 113); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Aia-Lys)-dVal-dPro-NH2 (SEQ ID NO: 114); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Phe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 115); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Tyr-Lys)-dVal-dPro-NH2 (SEQ ID NO: 116); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-His-Lys)-dVal-dPro-NH2 (SEQ ID NO: 117); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Ala-Lys)-dVal-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dNal(T)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 119); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dPhe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dNal(2’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dTyr-Lys)-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dHis-Lys)-dVal-dPro-NH2 (SEQ ID NO: 123); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dAla-Lys)-dVal-dPro-NH2 (SEQ ID NO: 124), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0410] In some embodiments of the sequence of Formula (I), R4 is dNal(2’). Alternatively, in some embodiments, R4 is an amino acid other than dNal(2’). For example, in some embodiments, when R4 is an amino acid other than dNal(2’), R4 is Bip. In some embodiments, the sequence of Formula (I) is Ac-Nle-c(Asp-Pro-Bip-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 125), wherein c represents cyclization through R2 and R7 via a lactam bond. [0411 ] In some embodiments of the sequence of Formula (I), Y1 is dVal and Y2 is dPro. Alternatively, in some embodiments, Y1 is an amino acid other than dVal and Y2 is an amino acid other than dPro. In some embodiments, Y1 is dVal and Y2 is an amino acid other than dPro. In some embodiments, Y1 is an amino acid other than dVal and Y2 is dPro.

[0412] In some embodiments, Y1 is dVal, Y2 is dPro, and the C-terminus is modified by NH2. In some embodiments, Y1 is an amino acid other than dVal, Y2 is an amino acid other than dPro, and the C-terminus is modified by NH2. In some embodiments, Y1 is dVal, Y2 is an amino acid other than dPro, and the C-terminus is modified by NH2. In some embodiments, Y1 is an amino acid other than dVal, Y2 is dPro, and the C-terminus is modified by NH2. In some embodiments, Y1 is dVal, Y2 is dPro, and the C-terminus is unmodified.

[0413] In embodiments of Formula (I) when Y1 is an amino acid other than dVal, then Y1 is selected from dPro, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, dLys, and dTle. In embodiments of Formula (I) when Y2 is an amino acid other than dPro, then Y2 or selected from dVal, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, and dTle. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-Pro-NH2 (SEQ ID NO: 126); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-OH (SEQ ID NO: 127); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-OH (SEQ ID NO: 128); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 129); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dHyp-NH2 (SEQ ID NO: 130); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-Hyp-NH2 (SEQ ID NO: 131); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-dHyp-NH2 (SEQ ID NO: 132); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-dVal-NH2 (SEQ ID NO: 133); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-dVal-NH2 (SEQ ID NO: 134); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-Val-NH2 (SEQ ID NO: 135); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-Val-NH2 (SEQ ID NO: 136); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-NH2 (SEQ ID NO: 137); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dPro-NH2 (SEQ ID NO: 138); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-NH2 (SEQ ID NO: 139); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-NH2 (SEQ ID NO: 140); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-NH2 (SEQ ID NO: 141); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Pro-NH2 (SEQ ID NO: 142); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Ala-NH2 (SEQ ID NO: 143); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAla-NH2 (SEQ ID NO: 144); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-NH2 (SEQ ID NO: 145); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-NH2 (SEQ ID NO: 146); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAla-dAla-NH2 (SEQ ID NO: 147); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Ala-Ala-NH2 (SEQ ID NO: 148); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Gly-Gly-NH2 (SEQ ID NO: 149); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Asp-NH2 (SEQ ID NO: 150); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Arg-NH2 (SEQ ID NO: 151); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Asn-NH2 (SEQ ID NO: 152); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dAsp-NH2 (SEQ ID NO: 153); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dArg-NH2 (SEQ ID NO: 154); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dAsn-NH2 (SEQ ID NO: 155); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asp-dPro-NH2 (SEQ ID NO: 156); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dPro-NH2 (SEQ ID NO: 157); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asn-dPro-NH2 (SEQ ID NO: 158); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsp-dPro-NH2 (SEQ ID NO: 159); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dPro-NH2 (SEQ ID NO: 160); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsn-dPro-NH2 (SEQ ID NO: 161); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asp-NH2 (SEQ ID NO: 162); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-NH2 (SEQ ID NO: 163); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asn-NH2 (SEQ ID NO: 164); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsp-NH2 (SEQ ID NO: 165); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-NH2 (SEQ ID NO: 166); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsn-NH2 (SEQ ID NO: 167); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-Pro-Val-NH2 (SEQ ID NO: 168); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dPro-dVal-NH2 (SEQ ID NO: 169); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dPro-dVal-NH2 (SEQ ID NO: 170); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dPro-NH2 (SEQ ID NO: 171); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dPro-NH2 (SEQ ID NO: 172); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-Val-Pro-NH2 (SEQ ID NO: 173); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dVal-dPro-NH2 (SEQ ID NO: 174); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dVal-dPro-NH2 (SEQ ID NO: 175); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-Pro-Val-NH2 (SEQ ID NO: 176); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dPro-dVal-NH2 (SEQ ID NO: 177); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dPro-dVal-NH2 (SEQ ID NO: 178); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-Val-Pro-NH2 (SEQ ID NO: 179); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dVal-dPro-NH2 (SEQ ID NO: 180); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dVal-dPro-NH2 (SEQ ID NO: 181); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dVal-dPro-NH2 (SEQ ID NO: 182); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dPro-NH2 (SEQ ID NO: 183); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dVal-NH2 (SEQ ID NO: 184); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dTle-NH2 (SEQ ID NO: 185); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dTle-dPro-NH2 (SEQ ID NO: 186); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dTle-dTle-d\ / al-NH2 (SEQ ID NO: 187); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dTle-NH2 (SEQ ID NO: 188); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dTle-NH2 (SEQ ID NO: 189), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0414] In some embodiments of the sequence of Formula (I) when Y3 is present and Y4-8 are absent, then each of Y1, Y2, and Y3 are independently selected form dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3 and Y4 are present and Y5-8 are absent, then each of Y1, Y2, Y3, and Y4 are independently selected from dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3-Y5 are present and Y6'8 are absent, then each of Y1-Y5 are independently selected form dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3-Y6 are present and Y7-8 are absent, then each of Y1-Y6 are independently selected form dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3-Y7are present and Y8 is absent, then each of Y1-Y7 are independently selected form dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3-Y8 are present, then each of Y1-Y8 are independently selected from dVal and dPro. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-d\ / al-d\ / al-dPro-NH2 (SEQ ID NO: 190); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-dPro-NH2 (SEQ ID NO: 191); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 192); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 193); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 194), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0415] In some embodiments of the sequence of Formula (I), X1 is present and is acetylated norleucine, and R1 is present and is norleucine. In some embodiments, X2 is present and is norleucine. In some embodiments, X3 is present and is norleucine. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 195); Ac-Nle-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 196); and Ac-Nle-Nle-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 197), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0416] As described above, some of the non-naturally occurring melanocortin analogs comprising the sequence of Formula (I) may bind the melanocortin 3 receptor and the melanocortin 4 receptor with the same or generally similar affinity. Other non-naturally occurring melanocortin analogs comprising the sequence of Formula (I) may bind the melanocortin 3 receptor with greater affinity than the melanocortin 4 receptor. In some embodiments, when the melanocortin antagonist of the present technology binds the melanocortin 3 receptor with greater affinity than the melanocortin 4 receptor, then the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 198); Ac-Nle-c(Asp-Trp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 199); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dTrp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 200); c(CO-cis-CH=CH-CO-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 201); Ac-Nle-c(Asp-p-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 202); Ac-Nle-c(Asp-Mamb-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 203); Ac-Nle-c(Asp-Acpc-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 204); Ac-c(Cys-Arg-dPhe-Cys)-Trp-dVal-dPro-NH2 (SEQ ID NO: 205); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Trp-NH2 (SEQ ID NO: 206); Ac-Nle-c(Asp-Aba-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 207); Ac-Nle-c(Asp-Aia-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 208); and Ac-Nle-c(Asp-Ata-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 209), wherein c represents cyclization through R1 or R2 and R7 or R8 via a lactam bond or through R2 and R5 via a disulfide bond.

[0417] Some non-naturally occurring melanocortin analogs comprising the sequence of Formula (I) may bind the melanocortin 4 receptor with greater affinity than the melanocortin 3 receptor. In some embodiments, when the melanocortin antagonist binds the melanocortin 4 receptor with greater affinity than the melanocortin 3 receptor, then the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Aic-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 210); Ac-Nle-c(Asp-Cpe-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 211); Ac-Nle-c(Asp-Che-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 212); Ac-Nle-c(Asp-Oic-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 213); Ac-Nle-c(Asp-loc-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 214); Ac-Nle-c(Asp-Tic-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 215); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 216); Ac-Nle-c(Asp-His-dNal(2’)-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 217); Ac-Nle-c(Asp-His-dNal(2’)-fransPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 218); Ac-Nle-c(Asp-His-dNal(2’)-c / sPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 219); Ac-Nle-c(Asp-Pro-dNal(2’)-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 220); Ac-Nle-c(Asp-Pro-dNal(2’HransPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 221); Ac-Nle-c(Asp-Pro-dNal(2’)-c / sPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 222); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Aba-Lys)-dVal-dPro-NH2 (SEQ ID NO: 223); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Ata-Lys)-dVal-dPro-NH2 (SEQ ID NO: 224); Ac-Nle-c(Asp-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 225); Ac-Nle-c(Asp-Glu-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO: 226); Ac-Nle-c(Asp-Pro-Glu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 227); Ac-Nle-c(Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO: 228); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO: 229); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 230); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 231); Ac-Glu-c(Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys)-dPro-dPro-Lys-Asp-NH2 (SEQ ID NO: 232); and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dPro-dLys-dAsp-NH2 (SEQ ID NO: 233), wherein c represents cyclization through R1 or R2 and R7 or R8 via a lactam bond.

[0418] In some embodiments of the sequence of Formula (I), when X1 is present and X2 and X3 are absent, the sequence of Formula (I) is cyclized through a lactam bond or a disulfide bond between R1 and any one of R5-8. In some embodiments, when X1 is present and X2 and X3 are absent, the sequence of Formula (I) is cyclized through a lactam bond between R1 and R6 In some embodiments, when X1 is present and X2 and X3 are absent, the sequence of Formula (I) is cyclized through a lactam bond between R1 and R7 In some embodiments, Y1 and Y2 are present and are dVal and dPro, respectively, and y3-Y8 are absent. In some embodiments, Y1-Y8 are absent. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Glu-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 234); Ac-Nle-c(Asp-Glu-His-dNal(2’)-Arg-Trp-Gly-Lys)-dVal-dPro-NH2 (SEQ ID NO: 235); Ac-Nle-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 236); Ac-Arg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 237); Ac-Arg-c(Asp-dAla-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 238); Ac-Arg-c(Cys-dAla-His-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 239); Ac-dArg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 240); Ac-Arg-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 241); Ac-dArg-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 242); Ac-Nle-c(Asp-Ala-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 243); Ac-Arg-c(Asp-Ala-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 244); Ac-dArg-c(Asp-Ala-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 245); Ac-Nle-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 246); Ac-Nle-c(Asp-Pro-Trp-dNal(2’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 247); Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2’)-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 248); Ac-Nle-c(Asp-Pro-Trp-Arg-dNal(2’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 249); Ac-Nle-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-dVal-dPro-NH2 (SEQ ID NO: 250); Ac-Arg-c(Cys-dAla-His-dNal(2’)-Arg-Trp-Cys)-NH2 (SEQ ID NO: 251); Ac-Arg-c(Asp-dAla-His-dNal(2’)-Arg-Trp-Lys)-NH2 (SEQ ID NO: 252); Ac-Arg-c(Asp-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 253); and Ac-Arg-c(Asp-Glu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 254), wherein c represents cyclization through R1 or R2 and any one of R5'8 via a lactam bond or a disulfide bond.

[0419] In some embodiments of the sequence of Formula (I), when X1 and X2 are present and X3 is absent, the sequence of Formula (I) is cyclized through a lactam bond between R2 and R7. In such embodiments, X1 and X2 are each independently selected from dVal and dPro. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-Nle-NH2 (SEQ ID NO: 255); Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-Nle-NH2 (SEQ ID NO: 256); Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-Nle-Nle-NH2 (SEQ ID NO: 257); Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-Nle-Nle-NH2 (SEQ ID NO: 258); Ac-dVal-dPro-c(Asp-Trp-Arg-dNal(2’)-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 259); and Ac-dVal-dPro-c(Lys-Trp-Arg-dNal(2’)-Pro-Asp)-dVal-dPro-NH2 (SEQ ID NO: 260), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0420] In some embodiments of the sequence of Formula (I), R1 is Nie and one or more of X1 and X2 are present. In some embodiments, R1 is Nie X1 is present, and X2 is absent. In some embodiments, R1 is Nie, and X1 and X2 are present. In some embodiments, the sequence of Formula (I) is: Ac-dVal-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 261); or Tyr-Val-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 262), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0421] In some embodiments of the sequence of Formula (I), R1 is Ac-Glu. In some embodiments, R1 is Ac-Glu, R2 is Asp, R3 is Glu, His, or Arg, R4 is dNal(2’), R5 is Arg, R6 is Trp, and R7 is Lys. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Glu-c(Asp-Glu-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 263); Ac-Glu-c(Asp-His-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 264); and Ac-Glu-c(Asp-Arg-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 265), wherein c represents cyclization through R2 and R7 via a lactam bond.

[0422] In some embodiments of the sequence of Formula (I), R5 is His. In some embodiments, when R5 is His, then R3 is His and the sequence of Formula (I) is cyclized via a lactam bond through R1 or R2 and R7. In some embodiments, X1 is Ac-Arg or absent, R1 is Ac-Nle, Asp or absent, R2 is Asp or Pro, R3 is His, R4 is dNal(2 ), R5 is His, R6 is Trp, and R7 is Lys or Dap. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 266); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 267); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 268); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 269); Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 270); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 271); Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 272); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 273); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 274); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 275); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 276); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 277); Ac-Nle-c(Asp-Pro-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 278); Ac-Nle-c(Asp-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 279); Ac-Arg-c(Asp-Pro-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 280); Ac-Arg-c(Asp-His-dNal(2’)-His-Trp-Dap)-dVal-dPro-NH2 (SEQ ID NO: 281); wherein c represents cyclization through R1 or R2 and R7 via a lactam bond.

[0423] In some embodiments of the sequence of Formula (I), R1 is Ac-Nle, R2 is Asp and dAsp, R3 is Pro or His, R4 is dNal(2’), R5 is Arg, R6 is Trp, and R7 is Lys and dLys. In such embodiments, Y1, Y2, and Y3 are varied. In some embodiments, the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dThr-dPro-dThr-NH2 (SEQ ID NO: 282); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 283); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 284); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 285); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 286); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 287); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 288); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 289); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 290); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 291); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 292); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 293); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-p-Pro-p-Val-NH2 (SEQ ID NO: 294); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-p3Pro-p2Val-NH2 (SEQ ID NO: 295); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-p3Pro-p3Val-NH2 (SEQ ID NO: 296); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-p-Pro-p-Val-NH2 (SEQ ID NO: 297); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-p-Pro-p-Val-NH2 (SEQ ID NO: 298); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-p-Pro-p-Val-NH2 (SEQ ID NO: 299); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-p-Val-p-Pro-NH2 (SEQ ID NO: 300); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-p2Val-p3Pro-NH2 (SEQ ID NO: 301); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-p3Val-p3Pro-NH2 (SEQ ID NO: 302); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-p-Val-p-Pro-NH2 (SEQ ID NO: 303); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-p-Val-p-Pro-NH2 (SEQ ID NO: 304); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-p-Val-p-Pro-NH2 (SEQ ID NO: 305); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-p-Pro-p-Pro-NH2 (SEQ ID NO: 306); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-p3Pro-p3Pro-NH2 (SEQ ID NO: 307); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-p-Pro-p-Pro-NH2 (SEQ ID NO: 308); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-p-Pro-p-Pro-NH2 (SEQ ID NO: 309); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-p-Pro-p-Pro-NH2 (SEQ ID NO: 310); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-p-Val-p-Val-NH2 (SEQ ID NO: 311); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-P-Val-P-Val-NH2 (SEQ ID NO: 312); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-p-Val-p-Val-NH2 (SEQ ID NO: 313); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-p-Val-p-Val-NH2 (SEQ ID NO: 314); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-(3-methyl)-p-Val-p-Val-NH2 (SEQ ID NO: 315); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-(3-methyl)-p-Val-p-Val-NH2 (SEQ ID NO: 316); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-(3-methyl)-p-Val-p-Val-NH2 (SEQ ID NO: 317); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-(3-methyl)-p-Val-p-Val-NH2 (SEQ ID NO: 318); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-(3-methyl)-p-Val-p-Pro-NH2 (SEQ ID NO: 319); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-(3-methyl)-p-Val-p-Pro-NH2 (SEQ ID NO: 320); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-(3-methyl)-p-Val-p-Pro-NH2 (SEQ ID NO: 321); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-(3-methyl)-p-Val-p-Pro-NH2 (SEQ ID NO: 322); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-p-Thr-p-Pro-p-Thr (SEQ ID NO: 323); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-p-Thr-p-Pro-p-Thr (SEQ ID NO: 324); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-p-Thr-p-Pro-p-Thr (SEQ ID NO: 325); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-p-Thr-p-Pro-p-Thr (SEQ ID NO: 326); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 327); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 328); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dPro-dAla-NH2 (SEQ ID NO: 329); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 330); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-dPra-NH2 (SEQ ID NO: 331); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dAla-dPro-NH2 (SEQ ID NO: 332); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dAla-dPro-NH2 (SEQ ID NO: 333); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dAla-dPro-NH2 (SEQ ID NO: 334); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-p-Pro-p-Ala-NH2 (SEQ ID NO: 335); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-P-Pro-P-Ala-NH2 (SEQ ID NO: 336); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-p-Pro-p-Ala-NH2 (SEQ ID NO: 337); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-p-Pro-p-Ala-NH2 (SEQ ID NO: 338); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-p-Ala-p-Pro-NH2 (SEQ ID NO: 339); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-p-Ala-p-Pro-NH2 (SEQ ID NO: 340); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-p-Ala-p-Pro-NH2 (SEQ ID NO: 341); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-p-Ala-p-Pro-NH2 (SEQ ID NO: 342); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-p-Val-p-Ala-NH2 (SEQ ID NO: 343); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-P-Val-P-Ala-NH2 (SEQ ID NO: 344); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-p-Val-p-Ala-NH2 (SEQ ID NO: 345); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-p-Val-p-Ala-NH2 (SEQ ID NO: 346); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-(3-methyl)-p-Val-p-Ala-NH2 (SEQ ID NO: 347); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-(3-methyl)-p-Val-p-Ala-NH2 (SEQ ID NO: 348); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-(3-methyl)-p-Val-p-Ala-NH2 (SEQ ID NO: 349); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-(3-methyl)-p-Val-p-Ala-NH2 (SEQ ID NO: 350) Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 351); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 352); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 353); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 354); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 355); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 356); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO: 357); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO: 358); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-p-Pro-p-Leu-NH2 (SEQ ID NO: 359); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-p-Pro-p-Leu-NH2 (SEQ ID NO: 360); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-p-Pro-p-Leu-NH2 (SEQ ID NO: 361); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-p-Pro-p-Leu-NH2 (SEQ ID NO: 362); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-p-Leu-p-Pro-NH2 (SEQ ID NO: 363); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-p-Leu-p-Pro-NH2 (SEQ ID NO: 364); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-p-Leu-p-Pro-NH2 (SEQ ID NO: 365); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-p-Leu-p-Pro-NH2 (SEQ ID NO: 366); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-p-Val-p-Leu-NH2 (SEQ ID NO: 367); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-p-Val-p-Leu-NH2 (SEQ ID NO: 368); Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-dLys)-p-Val-p-Leu-NH2 (SEQ ID NO: 369); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-p-Val-p-Leu-NH2 (SEQ ID NO: 370); Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-(3-methyl)-p-Val-p-Leu-NH2 (SEQ ID NO: 371); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Lys)-(3-methyl)-p-Val-p-Leu-NH2 (SEQ ID NO: 372); Ac-Nle-c(dAsp-Pra-dNal(2')-Arg-Trp-dLys)-(3-methyl)-p-Val-p-Leu-NH2 (SEQ ID NO: 373); and Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-(3-methyl)-p-Val-P-Leu-NH2 (SEQ ID NO: 374), wherein c represents cyclization through R1 and R7 via a lactam bond.

[0424] Alternatively, in some embodiments, the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of: Ac-Nle-c(Asp-Pro-dPhe-Arg-dTrp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 375); Ac-Nle-c(Asp-His-Arg-p(l)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2 (SEQ ID NO: 376); Ac-Nle-c(Asp-His-Arg-dBip-Arg-Tic-Lys)-dVal-dPro-NH2 (SEQ ID NO: 377); Ac-Nle-c(Asp-Pro-Arg-p(l)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2 (SEQ ID NO: 378); Ac-Nle-c(Asp-Pro-Arg-dBip-Arg-Tic-Lys)-dVal-dPro-NH2 (SEQ ID NO: 379); Ac-Nle-c(Asp-Arg-Pro-p(l)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2 (SEQ ID NO: 380); Ac-Nle-c(Asp-Arg-Pro-dBip-Arg-Tic-Lys)-dVal-dPro-NH2 (SEQ ID NO: 381); Ac-Nle-c(Asp-Aba-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 382); Ac-Nle-c(Asp-Aia-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 383); Ac-Nle-c(Asp-Ata-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 384); Ac-Nle-c(Asp-Aba-p(CI)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 385); Ac-Nle-c(Asp-Aia-p(CI)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 386); Ac-Nle-c(Asp-Ata-p(CI)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 387); Ac-Nle-c(Asp-Atc-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 388); Ac-Nle-c(Asp-APC-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 389); Ac-Nle-c(Asp-APPC-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 390); Ac-Nle-c(Asp-Pro-p(CI)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 391); Ac-Nle-c(Asp-Pro-p(l)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 392); Ac-Nle-c(Asp-Pro-p(Br)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 393); Ac-Nle-c(Asp-Pro-p(F)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 394); Ac-Nle-c(Asp-Pro-p(CF3)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 395); Ac-Nle-c(Asp-His-p(CI)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 396); Ac-Nle-c(Asp-His-p(l)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 397); Ac-Nle-c(Asp-His-p(Br)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 398); Ac-Nle-c(Asp-His-p(F)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 399); Ac-Nle-c(Asp-His-p(CF3)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 400); Ac-Nle-c(Asp-Pro-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 401); Ac-Nle-c(Asp-Trp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 402); Ac-Nle-c(Asp-His-dPhe-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 403); Ac-Nle-c(Asp-His-dPhe-transPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 404); Ac-Nle-c(Asp-His-dPhe-c / sPro(guan)-Trp-Lys)-d\ / al-dPro-NH2 (SEQ ID NO: 405); Ac-Nle-c(Asp-Pro-dPhe-Pro-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 406); Ac-Nle-c(Asp-Pro-dPhe-fransPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 407); Ac-Nle-c(Asp-Pro-dPhe-c / sPro(guan)-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 408); Ac-Nle-c(Asp-Pro-dPhe-Arg-Aia-Lys)-dVal-dPro-NH2 (SEQ ID NO: 409); Ac-Nle-c(Asp-Pro-dPhe-Arg-Aba-Lys)-dVal-dPro-NH2 (SEQ ID NO: 410); Ac-Nle-c(Asp-Pro-dPhe-Arg-Ata-Lys)-dVal-dPro-NH2 (SEQ ID NO: 411); Ac-Nle-c(Asp-Pro-p(CF3)dPhe-Arg-Aia-Lys)-dVal-dPro-NH2 (SEQ ID NO: 412); Ac-Nle-c(Asp-Pro-p(CF3)dPhe-Arg-Aba-Lys)-dVal-dPro-NH2 (SEQ ID NO: 413); Ac-Nle-c(Asp-Pro-p(CF3)dPhe-Arg-Ata-Lys)-dVal-dPro-NH2 (SEQ ID NO: 414); and Ac-Arg-c(Asp-dAla-His-dPhe-Arg-Trp-Lys)-NH2 (SEQ ID NO: 415), wherein c represents cyclization through R1 and R7 or R8 via a lactam bond.

[0425] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of: Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dThr-dPro-dThr(SEQ ID NO: 416); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 417); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 418); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dlys)-dThr-dPro-dThr (SEQ ID NO: 419); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 420); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 421); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 422); Ac-Nle-c(Asp-His-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 423); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 424); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 425); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 426); Ac-Nle-c(dAsp-His-dNal(2’)-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 427); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-pPro-pVal-NH2 (SEQ ID NO: 428); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-pPro-pVal-NH2 (SEQ ID NO: 429); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-pPro-pVal-NH2 (SEQ ID NO: 430); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-pPro-pVal-NH2 (SEQ ID NO: 431); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-pVal-pPro-NH2 (SEQ ID NO: 432); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-pVal-pPro-NH2 (SEQ ID NO: 433); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-pVal-pPro-NH2 (SEQ ID NO: 434); Ac-Nle-c(dAsp-His-dNal(2’)-Arg-Trp-dLys)-pVal-pPro-NH2 (SEQ ID NO: 435); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-pPro-pPro-NH2 (SEQ ID NO: 436); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-pPro-pPro-NH2 (SEQ ID NO: 437); Ac-Nle-c(dAsp-Pro-dNal(2’)-Arg-Trp-dLys)-pPro-pPro-NH2 (SEQ ID NO: 438); Ac-Nle-c(dAsp-His-dNal(2’)-Arg-Trp-dLys)-pPro-pPro-NH2 (SEQ ID NO: 439); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-pVal-pVal-NH2 (SEQ ID NO: 440); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-pVal-pVal-NH2 (SEQ ID NO: 441); Ac-Nle-c(dAsp-Pro-Phe-Arg-Trp-dLys)-pVal-pVal-NH2 (SEQ ID NO: 442); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-pVal-pVal-NH2 (SEQ ID NO: 443); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-pVal-pVal-NH2 (SEQ ID NO: 444); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-pVal-pVal-NH2 (SEQ ID NO: 445); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-(3-methyl)-pVal-pVal-NH2 (SEQ ID NO: 446); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-pVal-pVal-NH2 (SEQ ID NO: 447); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-pVal-pPro-NH2 (SEQ ID NO: 448); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-pVal-pPro-NH2 (SEQ ID NO: 449); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-(3-methyl)-pVal-pPro-NH2 (SEQ ID NO: 450); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-pVal-pPro-NH2 (SEQ ID NO: 451); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-pThr-pPro-pThr (SEQ ID NO: 452); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-pThr-pPro-pThr (SEQ ID NO: 453); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-pThr-pPro-pThr (SEQ ID NO: 454); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-pThr-pPro-pThr (SEQ ID NO: 455); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 456); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 457); Ac-Nle-c(dAsp-Pra-dPhe-Arg-Trp-dLys)-dPro-dAla-NH2 (SEQ ID NO: 458); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dPro-dAla-NH2 (SEQ ID NO: 459); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dAla-dPro-NH2 (SEQ ID NO: 460); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dAla-dPro-NH2 (SEQ ID NO: 461); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dAla-dPro-NH2 (SEQ ID NO: 462); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dAla-dPro-NH2 (SEQ ID NO: 463); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-pPro-pAla-NH2 (SEQ ID NO: 464); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-pPro-pAla-NH2 (SEQ ID NO: 465); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-pPro-pAla-NH2 (SEQ ID NO: 466); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-pPro-pAla-NH2 (SEQ ID NO: 467); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-pAla-pPro-NH2 (SEQ ID NO: 468); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-pAla-pPro-NH2 (SEQ ID NO: 469); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-pAla-pPro-NH2 (SEQ ID NO: 470); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-pAla-pPro-NH2 (SEQ ID NO: 471); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-pVal-pAla-NH2 (SEQ ID NO: 472); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-pVal-pAla-NH2 (SEQ ID NO: 473); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-pVal-pAla-NH2 (SEQ ID NO: 474); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-pVal-pAla-NH2 (SEQ ID NO: 475); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-pVal-pAla-NH2 (SEQ ID NO: 476); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-pVal-pAla-NH2 (SEQ ID NO: 477); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-(3-rnethyl)-pVal-pAla-NH2 (SEQ ID NO: 478); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-p-Val-p-Ala-NH2 (SEQ ID NO: 479); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 480); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 481); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dPro-dLeu-NH2 (SEQ ID NO: 482); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 483); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 484); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 485); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO: 486); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO: 487); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-p-Pro-p-Leu-NH2 (SEQ ID NO: 488); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-p-Pro-p-Leu-NH2 (SEQ ID NO: 489); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-p-Pro-p-Leu-NH2 (SEQ ID NO: 490); Ac-Nle-c(dAsp-His-dNal(2')-Arg-Trp-dLys)-p-Pro-p-Leu-NH2 (SEQ ID NO: 491); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-p-Leu-p-Pro-NH2 (SEQ ID NO: 492); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-p-Leu-p-Pro-NH2 (SEQ ID NO: 493); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-p-Leu-p-Pro-NH2 (SEQ ID NO: 494); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-p-Leu-p-Pro-NH2 (SEQ ID NO: 495); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-p-Val-p-Leu-NH2 (SEQ ID NO: 496); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-p-Val-p-Leu-NH2 (SEQ ID NO: 497); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-p-Val-p-Leu-NH2 (SEQ ID NO: 498); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-p-Val-p-Leu-NH2 (SEQ ID NO: 499); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-p-Val-p-Leu-NH2 (SEQ ID NO: 500); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-p-Val-p-Leu-NH2 (SEQ ID NO: 501); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-p-Val-p-Leu-NH2 (SEQ ID NO: 502); and Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-p-Val-p-Leu-NH2 (SEQ ID NO: 503), wherein c represents cyclization through R1 and R7 via a lactam bond.

[0426] In some embodiments, the non-naturally occurring melanocortin analog is a melanocortin receptor antagonist, such as a melanocortin 3 receptor and / or a melanocortin 4 receptor antagonist In some embodiments, the non-naturally occurring melanocortin analog is a melanocortin receptor agonist, such as a melanocortin 1 receptor, melanocortin 3 receptor, melanocortin 4 receptor, and / or melanocortin 5 receptor agonist. For example, in some embodiments, the melanocortin analog has agonist activity at the melanocortin 3 receptor and / or the melanocortin 4 receptor, as well as the melanocortin 1 and melanocortin 5 receptors. In other embodiments, the melanocortin analog has antagonist activity at the melanocortin 3 receptor and / or the melanocortin 4 receptor, as well as agonist activity at the melanocortin 1 and melanocortin 5 receptors.

[0427] In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-374. In some embodiments, the non-naturally occurring melanocortin antagonist analog comprises any one of the sequences of SEQ ID NOs: 2-281. In some embodiments, the non-naturally occurring melanocortin antagonist analog comprises any one of the sequences of SEQ ID NOs: 3, 20, 29-32, 67-70, 99-102, 127-130, 159, 163-166, 187-190, 387, 391, 394, 396, 398 and 399. In some embodiments, the non-naturally occurring melanocortin antagonist analog comprises any one of the sequences of SEQ ID NOs: 10, 14, 33-39, 82-96, 108111, 119-124, 128, 182-189, 212-281,394 and 399.

[0428] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3 (TCMCB07). The structure of TCMCB07 (“B07”), which comprises Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2, is shown below: TCMCB07. Anti-cancer Agents

[0429] The anti-cancer agent described herein is a therapeutic agent useful for the treatment or prevention of neoplasm, of tumor or cancer cell division, growth, proliferation and / or metastasis in a subject; induction of death or apoptosis of tumor and / or cancer cells; and / or any other forms of proliferative disorder. In some embodiments, such anti-cancer agents may be effective to treat, reduce, prevent, or otherwise be useful for a subject having a disease or condition that is not cancer, or besides cancer. The present technology is expected to be useful for subjects that may receive, have received, or are receiving one or more doses of an anti-cancer agent regardless of the underlying disease or condition that the subject has or develops.

[0430] Conventional anti-cancer agents include chemotherapeutic agents such as platinum-based chemotherapeutic agents and non-platinum-based chemotherapeutic agents. Conventional cancer therapies may include more than one anti-cancer agent, for example, a combination of two or more chemotherapeutic agents (e.g., 5-FU plus leucovorin (FOLFOX), sunitinib plus oxaliplatin), a combination of chemotherapeutic agent and immunotherapy, as well as a combination of two or more immunotherapies. In contrast, the methods of the present technology are directed to administration of a non-naturally occurring melanocortin analog prior to, during, and / or after administration of an anti-cancer agent.

[0431] Exemplary chemotherapeutic agents include, but are not limited to, (i) alkylating antineoplastic agents such as cyclophosphamide (CYTOXAN), thiotepa, busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, mercaptopurine, and procarbazine; (ii) antimetabolites such as 5-fluorouracil (5-FU), cladribine, cytarabine, fludarabine, gemcitabine (GEMZAR), tegafur (UFTORAL), pentostatin, clofarabine, capecitabine (XELODA), methotrexate, pemetrexed, and thioguanine; (iii) cytotoxic antibiotics such as doxorubicin (including ADRIAMYCIN, morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin, a doxorubicin salt (e.g., hydrochloride salt), doxorubicin HCI liposome injection (DOXIL), and deoxydoxorubicin), daunorubicin, idarubicin, mitomycins such as mitomycin C, actinomycin, epirubicin, calicheamicin, dynemicin, including dynemicin A, aclacinomysins, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, esorubicin, idarubicin, marcellomycin, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; (iv) tubulin binding agents such as vincristine (ONCOVIN), paclitaxel, epothilone, docetaxel, discodermolide, etoposide, vinblastine, teniposide, vinorelbine, and vindesine; and (v) platinum-coordination complexes such as cisplatin, oxaliplatin, carboplatin, and nedaplatin.

[0432] Additional examples of chemotherapeutic agents include, but are not limited to, tyrosine-kinase inhibitors such as imatinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, and sunitinib; topoisomerase inhibitors such as CPT-11 (irinotecan, CAMPTOSAR), mitoxantrone, and topotecan (HYCAMTIN); thymidine phosphorylase (TPase) inhibitors such astipiracil, and trifluridine; mitotic inhibitors; cell cycle inhibitors; enzymes; biological response modifiers; antiangiogenic agents such as MMP-2, MMP-9, and COX-2 inhibitor; anti-androgens such asfiutamide, nilutamide and bicalutamide; a substituted urea such as hydroxyurea; adrenocortical suppressants such as mitotane, aminoglutethimide, and trilostane; anti-hormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX tamoxifen), raloxifene (EVISTA), droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 11 7018, onapristone, and toremifene (FARESTON®); hormone and / or hormone antagonists such as the adrenocorticosteriods (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate), and estrogens (e.g., diethylstilbestrol); androgens, such as testosterone propionate; and aromatase inhibitors, such as anastrozole (ARIMIDEX), exemestane (AROMASIN), 4(5)-imidazoles, aminoglutethimide, megestrol acetate (MEGASE), formestanie, fadrozole, vorozole (RJVISOR), and letrozole (FEMARA).

[0433] In some embodiments, the anti-cancer agent comprises a chemotherapy and the chemotherapy comprises at least one chemotherapeutic agent. In some embodiments, the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of a platinum-coordination complex, an antimetabolite, a tubulin binding agent or a plant alkaloid, an alkylating antineoplastic agent, and a cytotoxic antibiotic. In some embodiments, the chemotherapeutic agent is an antimetabolite, a pyrimidine antagonist, an alkylating agent, a topoisomerase inhibitor, a mitotic inhibitor, an antitumor antibiotic, a protein kinase inhibitor, a proteosome inhibitor, a poly(ADP-ribose) polymerase inhibitor, a plant alkaloid, an antimicrotubule agent, an antineoplastic agent, or an enzyme.

[0434] In some embodiments, the chemotherapeutic agent is an antimetabolite. Nonlimiting examples of antimetabolites include fluorouracil, 5-fluorouracil, 6-mercaptopurine, azacytidine, capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil. In some embodiments, the chemotherapeutic agent comprises an antimetabolite selected from the group consisting of 5-fluorouracil (5-FU), 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil.

[0435] In some embodiments, the chemotherapeutic agent is a pyrimidine antagonist. Nonlimiting examples of pyrimidine antagonists include vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and topotecan.

[0436] In some embodiments, the chemotherapeutic agent is an alkylating agent. Nonlimiting examples of alkylating agents include altretamine, bendamustine, busulfan, carboplatin, carmustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.

[0437] In some embodiments, the chemotherapeutic agent is a topoisomerase inhibitor. Nonlimiting examples of topoisomerase inhibitors include irinotecan, camptothecin, etoposide, doxorubicin, topotecan, mitoxantrone, teniposide, daunorubicin, idarubicin, epirubicin, SN-38, dexrazoxane, belotecan, levofloxacin, anthracycline, rubitecan, sacituzumab govitecan, moxifloxacin, gatifloxacin, rubitecan, nalidixic acid, nalidixic acid, novobiocin, enoxacin, flumequine, clinafloxacin.

[0438] In some embodiments, the chemotherapeutic agent is a mitotic inhibitor. Nonlimiting examples of mitotic inhibitors include paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, ixabepilone, colchicine, demecolcine, etoposide, teniposide, alisertib, barasertib, volasertib, paclitaxel protein-bound particles, albumin-bound paclitaxel, ispinesib, and eribulin.

[0439] In some embodiments, the chemotherapeutic agent is an antitumor antibiotic. Nonlimiting examples of antitumor antibiotics include daunorubicin, doxorubicin, liposomal doxorubicin, epirubicin, idarubicin, mitomycin, and valrubicin.

[0440] In some embodiments, the chemotherapeutic agent is a protein kinase inhibitor. Nonlimiting examples of protein kinase inhibitors include imatinib, dasatinib, nilotinib, bosutinib, ponatinib, sorafenib, sunitinib, pazopanib, cabozantinib, vandetanib, crizotinib, ceritinib, alectinib, brigatinib, osimertinib, larotrectinib, entrectinib, dabrafenib, trametinib, and cobimetinib.

[0441] In some embodiments, the chemotherapeutic agent is a proteosome inhibitor. Nonlimiting examples of proteosome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib, delanzomib, oprozomib, delanzomib, belinostat, panobinostat, romidepsin, vorinostat, belinostat, pracinostat, resminostat, givinostat, quisinostat, mocetinostat, chidamide, rocilinostat, and tucidinostat.

[0442] In some embodiments, the chemotherapeutic agent is a poly(ADP-ribose) polymerase inhibitor. Nonlimiting examples of poly(ADP-ribose) polymerase inhibitors include olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, ceralasertib, talazoparib, iniparib, niraparib, olaparib, rucaparib, veliparib, talazoparib, pamiparib, iniparib, veliparib, olaparib, talazoparib, and rucaparib.

[0443] In some embodiments, the chemotherapeutic agent is a plant alkaloid. Nonlimiting examples of plant alkaloids include vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and topotecan.

[0444] In some embodiments, the chemotherapeutic agent is an antimicrotubule agent. Nonlimiting examples of antimicrotubule agents include docetaxel, paclitaxel, vinblastine, vincristine, vinorelbine, eribulin, ixabepilone, and cabazitaxel.

[0445] In some embodiments, the chemotherapeutic agent is an antineoplastic agent. Nonlimiting examples of antineoplastic agents include estramustine, mitomycin, hydroxydaunorubicin, chlorambucil, cisplatin, carboplatin, oxaliplatin, methotrexate, 5-fluorouracil, capecitabine, doxorubicin, epirubicin, idarubicin, daunorubicin, bleomycin, etoposide, teniposide, mitoxantrone, irinotecan, topotecan, gemcitabine, pemetrexed, paclitaxel, and docetaxel.

[0446] In some embodiments, the chemotherapeutic agent is an enzyme. Nonlimiting examples of enzymes include L-asparaginase, pegaspargase, glucarpidase, carboxypeptidase G2, methioninase, arginine deiminase, ADI-PEG 20, protease-activated receptor 1 (PAR-1) inhibitors, thymidylate synthase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, dihydrofolate reductase inhibitors, ribonucleotide reductase inhibitors, hypoxanthine-guanine phosphoribosyltransferase inhibitors, DNA polymerase inhibitors, telomerase inhibitors, histone deacetylase inhibitors, protein kinase C inhibitors, sirtuin inhibitors, and matrix metalloproteinase inhibitors.

[0447] In some embodiments, the at least one chemotherapeutic agent comprises a platinum-coordination complex. In some embodiments, the platinum-coordination complex is carboplatin and / or cisplatin.

[0448] In some embodiments, the at least one chemotherapeutic agent comprises a tubulin binding agent or a plant alkaloid. In some embodiments, the tubulin binding agent or the plant alkaloid is at least one selected from the group consisting of vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and Topotecan.

[0449] In some embodiments, the at least one chemotherapeutic agent comprises an alkylating antineoplastic agent. In some embodiments, the alkylating antineoplastic agent is at least one selected from the group consisting of altretamine, busulfan, carmustine, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.

[0450] In some embodiments, the at least one chemotherapeutic agent comprises a cytotoxic antibiotic. In some embodiments, the cytotoxic antibiotic is at least one selected from the group consisting of daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, and valrubicin.

[0451] In some embodiments, the platinum-coordination complex is cisplatin. In some embodiments, the chemotherapy comprises cisplatin, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-d\ / al-dPro-NH2 (SEQ ID NO: 3).

[0452] In some embodiments, the antimetabolite is 5-fluorouracil (5-FU). In some embodiments, the chemotherapy comprises 5-FU, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3).

[0453] In some embodiments, the tubulin binding agent or the plant alkaloid is vincristine. In some embodiments, the chemotherapy comprises vincristine, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3).

[0454] In some embodiments, the alkylating antineoplastic agent is cyclophosphamide. In some embodiments, the chemotherapy comprises cyclophosphamide, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3).

[0455] In some embodiments, the cytotoxic antibiotic is doxorubicin. In some embodiments, the chemotherapy comprises doxorubicin, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3).

[0456] The present technology further encompasses combinations of two or more anti-cancer agents, including the above chemotherapeutic agents, as the anti-cancer agent of the combination therapy. Non-limiting examples include gemcitabine in combination with cisplatin; carboplatin in combination with pemetrexed; CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin combined with 5-FU and leucovovin.

[0457] In some embodiments, the method further comprises administering an antibody, or antigen binding fragment thereof, that specifically binds to human growth differentiation factor 15 (GDF15) such as, but not limited to, ponsegromab. See U.S. Patent No. 11,566,066 (or U.S. Patent Application No. 16 / 541,817, incorporated herein by reference). In some embodiments, the non-naturally occurring melanocortin analog treats, prevents, and / or reduces one or more side effects that an antibody, or antigen binding fragment thereof, that specifically binds to GDF15 may also treat, prevent, and / or reduce. Formulations

[0458] The compositions comprising the carriers and / or excipients described in the present technology facilitate delivery of the non-naturally occurring melanocortin analog and / or one or more anti-cancer agents described herein in any of its embodiments to a subject.

[0459] In some embodiments, the one or more anti-cancer agents is present in a composition.

[0460] In some embodiments, the non-naturally occurring melanocortin analog is present in a composition.

[0461] In some embodiments, the non-naturally occurring melanocortin analog is present in the composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the composition. For example, the non-naturally occurring melanocortin analog is present in the composition in a concentration of 0.1 mg / mL to 500 mg / ml_, 0.5 mg / mL to 250 mg / mL, 1 mg / mL to 100 mg / mL, 2.5 mg / mL to 50 mg / mL, or 5 mg / mL to 25 mg / mL, relative to a total volume of the composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

[0462] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3), and the non-naturally occurring melanocortin analog is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the composition. For example, the non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-d\ / al-dPro-NH2 (SEQ ID NO: 3) is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, 10 mg / mL to 75 mg / mL, 15 mg / mL to 50 mg / mL, 20 mg / mL to 40 mg / mL, or 25 mg / mL to 30 mg / mL, relative to a total volume of the composition. In some embodiments, the non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-d\ / al-dPro-NH2 (SEQ ID NO: 3) is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

[0463] In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally. In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

[0464] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises the non-naturally occurring melanocortin analog of formula (I) at a concentration at about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol, or even more, depending on the specific peptide selected, the desired response, the route of administration, the formulation and other factors known to those of skill in the art. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-d\ / al-dPro-NH2 (SEQ ID NO: 3).

[0465] In some embodiments, the non-naturally occurring melanocortin analog crosses blood-brain-barrier (BBB) of the subject.

[0466] In some embodiments, the subject is a mammal, including but not limited to a human, a non-human primate such as a chimpanzee, a domestic livestock or a farm animal such as a cow, a bison, sheep, a pig, a goat, a horse, a chicken, and a rooster, a domestic pet animal such as a dog, a cat, a rat, a mouse, and a rabbit, and a laboratory subject such as a rodent, including a rat, a mouse, and a guinea pig. In some embodiments, the subject is a human. In some embodiments, the subject is an animal such as a rat or a dog.

[0467] In some embodiments, the subject has a body mass index (BMI) of 18.5 kg / m2 to 35 kg / m2. In some embodiments, the subject has a BMI of less than 35 kg / m2. In some embodiments, the subject has a BMI of less than 18.5 kg / m2.

[0468] In some embodiments, the subject is an underweight subject. Underweight subjects include those having a body weight about 3%, 5% or less, 10% or less, 20% or less, or 30% or less, than the lower end of “normal” BMI (e.g., 18.5 kg / m2).

[0469] In some embodiments, the compositions of the present technology are administered to the subject at a dose that is based on the subject’s BMI. In some embodiments, two or more doses of the compositions of the present technology are administered to the subject, wherein the two or more doses are titrated (e.g., inversely titrated) based on the subject’s BMI at the time of each administration.

[0470] The compositions comprising the carriers and / or excipients described in the present technology facilitate delivery (e.g., parenteral administration, in particular subcutaneous injection) of the non-naturally occurring melanocortin analog described herein in any of its embodiments to a subject. Other purposes of the compositions comprising the carriers and / or excipients are to enhance dispersion, solubility, and stability of the non-naturally occurring melanocortin analog, and to reduce adverse injection site reactions. [0471 ] The carriers and / or excipients of the composition may generally include one or more of the following components: a pH buffered aqueous solution comprising (a) sodium acetate, (b) Tris, and (c) water. In some embodiments, all components are compatible with the non-naturally occurring melanocortin analog (i.e., do not react or cause the non-naturally occurring melanocortin analog to react) and are homogeneously dispersed or dissolved uniformly in the composition.

[0472] In some embodiments, the carrier and / or excipient is isotonic.

[0473] In order to achieve a desirable tonicity, the composition of the present technology may further include a salt such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. In some embodiments, the salt is present in the composition in a concentration of 0.1 mg / mL to 50 mg / mL, 1 mg / mL to 25 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0474] The carriers and / or excipients of the composition also includes a pH buffered aqueous solution which comprises (a) sodium acetate, (b) Tris, and (c) water.

[0475] The water used herein may act as a diluent and include, without limitation, water for injection (WFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, bidistilled water, deionized water, deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pH buffered aqueous solution is water for injection.

[0476] In some embodiments, the composition includes water in an amount of about 1 wt% to about 90 wt%, about 10 wt% to about 75 wt%, or about 25 wt% to about 50 wt%, relative to a total weight of the composition.

[0477] In some embodiments, sodium acetate is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0478] In some embodiments, sodium acetate is present in the composition in a concentration of about 6 mg / mL to about 8 mg / mL, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a concentration of 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.1 mg / mL, 7.5 mg / mL, or 8 mg / mL, relative to a total volume of the composition.

[0479] In some embodiments, sodium acetate is present in the composition in a molar concentration of 5 mM to 700 mM, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a molar concentration of 5 mM to 700 mM, 10 mM to 600 mM, 20 mM to 500 mM, 30 mM to 400 mM, 40 mM to 300 mM, 50 mM to 200 mM, 60 mM to 100 mM, or 70 mM to 80 mM, relative to a total volume of the composition.

[0480] In some embodiments, sodium acetate is present in the composition in a molar concentration of about 80 mM to about 100 mM, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a molar concentration of 80 mM, 85 mM, 87 mM, 90 mM, 95 mM, or 100 mM, relative to a total volume of the composition.

[0481] The term “Tris” represents tris(hydroxymethyl)aminomethane also known as Tris buffer, Tris base, TRIS, tromethamine, tromethamine buffer, Trizma®, Trisamine, Trometamol, Tromethane, Trisaminol, orTHAM. In some embodiments, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0482] In some embodiments, Tris is present in the composition in a concentration of about 6 mg / mL to about 8 mg / mL, relative to a total volume of the composition. For example, Tris is present in the composition in a concentration of 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.3 mg / mL, 7.6 mg / mL, or 8 mg / mL, relative to a total volume of the composition.

[0483] In some embodiments, Tris is present in the composition in a molar concentration of 2 mM to 500 mM, relative to a total volume of the composition. For example, Tris is present in the composition in a molar concentration of 2 mM to 500 mM, 5 mM to 400 mM, 10 mM to 300 mM, 20 mM to 200 mM, 30 mM to 150 mM, 40 mM to 100 mM, 50 mM to 80 mM, or 60 mM to 70 mM, relative to a total volume of the composition.

[0484] In some embodiments, Tris is present in the composition in a molar concentration of about 50 mM to about 70 mM, relative to a total volume of the composition. For example, Tris is present in the composition in a molar concentration of 50 mM, 55 mM, 60 mM, 65 mM, or 70 mM, relative to a total volume of the composition.

[0485] In some embodiments, the pH buffered aqueous solution provides the composition with a pH equivalent or close to the physiological pH levels. This may reduce adverse injection site reactions and also provide the non-naturally occurring melanocortin analog with enhanced stability and resistance to aggregation and degradation.

[0486] In addition to sodium acetate and Tris, the composition may include other buffering agents. Non-limiting examples of additional buffering agents include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid, ascorbate, tartartic acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate, malate, imidazole, and mixtures thereof. In some embodiments, the composition comprises acetic acid as an additional buffering agent.

[0487] In some embodiments, a weight ratio of sodium acetate to Tris is 1:4 to 4:1, 2:7 to 7:2, 1:3 to 3:1, 2:5 to 5:2, 1:2 to 2:1, 2:3 to 3:2, or about 1:1. In some embodiments, the weight ratio of sodium acetate to Tris is about 1:1.

[0488] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is 1:1 to 20:1, 3:2 to 15:1, 2:1 to 12:1, 3:1 to 10:1,4:1 to 9:1, 5:1 to 8:1, or 6:1 to 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is about 7:1.

[0489] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is 1:1 to 20:1, 3:2 to 15:1, 2:1 to 12:1, 3:1 to 10:1, 4:1 to 9:1, 5:1 to 8:1, or 6:1 to 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is about 7:1.

[0490] The composition may also comprise a preservative agent. Exemplary preservative agents include, but are not limited to, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, phenol, m-cresol, benzyl alcohol, alpha-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, benzalkonium chloride, phenoxyethanol, and methyl paraben.

[0491] If present, the concentration of the preservative agent may range from 0.001 mg / mL to 50 mg / mL, 0.01 mg / mL to 25 mg / mL, 0.1 mg / mL to 10 mg / mL, or 1 mg / mL to 5 mg / mL, relative to a total volume of the composition.

[0492] In some embodiments, the composition is in the form of an aqueous solution or a suspension. In some embodiments, the composition is in the form of an emulsion. In some embodiments, the composition is in the form of an aqueous solution. In some embodiments, the composition is in the form of an aqueous solution which is clear, colorless, and / or free of visible foreign matter.

[0493] In some embodiments, the composition has a pH ranging from 6.5 to 8.5. In some embodiments, the composition has a pH of about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or8.5.

[0494] In some embodiments, the composition is basic and has a pH of about 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5. In some embodiments, the composition has a pH ranging from about 7.3 to about 7.4. In some embodiments, the composition has a pH of 7.3 or 7.4.

[0495] In some embodiments, the composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the composition has an osmolality ranging from 250 mOsm / kg to 360 mOsm / kg, 260 mOsm / kg to 340 mOsm / kg, 270 mOsm / kg to 330 mOsm / kg, 280 mOsm / kg to 320 mOsm / kg, 290 mOsm / kg to 310 mOsm / kg, or about 300 mOsm / kg. In some embodiments, the composition has an osmolarity of about 250 mOsm / kg, about 260 mOsm / kg, about 270 mOsm / kg, about 280 mOsm / kg, about 290 mOsm / kg, about 300 mOsm / kg, about 310 mOsm / kg, about 320 mOsm / kg, about 330 mOsm / kg, about 340 mOsm / kg, about 350 mOsm / kg, or about 360 mOsm / kg. In some embodiments, the composition has an osmolality ranging from about 275 mOsm / kg to about 330 mOsm / kg. In some embodiments, the composition has an osmolality of about 279 mOsm / kg, about 314 mOsm / kg, or about 329 mOsm / kg.

[0496] In some embodiments, the composition has a viscosity ranging from 0.5 cP to 5 cP. For example, the composition has a viscosity ranging from 0.5 cP to 5 cP, 0.75 cP to 4.5 cP, 1.0 cP to 4 cP, 1.2 cP to 3.5 cP, 1.3 cP to 3 cP, 1.4 cP to 2.5 cP, 1.5 cP to 2 cP, or 1.6 cP to 1.8 cP. In some embodiments, the composition has a viscosity of about 0.5 cP, 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, or 2.0 cP. In some embodiments, the composition has a viscosity of about 1.4 cP or 1.6 cP.

[0497] The composition described herein in any of its embodiments may be formulated for parenteral administration, such as, for example, in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. The term “parenteral”, as used herein, includes subcutaneous, intravenous, intraperitoneal, intramuscular, and intralesional, or infusion techniques.

[0498] The active ingredient(s) (e.g., the non-naturally occurring melanocortin analog) may be dissolved or suspended in the aforementioned carrier and / or excipient. Additional aqueous or non-aqueous carriers that may facilitate dissolution of the active ingredient include, but are not limited to, ethanol, benzyl alcohol, DMSO, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, and / or various buffers.

[0499] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises a non-naturally occurring melanocortin analog at a concentration at about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol, or even more, depending on the specific peptide selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.

[0500] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises sodium acetate at a concentration at about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 76 mM, 77 mM, 78 mM, 79 mM, 80 mM, 81 mM, 82 mM, 83 mM, 84 mM, 85 mM, 86 mM, 87 mM, 88 mM, 89 mM, 90 mM, 91 mM, 92 mM, 93 mM, 94 mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM, 100 mM, 105 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM.

[0501] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises Tris at a concentration at about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 3 5mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, or 120 mM.

[0502] The compositions of the present technology may be formulated for intranasal delivery. In some embodiments, the intranasal composition comprises a non-naturally occurring melanocortin analog of the present technology and a carrier and / or excipient.

[0503] The carriers and / or excipients of the composition may generally include one or more of the following components: (i) one or more antioxidants, (ii) one or more preservatives, (iii) one or more buffers, (iv) one or more tonicity adjustors, (v) one or more surfactants, (vi) flavor, (vii) propellants, and / or (viii) a vehicle or solvent. In some embodiments, all components are compatible with the non-naturally occurring melanocortin analog (i.e., do not react or cause the non-naturally occurring melanocortin analog to react) and are homogeneously dispersed or dissolved uniformly in the composition.

[0504] In some embodiments, the carrier and / or excipient is isotonic to nasal fluids.

[0505] In order to achieve a desirable tonicity, the composition of the present technology may further include a salt such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. In some embodiments, the salt is present in the composition in a concentration of 0.1 mg / mL to 50 mg / mL, 1 mg / mL to 25 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the composition. In some aspects, the salt is sodium chloride at a concentration of 0.9% wt.

[0506] The carriers and / or excipients of the composition also includes a pH buffered aqueous solution which comprises sodium acetate, Tris, and / or a phosphate buffer.

[0507] The water used herein may act as a diluent and include, without limitation, water for injection (WFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, bidistilled water, deionized water, deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pH buffered aqueous solution is water for injection.

[0508] In some embodiments, the composition includes water (e.g., water for injection) in an amount of about 1 wt% to about 90 wt%, about 10 wt% to about 75 wt%, or about 25 wt% to about 50 wt%, relative to a total weight of the composition.

[0509] In some embodiments, sodium acetate is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0510] In some embodiments, sodium acetate is present in the composition in a molar concentration of about 80 mM to about 100 mM, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a molar concentration of 80 mM, 85 mM, 87 mM, 90 mM, 95 mM, or 100 mM, relative to a total volume of the composition.

[0511] The term “Tris” represents tris(hydroxymethyl)aminomethane also known as Tris buffer, Tris base, TRIS, tromethamine, tromethamine buffer, Trizma®, Trisamine, Trometamol, Tromethane, Trisaminol, orTHAM. In some embodiments, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0512] In some embodiments, the pH buffered aqueous solution provides the composition with a pH equivalent or close to the physiological pH levels. This may reduce adverse injection site reactions and also provide the non-naturally occurring melanocortin analog with enhanced stability and resistance to aggregation and degradation.

[0513] In addition to sodium acetate and Tris, the composition may include other buffering agents. Non-limiting examples of additional buffering agents include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid, ascorbate, tartartic acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate, malate, imidazole, and mixtures thereof. In some embodiments, the composition comprises acetic acid as an additional buffering agent.

[0514] In some embodiments, sodium phosphate is present in the composition in a molar concentration of 5 mM to 700 mM, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a molar concentration of 5 mM to 700 mM, 10 mM to 600 mM, 20 mM to 500 mM, 30 mM to 400 mM, 40 mM to 300 mM, 50 mM to 200 mM, 60 mM to 100 mM, or 70 mM to 80 mM, relative to a total volume of the composition.

[0515] The composition may also comprise a preservative agent. Exemplary preservative agents include, but are not limited to, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, phenol, m-cresol, benzyl alcohol, benzalkonium chloride, alpha-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, benzalkonium chloride, phenoxyethanol, and methyl paraben.

[0516] If present, the concentration of the preservative agent may range from 0.001 mg / mL to 50 mg / mL, 0.01 mg / mL to 25 mg / mL, 0.1 mg / mL to 10 mg / mL, or 1 mg / mL to 5 mg / mL, relative to a total volume of the composition.

[0517] In some embodiments, the composition is in the form of an aqueous solution or a suspension. In some embodiments, the composition is in the form of an emulsion. In some embodiments, the composition is in the form of an aqueous solution. In some embodiments, the composition is in the form of an aqueous solution which is clear, colorless, and / or free of visible foreign matter.

[0518] In some embodiments, the composition has a pH approximating the normal pH range of the nasal fluid. In some embodiments, the composition has a pH ranging from 5.5 to 6.5. In some embodiments, the composition has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1,6.2, 6.3, 6.4, or 6.5.

[0519] In some embodiments, the composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the composition has an osmolality ranging from 250 mOsm / kg to 360 mOsm / kg, 260 mOsm / kg to 340 mOsm / kg, 270 mOsm / kg to 330 mOsm / kg, 280 mOsm / kg to 320 mOsm / kg, 290 mOsm / kg to 310 mOsm / kg, or about 300 mOsm / kg. In some embodiments, the composition has an osmolarity of about 250 mOsm / kg, about 260 mOsm / kg, about 270 mOsm / kg, about 280 mOsm / kg, about 290 mOsm / kg, about 300 mOsm / kg, about 310 mOsm / kg, about 320 mOsm / kg, about 330 mOsm / kg, about 340 mOsm / kg, about 350 mOsm / kg, or about 360 mOsm / kg. In some embodiments, the composition has an osmolality ranging from about 275 mOsm / kg to about 330 mOsm / kg. In some embodiments, the composition has an osmolality of about 279 mOsm / kg, about 314 mOsm / kg, or about 329 mOsm / kg.

[0520] In some embodiments, the composition has a viscosity ranging from 0.5 cP to 5 cP. For example, the composition has a viscosity ranging from 0.5 cP to 5 cP, 0.75 cP to 4.5 cP, 1.0 cP to 4 cP, 1.2 cP to 3.5 cP, 1.3 cP to 3 cP, 1.4 cP to 2.5 cP, 1.5 cP to 2 cP, or 1.6 cP to 1.8 cP. In some embodiments, the composition has a viscosity of about 0.5 cP, 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, or 2.0 cP. In some embodiments, the composition has a viscosity of about 1.4 cP or 1.6 cP.

[0521] In some embodiments, the composition comprises one or more antioxidants. For example, the composition may comprise ascorbic acid, cysteine, sodium metabisulfite, propyl gallate, butylated hydroxytoluene, and / or butylated hydroxyanisole.

[0522] In some embodiments, the composition comprises a surfactant, such as a sorbitan ester.

[0523] In some embodiments, the composition comprises a flavoring or scent, such as an aromatic oil.

[0524] The active ingredient(s) (e.g., the non-naturally occurring melanocortin analog) may be dissolved or suspended in the aforementioned carrier and / or excipient. Additional aqueous or non-aqueous carriers that may facilitate dissolution of the active ingredient include, but are not limited to, ethanol, benzyl alcohol, DMSO, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, and / or various buffers.

[0525] In some embodiments, the non-naturally occurring melanocortin analog is solubilized or suspended in a solvent or vehicle. In some aspects, the solvent or vehicle is purified water, ethyl alcohol, propylene glycol. The composition may comprise between 0.03% wt and 1% wt melanocortin solubilized or suspended in a solvent or vehicle. The composition may comprise about 0.03% wt, 0.05% wt, 0.1% wt, 0.15% wt, 0.2% wt, 0.25% wt, 0.3% wt, 0.35% wt, 0.4% wt, 0.45% wt, 0.5% wt, 0.55% wt, 0.6% wt, 0.65% wt 0.7% wt, 0.75% wt, 0.8% wt, 0.85% wt, 0.9% wt, 0.95% wt, or 1% wt melanocortin.

[0526] In some embodiments, the composition formulated for intranasal administration comprises a non-naturally occurring melanocortin analog at a concentration at about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol, or even more, depending on the specific peptide selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.

[0527] The composition may be formulated to be delivered by nose drop, spray device, ortopical solution. In some embodiments, the pharmaceutical composition may be formulated as an aerosol, atomizer, inhalation, insufflation, metered-dose inhaler, nebulizer, or hydrobromide. In some embodiments, the composition includes a propellant, such as hydrofluoroalkane.

[0528] In some embodiments, the composition may be configured to be administered using a spray device or nasal inhaler. The spray device or nasal inhaler may be configured to deliver 1 ug to 10Oug per spray. In some embodiments, the spray device or nasal inhaler may be configured to deliver 1ug to 100ug, 5ug to 90ug, 10ug to 80ug, 15ug to 70ug, 20ug to 60ug, 25ug, to 50ug, or 30ug to 40ug per spray. Pharmacokinetics and Pharmacodynamics

[0529] The non-naturally occurring melanocortin analogs of the present technology exhibit pharmacokinetic (pK) and / or pharmacodynamic (pD) parameters. Such pK and / or pD may be expressed or otherwise determined relative to a control, which, in some instances, may be a non-naturally occurring melanocortin analog lacking one or more features of the non-naturally occurring melanocortin analogs of the present technology.

[0530] In some embodiments, the pK and / or pD of the non-naturally occurring melanocortin analogs may be assessed using concentration and / or temporal measurements (e.g., Tfinai, Cmax, T Vz (h)), AUC, orTmax. In some embodiments, the non-naturally occurring melanocortin analogs have reduced clearance and / or metabolism, increased uptake, absorption, and / or stability, relative to a control. Clearance

[0531] “Clearance” may refer to the elimination, absorption, and / or metabolism of the non-naturally occurring melanocortin analogs in the subject’s plasma. Clearance may be assessed as volume of plasma cleared of the non-naturally occurring melanocortin analogs overtime (e.g., mL / min, L / hr, or L / day) and / or may be normalized to body weight of the subject (e.g., mL / min / kg). Reduced clearance may also be represented by an increase in half-life or volume of distribution (Vd). In some embodiments, measuring clearance comprises measuring a terminal elimination rate constant (Az) or an inter-compartmental clearance (Q).

[0532] In some embodiments, the reduction in clearance comprises a measurement about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0533] In some embodiments, the reduction in clearance comprises a measurement during administration of the non-naturally occurring melanocortin analogs. In some embodiments, the reduction in clearance comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs. Concentration

[0534] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise an increased tissue, plasma, and / or serum concentration relative to a control. “Concentration” may comprise a measurement reflecting one or more of the absolute amounts of the non-naturally occurring melanocortin analogs, the absorption of the non-naturally occurring melanocortin analogs, the metabolism of non-naturally occurring melanocortin analogs, or the elimination of non-naturally occurring melanocortin analogs.

[0535] The increased tissue, plasma, and / or serum concentration may be an increase in concentration of the non-naturally occurring melanocortin analogs at a given time point relative to a control administered at the same dose and measured at the same time point. The concentration may be measured at an intermediate time point or a final time point and may be measured as a mean residence time (MRT), an average concentration (Cavg), a trough concentration (Ctrough), or a concentration at the end of administration (e.g., infusion) time (Ct).

[0536] In some embodiments, the increased concentration is reflected by an increase in peak plasma concentration (Cmax). An increase in Cmax may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. In some embodiments, Cmax comprises a dose normalized Cmax (DNCmax).

[0537] In some embodiments, the increased concentration is reflected by an increase in minimum plasma concentration (Cmin). An increase in Cmin may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. In some embodiments, Cmin comprises a dose normalized Cmin (DNCmin).

[0538] In some embodiments, the increased concentration is reflected by a reduction in time to reach Cmax (Tmax). A reduced Tmax may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control.

[0539] In some embodiments, the increased concentration is reflected by a final measurable concentration (Tfinai). An increased Tfinai may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control.

[0540] In some embodiments, the increased concentration is reflected by an increase in area under the curve (AUC). An increase in AUC may signify increased exposure to the non-naturally occurring melanocortin analogs and / or may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. The AUC measurement may comprise an Area Under the Curve for Concentration of Drug in Non-Compartmental Analysis (DNAUC).

[0541] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0542] In some embod...

Claims

l / We claim:

1. A method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

2. A method of maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

3. A method of maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anticancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

4. The method of claim 2 or 3, wherein the subject experiences an increase in weight by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or500% compared to baseline ora control.

5. A method of maintaining or increasing muscle mass, fat mass, or cardiac mass in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject6. The method of claim 5, wherein the subject experiences an increase in muscle mass, fat mass, or cardiac mass by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

7. A method of maintaining or increasing bone density in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject.

8. The method of claim 7, wherein the subject experiences an increase in bone density by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

9. A method of increasing or maintaining a Functional Assessment of Anorexia / Cachexia Therapy (FAACT) score in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject.

10. The method of claim 9, wherein the subject experiences an increase in the FAACT score compared to baseline or control by at least 1,2, 3, 4, or 5 points.

11. A method of stimulating appetite or reducing loss of appetite induced by an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anticancer agent.

12. The method of claim 11, wherein the subject experiences an increase in appetite as measured by an increased food intake by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, or more calories compared to baseline a control.

13. A method of preventing, reducing, or restoring weight loss induced by an anticancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent.

14. A method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

15. A method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

16. A method of preventing or reducing an anti-cancer agent induced side effect in a subject having cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

17. A method of treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in a subject having cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

18. A method of preventing reduction of, maintaining, or improving Eastern Cooperative Oncology Group (ECOG) and / or Karnofsky performance status (KPS) score of a subject having cancer relative to a baseline or a control, comprising administering an anticancer agent and a non-naturally occurring melanocortin analog to the subject.

19. The method of claim 18, wherein the subject experiences a reduction in ECOG performance score by about 1, 2, or 3 compared to baseline or control.

20. The method of claim 18, wherein the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to baseline or control.

21. A method of preventing reduction of, maintaining, or improving overall survival (OS) or progression free survival (PFS) in a subject having cancer relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

22. The method of claim 21, wherein the subject experiences an increase in OS or an increase in PFS compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

23. A method of reducing time to cancer treatment failure in a subject having cancer relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

24. A method of increasing or maintaining body mass index (BMI) in a subject relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

25. The method of claim 24, wherein the subject experiences an increase in BMI compared to baseline or control by at least 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 points.

26. The method of claim 24 or 25, wherein the subject experiences in an increase in BMI durability compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

27. A method of reducing a pro inflammatory transcript or protein level in a subject having cancer relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

28. The method of claim 27, wherein the subject experiences a reduction in an inflammatory transcript level compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

29. The method of claim 27, wherein the subject experiences a reduction in an inflammatory protein level compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

30. The method of claim 27 or claim 28, wherein the proinflammatory transcript is a transcript selected from the group consisting of an IL1 transcript, an IL6 transcript, an IL1R1 transcript, a TNFa transcript, a Selectin P transcript, a cytokine transcript, and a chemokine transcript.

31. The method of claim 27 or claim 29, wherein the proinflammatory protein is a protein selected from the group consisting of an IL1 protein, an IL6 protein, an IL1R1 protein, a TNFa protein, a Selectin P protein, and a cytokine protein.

32. The method of claim 1, wherein the method maintains or increases lean body mass, fat body mass, and / or weight of the subject relative to a baseline or a control.

33. The method of claim 11, wherein the method maintains or increases lean body mass, fat body mass, and / or body weight of the subject relative to a baseline or a control.

34. The method of claim 14, wherein the failure to respond to an antiemetic treatment further comprises clinically and / or therapeutically insufficient weight gain, muscle mass gain, fat mass gain, increased appetite, and / or increased food intake in the subject.

35. The method of claim 15, wherein the nutritional intervention further comprises nutritional supplementation.

36. The method of claim 16, wherein the side effect is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, loss of appetite, vomiting, diarrhea, nausea, and fatigue.

37. The method of claim 17, wherein the iatrogenic injury is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

38. The method of claim 18, wherein the improvement, maintenance, or prevented reduction of ECOG and / or KPS score occurs by inhibiting or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

39. The method of any one of claims 1 -38, wherein the subject has a cancer.

40. The method of any one of claims 1-39, wherein the anti-cancer agent comprises a chemotherapy.

41. The method of claim 40, wherein the method reduces chemotherapy induced mass loss and / or wasting in the subject and increases lean body mass and body weight of the subject relative to a baseline or a control.

42. The method of claim 40, wherein the method maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and wherein the method reduces mass loss and / or wasting in the subject relative to a baseline or a control.

43. The method of any one of claims 1 -18, wherein the anorexia is associated with weight loss.

44. The method of any one of claims 1-43, wherein the subject has not previously received an anti-cancer agent.

45. The method of any one of claims 1-43, wherein the subject has previously received an anti-cancer agent.

46. The method of any one of claims 1 -43, wherein the subject is receiving an anticancer agent.

47. The method of any one of claims 1-46, wherein the administration of the non-naturally occurring melanocortin analog enhances tolerability of the anti-cancer agent.

48. The method of claim 47, wherein the enhanced tolerability results in a greater dosage, an increased frequency of administration, and / or an increased duration of administration of the anti-cancer agent, relative to a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

49. The method of claim 47, wherein the anti-cancer agent comprises a chemotherapy comprising at least two chemotherapeutic agents, and wherein the enhanced tolerability results in a second chemotherapeutic agent being administered to the subject during or after administration of a first chemotherapeutic agent.

50. The method of any one of claims 1-49, wherein the administration of the non-naturally occurring melanocortin analog prevents or reduces a downward titration in dosing regimen of the anti-cancer agent relative to a baseline or a control.

51. The method of claim 50, wherein the downward titration comprises a decreased dosage, a decreased frequency of administration, and / or a decreased duration of administration, compared to a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

52. The method of any one of claims 1-51, wherein the subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss prior to the administration of the non-naturally occurring melanocortin analog.

53. The method of claim 52, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by cancer.

54. The method of claim 52, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the anti-cancer agent.

55. The method of any one of claims 1-54 wherein the subject is receiving or has received an antiemetic.

56. The method of claim 55, wherein the antiemetic is marijuana, megestrol, somatropin, or dronabinol.

57. The method of any one of claims 1-56, wherein the non-naturally occurring melanocortin analog and the anti-cancer agent are administered concurrently.

58. The method of any one of claims 1-56, wherein the non-naturally occurring melanocortin analog is administered before and / or after the anti-cancer agent.

59. The method of claim 1, wherein administration of the non-naturally occurring melanocortin analog treats, prevents or reduces the one or more side effects associated with an anti-cancer agent in a subject.

60. The method of claim 2, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

61. The method of claim 3, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing one or more side effects selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

62. The method of claim 11, wherein administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anticancer agent in the subject relative to a baseline or a control.

63. The method of claim 13, wherein administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores weight loss induced by an anti-cancer agent in the subject relative to a baseline or a control.

64. The method of claim 14, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and / or therapeutically to an antiemetic treatment, relative to a baseline or a control.

65. The method of claim 15, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and / or therapeutically to nutritional intervention, relative to a baseline or a control.

66. The method of claim 16, wherein administration of the non-naturally occurring melanocortin analog prevents or reduces the anti-cancer agent induced side effect in the subject, relative to a baseline or a control.

67. The method of claim 17, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the iatrogenic injury caused by an anticancer agent in the subject, relative to a baseline or a control.

68. The method of claim 18, wherein administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves ECOG and / or KPS score of the subject, relative to a baseline or a control.

69. The method of any one of claims 1-18, wherein the subject’s mass and / or weight is not more than 5% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

70. The method of any one of claims 1-18, wherein the subject’s mass and / or weight is not more than 10% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

71. The method of any one of claims 1-70, wherein the subject has an ECOG score of 1 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

72. The method of any one of claims 1-70, wherein the subject has an ECOG score of 2 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

73. The method of claim 71 or 72, wherein the method lowers the ECOG scale of the subject, relative to a baseline or a control.

74. The method of any one of claims 1-73, wherein the subject has a KPS score not more than 70 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

75. The method of any one of claims 1-73, wherein the subject has a KPS score not more than 50 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

76. The method of claim 74 or 75, wherein the method increases the KPS score of the subject relative to a baseline or control.

77. The method of any one of claims 1-76, wherein the method increases the subject’s cumulative mass relative to a baseline or control.

78. The method of any one of claims 1-76, wherein the method reduces the subject’s rate of loss of cumulative mass relative to a baseline or control.

79. The method of any one of claims 1-76, wherein the method increases a net weight gain in the subject relative to a baseline or control.

80. The method of claim 79, wherein the net weight gain is the change in weight between two or more time points.

81. The method of claim 79 or 80, wherein the net weight gain is the change in weight between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

82. The method of claim 80, wherein the two or more time points comprises an intermediate time point.

83. The method of any one of claims 1-82, wherein the method increases the subject’s cumulative food intake relative to a baseline or control.

84. The method of claim 83, wherein the cumulative food intake is the total food intake between two or more time points.

85. The method of claim 83 or 84, wherein the cumulative food intake is the total in food intake between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

86. The method of claim 80, wherein the two or more time points comprises an intermediate time point.

87. The method of any one of claims 1-86, wherein the method increases the subject’s BMI relative to a baseline or control.

88. The method of claim 87, wherein the increase in BMI is the change in BMI between two or more time points.

89. The method of claim 87 or 88, wherein the increase in BMI is a change in BMI between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

90. The method of claim 88, wherein the two or more time points comprises an intermediate time point.

91. The method of any one of claims 87-90, wherein the non-naturally occurring melanocortin analog is administered to the subject based on the subject’s BMI at the time of administration.

92. The method of claim 91, wherein the subject is administered the non-naturally occurring melanocortin analog at two or more doses based on the subject’s BMI at the time of each administration.

93. The method of claim 92, wherein the two or more doses are inversely titrated based on the subject’s BMI at the time of each administration.

94. The method of any one of claims 1-93, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I), X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8 (I) wherein:R1 is absent or is selected from the group consisting of cysteine, norleucine (Nie), acetylated norleucine (Ac-Nle), frans-4-guanidinyl-proline (fransPro(guan)), c / s-4-guanidinyl-proline (c / sPro(guan)), acetylated frans-4-guanidinyl-proline (Ac-fransPro(guan)), acetylated c / s-4-guanidinyl-proline (Ac-c / sPro(guan)), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid;R2 is absent or is selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), transPro(guan), c / sPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, norleucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine;R3 is absent or is selected from the group consisting of histidine, L-proline, fransPro(guan), c / sPro(guan), D-valine, glutamic acid, tryptylarginine (Trp-Arg), glycine, D-leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-( 1,5-a)(1,4)diazepin-6(5H)-one     (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2 / - / )-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1-amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), and indoline-2-carboxylic acid (loc),R4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);R5 is absent or is selected from the group consisting of arginine, homoarginine, proline, transPro(guan), c / sPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(l)dPhe;R6 is absent or is selected from the group consisting of L-tryptophan, D-phenylalanine, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(T), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine;R7 is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, ornithine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), and tetrahydro-isoquinoline-3-carboxylic acid (Tic);R8 is absent or is lysine;R9-R20 are absent;X1 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, p-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid,asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine;X2 is absent or is D-proline;X3 is absent;Y1 is absent or is selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline;Y2 is absent or is selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine;Y3 is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;Y4 is absent or is D-aspartic acid or aspartic acid;Y5-Y8 are absent;the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:a disulfide bond between R1 and R7 when R1 is cysteine and R7 is cysteine;a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid;a side-chain lactam bridge between R1 or R2 and R7 when R1 or R2 is glutamic acid or aspartic acid, and R7 is lysine, Dap, or ornithine;a side-chain lactam bridge between R2 and R7 when R2 is lysine, and R7 is glutamic acid or aspartic acid;a side-chain lactam bridge between R1 or R2 and R8 when R1 or R2 is glutamic acid or aspartic acid, R8 is lysine, and R7 is proline, glycine or tryptophan;provided that:when R2 is dAsp, then R7 is not dLys;when R2-R4 is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7 is not Arg-Trp-Lys;when Y1 is dPro, Y2 is dVal, and Y3-Y8 are absent, then R4 is not dNal(2’) or R4 is dNal(2’) and the C-terminus is not modified;when R3 is Aba, Ata, or Aia, R6 is Aia, or R7 is Orn, then R4 is not dNal(2’), or R4 is dNal(2’) and R5 is not Arg;when R4 is p(CI)dPhe, then R3 is not Pro or His;when R4 is p(l)dPhe then the non-naturally occurring melanocortin analog is cyclized through a side-chain lactam bridge between R1 and R7 and at least one of R2 and R3 is Pro;when Y2-Y4 are absent, then Y1 is absent or is norleucine;when R2 is Pro orY2 is Hyp, then R3 is not Pro;when R3, R5, or R6 is absent, then the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1 and R7 orX1-X2 are present and are Ac-dVal-dPro;when R2-R7 is Asp-Pro-dNal(2’)-Arg-Trp-Lys (SEQ ID NO: 526) or Cys-Pro-dNal(2’)-Arg-Trp-Cys (SEQ ID NO: 527), then R1 is not Ac-Nle or Y1-Y2 is not dVal-dPro, dVal-dVal, dPro-dPro; andwhen the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2 and R8, then R3 is not His or Y1 is not dVal.

95. The method of any one of claims 1-18 and 73, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 10, 14, 33-39, 82-96, 108-111, 119-124, 126-135, 138, 192-199, 222-295, 408 and 413.

96. The method of any one of claims 1-18 and 73-74, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3).

97. The method of claim 40, wherein the chemotherapy comprises at least one chemotherapeutic agent.

98. The method of claim 97, wherein the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of aplatinum-coordination complex, an antimetabolite, a tubulin binding agent or a plant alkaloid, an alkylating antineoplastic agent, and a cytotoxic antibiotic.

99. The method of claim 98, wherein the at least one chemotherapeutic agent comprises a platinum-coordination complex.

100. The method of claim 98, wherein the at least one chemotherapeutic agent comprises an antimetabolite.

101. The method of claim 98, wherein the at least one chemotherapeutic agent comprises a tubulin binding agent or a plant alkaloid.

102. The method of claim 98, wherein the at least one chemotherapeutic agentcomprises an alkylating antineoplastic agent.

103. The method of claim 98, wherein the at least one chemotherapeutic agentcomprises a cytotoxic antibiotic.

104. The method of claim 99, wherein the platinum-coordination complex iscarboplatin and / or cisplatin.

105. The method of claim 100, wherein the antimetabolite is at least one selected from the group consisting of 5-fluorouracil (5-Fll), 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil.

106. The method of claim 101, wherein the tubulin binding agent or the plant alkaloid is at least one selected from the group consisting of vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and Topotecan.

107. The method of claim 102, wherein the alkylating antineoplastic agent is at least one selected from the group consisting of altretamine, busulfan, carmustine, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.

108. The method of claim 103, wherein the cytotoxic antibiotic is at least one selected from the group consisting of daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, and valrubicin.

109. The method of claim 99, wherein the platinum-coordination complex is cisplatin.

110. The method of claim 109, wherein the chemotherapy comprises cisplatin, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 3).

111. The method of claim 100, wherein the antimetabolite is 5-fluorouracil (5-Fll).

112. The method of claim 111, wherein the chemotherapy comprises 5-FU, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 3).

113. The method of claim 101, wherein the tubulin binding agent or the plant alkaloid is vincristine.

114. The method of claim 102, wherein the alkylating antineoplastic agent is cyclophosphamide.

115. The method of claim 103, wherein the cytotoxic antibiotic is doxorubicin.

116. The method of claim 115, wherein the chemotherapy comprises doxorubicin, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3).

117. The method of claims 39 or 40, wherein the cancer is at least one selected from the group consisting of bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, colorectal cancer, oral cancer, skin cancer, and melanoma.

118. The method of claim 39 or 40, wherein the cancer is at least one selected from the group consisting of bone cancer, lung cancer, testicular cancer, breast cancer, prostate cancer, colorectal cancer, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer.

119. The method of claim 39 or 40, wherein the cancer is breast cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of an anthracycline, cyclophosphamide, epirubicin, fluorouracil, methotrexate, a taxane, and docetaxel.

120. The method of claim 119, wherein the anthracycline is doxorubicin.

121. The method of claim 119, wherein the taxane is paclitaxel.

122. The method of claim 39 or 40, wherein the cancer is lung cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel, docetaxel, gemcitabine, vinorelbine, etoposide, and pemetrexed.

123. The method of claim 39 or 40, wherein the cancer is prostate cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, and estramustine.

124. The method of claim 39 or 40, wherein the cancer is colorectal cancer, and wherein the anti-cancer agent is at least one selected from the group consisting of 5-FU, capecitabine, irinotecan, oxaliplatin, trifluridine, and tipiracil.

125. The method of claim 40 or 41, wherein the cancer is colorectal cancer, wherein the subject is receiving radiation therapy, and wherein the chemotherapy is at least one selected from the group consisting of cisplatin, cisplatin plus 5-FU, and mitomycin plus 5-FU.

126. The method of claim 40 or 41, wherein the cancer is colorectal cancer, wherein the subject is not receiving radiation therapy, and wherein the chemotherapy is at least one selected from the group consisting of gemcitabine plus cisplatin, methotrexate, vinblastine, doxorubicin, plus cisplatin, cisplatin, methotrexate, plus vinblastine, and gemcitabine plus paclitaxel.

127. The method of any one of claims 39-41, wherein the cancer is melanoma, and wherein the anti-cancer agent is dacarbazine and / or temozolomide.

128. The method of claim 39 or 40, wherein the cancer is non-Hodgkin's lymphoma, and wherein the anti-cancer agent is at least one selected from the group consisting of cyclophosphamide, chlorambucil, bendamustine, ifosfamide, prednisone, dexamethasone, cisplatin, carboplatin, oxaliplatin, fludarabine, pentostatin, cladribine (2-CdA), cytarabine (ara-C), gemcitabine, methotrexate, pralatrexate, doxorubicin, liposomal doxorubicin, hydroxydaunorubicin, vincristine, mitoxantrone, etoposide, and bleomycin.

129. The method of any one of claims 1 -128, wherein the method does not reduce efficacy of the anti-cancer agent.

130. The method of claim 39 or 40, wherein the subject with a cancer has previously undergone a treatment with the anti-cancer agent.

131. The method of claim 130, wherein the subject has previously experienced one or more adverse side effects when treated with the anti-cancer agent, wherein the adverse side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, and appetite reduction or loss of appetite.

132. The method of any one of claims 1 -131, wherein the subject is a human.

133. The method of any one of claims 1 -131, wherein the subject is an animal.

134. The method of any one of claims 1-38, wherein the muscle mass loss is cardiac muscle mass loss, skeletal muscle mass loss, or both.

135. The method of claim 134, wherein the cardiac muscle mass loss is determined by measuring change in heart weight.

136. The method of claim 134, wherein the skeletal muscle mass loss is determined by measuring change in gastrocnemius tissue weight.

137. The method of any one of claims 1 -38, wherein anorexia is determined by daily food intake, daily food consumption, and / or weekly food intake.

138. The method of claim 137, wherein the daily food intake is determined by total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 day.

139. The method of claim 137, wherein the daily food consumption is determined by the daily food intake normalized to daily body weight of the subject.

140. The method of claim 137, wherein the weekly food intake is determined total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 week.

141. The method of any one of claims 1-38, wherein the weight loss is determined by daily body weight, and / or daily body weight gain.

142. The method of any one of claims 1-38, wherein the fat mass of the subject treated with the method is at least 10% to 100% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

143. The method of any one of claims 1 -38, wherein the heart weight of the subject treated with the method is at least 0.1% to 10% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

144. The method of any one of claims 1-38, wherein the gastrocnemius tissue weight of the subject treated with the method is at least 0.1 % to 10% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

145. The method of any one of claims 1-38, wherein the daily food intake of the subject treated with the method is at least 5% to 50% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anticancer agent without the non-naturally occurring melanocortin analog.

146. The method of any one of claims 1-38, wherein the daily body weight of the subject treated with the method is at least 1% to 15% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anticancer agent without the non-naturally occurring melanocortin analog.

147. The method of any one of claims 1-38, wherein appetite of the subject is increased by at least 10% to 200% after the administration of the non-naturally occurring melanocortin analog.

148. The method of any one of claims 1-38, wherein appetite of the subject is increased by at least 25% to 100% after the administration of the non-naturally occurring melanocortin analog.

149. The method of claim 147 or 148, wherein appetite is increased for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years during the administration.

150. The method of claim 147 or 148, wherein appetite is increased for at least 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days during the administration.

151. The method of any one of claims 147-150, wherein the increased appetite is maintained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after the administration is stopped.

152. The method of any one of claims 147-151, wherein the appetite is assessed by a scale for measuring desire to eat, feeling of hunger, and / or level of satiety.

153. The method of claim 152, wherein the appetite is assessed between meals.

154. The method of any one of claims 147-152, wherein the subject comprises two or more subjects, and wherein the appetite is an average appetite of the two or more subjects.

155. The method of any one of claims 1-38, wherein anorexia is determined by food consumption.

156. The method of any one of claims 1-18, wherein the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.

157. The method of claim 156, wherein the pharmaceutical composition further comprises a pharmaceutical salt.

158. The method of claim 156, wherein the pharmaceutical composition further comprises a pharmaceutical carrier.

159. The method of claim 156, wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg / mL to 500 rng / mL, relative to a total volume of the pharmaceutical composition.

160. The method of claim 159, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3), and wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the pharmaceutical composition.

161. The method of claim 160, wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the pharmaceutical composition.

162. The method of claim 161, wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the pharmaceutical composition.

163. The method of any one of claims 1-18, wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

164. The method of any one of claims 156-162, wherein the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally.

165. The method of any one of claims 156-162, wherein the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

166. The method of any one of claims 1-18, wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

167. The method of claim 158, wherein the pharmaceutical carrier comprises water.

168. The method of any one of claims 1-18, wherein the non-naturally occurring melanocortin analog is administered to a subject prior to or after a meal.

169. The method of any one of claims 1-18, wherein the non-naturally occurring melanocortin analog is administered to a subject with a meal.

170. The method of any one of claims 1-18, wherein a therapeutically effective amount of the non-naturally occurring melanocortin analog is administered, and wherein thetherapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

171. The method of any one of claims 170, wherein the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.5 mg / kg to 10 mg / kg per body weight of the subject.

172. The method of any one of claims 1-18, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

173. The method of any one of claims 1-18, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg per body weight of the subject.

174. The method of claim 173, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3), and the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

175. The method of claim 173, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3), and the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.5 mg / kg to 10 mg / kg per body weight of the subject.

176. The method of any one of claims 1-18, wherein the non-naturally occurring melanocortin analog is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

177. The method of any one of claims 1-18, wherein the non-naturally occurring melanocortin analog is administered to the subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

178. The method of any one of claims 1 -18, wherein the anti-cancer agent and the non-naturally occurring melanocortin analog are administered simultaneously as a single composition.

179. The method of claim 178, wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the single composition.

180. The method of claim 179, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3), and wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the single composition.

181. The method of claim 180, wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the single composition.

182. The method of claim 180, wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of about 50 mg / mL, relative to a total volume of the single composition.

183. The method of claim 180, wherein the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 5 mg to about 500 mg in adose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

184. The method of claim 180, wherein the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

185. The method of claim 180, wherein the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

186. The method of any one of claims 183-185, wherein the administration is performed once per day.

187. The method of any one of claims 1 -18, wherein:the anti-cancer agent is present in a first pharmaceutical composition; andthe non-naturally occurring melanocortin analog is present in a second pharmaceutical composition.

188. The method of claim 187, wherein the first and the second pharmaceutical compositions are different and are administered sequentially.

189. The method of claim 187, wherein the first and the second pharmaceutical compositions are different and are administered simultaneously but separately.

190. The method of any one of claims 187-189, wherein the second pharmaceutical composition is administered subcutaneously.

191. The method of any one of claims 187-190, wherein the anti-cancer agent comprises a chemotherapy, and the chemotherapy is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition.

192. The method of claim 191, wherein the chemotherapy is cisplatin, and cisplatin is present in the first pharmaceutical composition in a concentration of 0.01 mg / mL to 50 mg / mL, relative to a total volume of the first pharmaceutical composition.

193. The method of claim 191, wherein the chemotherapy is 5-FU, and 5-FU is present in the first pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the first pharmaceutical composition.

194. The method of claim 191, wherein the chemotherapy is doxorubicin, and doxorubicin is present in the first pharmaceutical composition in a concentration of 0.01 mg / mL to 50, relative to a total volume of the first pharmaceutical composition.

195. The method of claim 187, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the second pharmaceutical composition.

196. The method of claim 195, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3), and wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the second pharmaceutical composition.

197. The method of claim 196, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the second pharmaceutical composition.

198. The method of claim 196, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the second pharmaceutical composition.

199. The method of claim 187, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

200. The method of claim 187, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

201. The method of claim 187, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

202. The method of any one of claims 199-201, wherein the administration is performed once per day.

203. The method of claim 187, wherein the anti-cancer agent comprises cisplatin, and wherein cisplatin is administered orally and / or intraperitoneally.

204. The method of claim 187, wherein the anti-cancer agent comprises 5-FU, and wherein 5-FU is administered orally and / or intraperitoneally.

205. The method of claim 187, wherein the anti-cancer agent comprises doxorubicin, and wherein doxorubicin is administered intraperitoneally.

206. The method of claim 187, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO:3).

207. The method of any one of claims 187-206, wherein a therapeutically effective amount of the anti-cancer agent is administered at least once per week.

208. The method of claim 207, wherein the anti-cancer agent comprises cisplatin, and the therapeutically effective amount of cisplatin is from 0.01 mg / kg to 25 mg / kg per body weight of the subject.

209. The method of claim 208, wherein the therapeutically effective amount of cisplatin is about 2.5 mg / kg per body weight of the subject.

210. The method of claim 207, wherein the anti-cancer agent comprises 5-Fll, and the therapeutically effective amount of 5-FU is from 0.1 mg / kg to 700 mg / kg per body weight of the subject.

211. The method of claim 210, wherein the therapeutically effective amount of 5-Fll is about 70 mg / kg per body weight of the subject.

212. The method of claim 207, wherein the anti-cancer agent comprises doxorubicin, and the therapeutically effective amount of doxorubicin is from 0.005 mg / kg to 50mg / kg per body weight of the subject.

213. The method of claim 212, wherein the therapeutically effective amount of doxorubicin is about 2 mg / kg per body weight of the subject.

214. The method of any one of claims 207-213, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

215. The method of any one of claims 207-213, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg per body weight of the subject.

216. The method of claim 187, wherein the anti-cancer agent comprises cisplatin, and cisplatin is administered at a dose of 0.01 mg / kg to 25 mg / kg per body weight of the subject at intervals of about 7 days, about 14 days, about 21 days, or about 28 days.

217. The method of claim 187, wherein the anti-cancer agent comprises 5-FU, and 5-FU is administered at a dose of 0.1 mg / kg to 700 mg / kg per body weight of the subject at intervals of about 7 days, about 14 days, about 21 days, or about 28 days.

218. The method of claim 187, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3), and the non-naturally occurring melanocortin analog is administered at a daily dose of 0.001 mg / kg to 25 mg / kg per body weight of the subject.

219. Use of a non-naturally occurring melanocortin analog to treat, prevent, or reduce one or more side effects associated with an anti-cancer agent in a subject, the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite, wherein the non-naturally occurring melanocortin analog is administered to the subject prior to, during, and / or after administration of the anti-cancer agent220. Use of a non-naturally occurring melanocortin analog to maintain or increase weight in a subject prior to, during, and / or after administration of an anti-cancer agent, wherein the weight of the subject is maintained or increased by preventing or reducinganorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

221. Use of a non-naturally occurring melanocortin analog to maintain or increase weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

222. The use of claim 220 or 221, wherein the subject experiences an increase in weight by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or500% compared to baseline ora control.

223. Use of a non-naturally occurring melanocortin analog to maintain or increase muscle mass, fat mass, or cardiac mass in a subject prior to, during, and / or after administration of an anti-cancer agent.

224. The use of claim 223, wherein the subject experiences an increase in muscle mass, fat mass, or cardiac mass by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

225. Use of a non-naturally occurring melanocortin analog to maintain or increase bone density in a subject prior to, during, and / or after administration of an anti-cancer agent.

226. The use of claim 225, wherein the subject experiences an increase in bone density by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

227. Use of a non-naturally occurring melanocortin analog to maintain or increase a Functional Assessment of Anorexia / Cachexia Therapy (FAACT) score in a subject prior to, during, and / or after administration of an anti-cancer agent.

228. The use of claim 227, wherein the subject experiences an increase in the FAACT score compared to baseline or control by at least 1,2, 3, 4, or 5 points.

229. Use of a non-naturally occurring melanocortin analog to stimulate appetite or reduce loss of appetite induced by an anti-cancer agent in a subject.

230. The use of claim 229, wherein the subject experiences an increase in appetite as measured by an increased food intake by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700,1800, 1900, 2000, 2500, 3000, or more calories compared to baseline a control.

231. Use of a non-naturally occurring melanocortin analog for preventing, reducing, or restoring weight loss induced by an anti-cancer agent in a subject.

232. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

233. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, the one or more side effects are selected fromthe group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

234. Use of a non-naturally occurring melanocortin analog for preventing or reducing an anti-cancer agent induced side effect in a subject having cancer.

235. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in a subject having cancer.

236. Use of a non-naturally occurring melanocortin analog prior to, during, and / or after administration of an anti-cancer agent for preventing reduction of, maintaining, or improving ECOG and / or KPS score of a subject having cancer relative to a baseline or a control.

237. The use of claim 236, wherein the subject experiences a reduction in ECOG performance score by about 1, 2, or 3 compared to baseline or control.

238. The use of claim 236, wherein the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to baseline or control.

239. Use of a non-naturally occurring melanocortin analog prior to, during, and / or after administration of an anti-cancer agent for preventing reduction of, maintaining, or improving overall survival (OS) or progression free survival (PFS) in a subject having cancer relative to a baseline or a control.

240. The use of claim 239, wherein the subject experiences an increase in OS or an increase in PFS compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

241. Use of a non-naturally occurring analog for reducing time to cancer treatment failure in a subject having cancer relative to a baseline or a control, prior to, during, and / or after administration of an anti-cancer agent.

242. Use of a non-naturally occurring melanocortin analog for increasing or maintaining body mass index (BMI) in a subject relative to a baseline or a control, prior to, during, and / or after administration of an anti-cancer agent.

243. The use of claim 242, wherein the subject experiences an increase in BMI compared to baseline or control by at least 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 points.

244. The use of claim 242 or 243, wherein the subject experiences in an increase in BMI durability compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

245. Use of a non-naturally occurring melanocortin analog for reducing a proinflammatory transcript or protein level in a subject having cancer relative to a baseline or a control, prior to, during, and / or after administration of an anti-cancer agent.

246. The use of claim 245, wherein the subject experiences a reduction in an inflammatory transcript level compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

247. The use of claim 245, wherein the subject experiences a reduction in an inflammatory protein level compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

248. The use of claim 245 or claim 329, wherein the proinflammatory transcript is a transcript selected from the group consisting of an IL1 transcript, an IL6 transcript, an IL1R1transcript, a TNFa transcript, a Selectin P transcript, a cytokine transcript, and a chemokine transcript.

249. The use of claim 245 or claim 329, wherein the proinflammatory protein is a protein selected from the group consisting of an IL1 protein, an IL6 protein, an IL1R1 protein, a TNFa protein, a Selectin P protein, a cytokine protein, and a chemokine protein.

250. The use of claim 219, wherein the use maintains or increases lean body mass, fat body mass, and / or weight of the subject relative to a baseline or a control.

251. The use of claim 229, wherein the use maintains or increases lean body mass, fat body mass, and / or body weight of the subject relative to a baseline or a control.

252. The use of claim 232, wherein the failure to respond to an antiemetic treatment further comprises clinically and / or therapeutically insufficient weight gain, muscle mass gain, fat mass gain, increased appetite, and / or increased food intake in the subject.

253. The use of claim 233, wherein the nutritional intervention further comprises nutritional supplementation.

254. The use of claim 234, wherein the side effect is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, loss of appetite, vomiting, diarrhea, nausea, and fatigue.

255. The use of claim 235, wherein the iatrogenic injury is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

256. The use of claim 236, wherein the improvement, maintenance, or prevented reduction of ECOG and / or KPS score occurs by inhibiting or reducing anorexia, weight loss,muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

257. The use of any one of claims 219-256, wherein the subject has a cancer.

258. The use of any one of claims 219-257, wherein the anti-cancer agent comprises a chemotherapy.

259. The use of claim 258, wherein the use reduces chemotherapy induced mass loss and / or wasting in the subject and increases lean body mass and body weight of the subject relative to a baseline or a control.

260. The use of claim 258, wherein the use maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and wherein the use reduces mass loss and / or wasting in the subject relative to a baseline or a control.

261. The use of any one of claims 219-236, wherein the anorexia is associated with weight loss.

262. The use of any one of claims 219-261, wherein the subject has not previously received an anti-cancer agent.

263. The use of any one of claims 219-261, wherein the subject has previously received an anti-cancer agent.

264. The use of any one of claims 219-261, wherein the subject is receiving an anticancer agent.

265. The use of any one of claims 219-264, wherein the administration of the non-naturally occurring melanocortin analog enhances tolerability of the anti-cancer agent.

266. The use of claim 265, wherein the enhanced tolerability results in a greater dosage, an increased frequency of administration, and / or an increased duration of administration of the anti-cancer agent, relative to a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

267. The use of claim 265, wherein the anti-cancer agent comprises a chemotherapy comprising at least two chemotherapeutic agents, and wherein the enhanced tolerability results in a second chemotherapeutic agent being administered to the subject during or after administration of a first chemotherapeutic agent.

268. The use of any one of claims 219-267, wherein the administration of the non-naturally occurring melanocortin analog prevents or reduces a downward titration in dosing regimen of the anti-cancer agent relative to a baseline or a control.

269. The use of claim 268, wherein the downward titration comprises a decreased dosage, a decreased frequency of administration, and / or a decreased duration of administration, compared to a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

270. The use of any one of claims 219-269, wherein the subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss prior to the administration of the non-naturally occurring melanocortin analog.

271. The use of claim 270, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by a cancer.

272. The use of claim 270, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the anti-cancer agent.

273. The use of any one of claims 219-272, wherein the subject is receiving or has received an antiemetic.

274. The use of claim 273, wherein the antiemetic is marijuana, megestrol, somatropin, or dronabinol.

275. The use of any one of claims 219-274, wherein the non-naturally occurring melanocortin analog and the anti-cancer agent are administered concurrently.

276. The use of any one of claims 219-274, wherein the non-naturally occurring melanocortin analog is administered before and / or after the anti-cancer agent.

277. The use of claim 219, wherein administration of the non-naturally occurring melanocortin analog treats, prevents or reduces the one or more side effects associated with an anti-cancer agent in a subject.

278. The use of claim 220, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

279. The use of claim 221, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing one or more side effects selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

280. The use of claim 229, wherein administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anticancer agent in the subject relative to a baseline or a control.

281. The use of claim 231, wherein administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores weight loss induced by an anti-cancer agent in the subject relative to a baseline or a control.

282. The use of claim 232, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and / or therapeutically to an antiemetic treatment, relative to a baseline or a control.

283. The use of claim 233, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects in the subject who failed to respond clinically and / or therapeutically to nutritional intervention, relative to a baseline or a control.

284. The use of claim 234, wherein administration of the non-naturally occurring melanocortin analog prevents or reduces the anti-cancer agent induced side effect in the subject, relative to a baseline or a control.

285. The use of claim 235, wherein administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the iatrogenic injury caused by an anticancer agent in the subject, relative to a baseline or a control.

286. The use of claim 236, wherein administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves ECOG and / or KPS score of the subject, relative to a baseline or a control.

287. The use of any one of claims 219-236, wherein the subject’s mass and / or weight is not more than 5% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

288. The use of any one of claims 219-236, wherein the subject’s mass and / or weight is not more than 10% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

289. The use of any one of claims 219-288, wherein the subject has an ECOG score of 1 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

290. The use of any one of claims 219-288, wherein the subject has an ECOG score of 2 or higher prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

291. The use of claim 289 or 290, wherein the use lowers the ECOG score of the subject, relative to a baseline or a control.

292. The use of any one of claims 219-291, wherein the subject’s KPS score is not more than 70 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

293. The use of any one of claims 219-291, wherein the subject’s KPS score is not more than 50 prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

294. The use of claim 292 or 293, wherein the use increases the subject’s KPS score relative to a baseline or control.

295. The use of any one of claims 219-294, wherein the use increases the subjects cumulative mass relative to a baseline or control.

296. The use of any one of claims 219-294, wherein the use reduces the subject’s rate of loss of cumulative mass relative to a baseline or control.

297. The use of any one of claims 219-294, wherein the use increases the subjects net weight gain relative to a baseline or control.

298. The use of claim 297, wherein the net weight gain is a change in weight between two or more time points.

299. The use of claim 297, wherein the net weight gain is a change in weight between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

300. The use of claim 298, wherein the two or more time points comprises an intermediate time point.

301. The use of any one of claims 219-300, wherein the use increases the subject’s cumulative food intake relative to a baseline or control.

302. The use of claim 301, wherein the cumulative food intake is a total food intake between two or more time points.

303. The use of claim 301, wherein the cumulative food intake is a total in food intake between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

304. The use of 366, wherein the two or more time points comprises an intermediate time point.

305. The use of any one of claims 219-304, wherein the use increases the subject’s BMI relative to a baseline or control.

306. The use of claim 305, wherein the increase in BMI is a change in BMI between two or more time points.

307. The use of claim 305, wherein the increase in BMI is a change in BMI between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

308. The use of claim 306, wherein the two or more time points comprises an intermediate time point.

309. The use of any one of claims 305 to 390, wherein the non-naturally occurring melanocortin analog is administered to the subject based on the subject’s BMI at the time of administration.

310. The use of claim 309, wherein the subject is administered the non-naturally occurring melanocortin analog at two or more doses based on the subject’s BMI at the time of each administration.

311. The use of claim 310, wherein the two or more doses are inversely titrated based on the subject’s BMI at the time of each administration.

312. The use of any one of claims 219-311, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I),X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y 8 (I)wherein:R1 is absent or is selected from the group consisting of cysteine, norleucine (Nie), acetylated norleucine (Ac-Nle), frans-4-guanidinyl-proline (fransPro(guan)), c / s-4-guanidinyl-proline (c / sPro(guan)), acetylated frans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated c / s-4-guanidinyl-proline (Ac-c / sPro(guan)), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, and acetylated glutamic acid;R2 is absent or is selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), fransPro(guan), c / sPro(guan), aspartic acid, glutamic acid, glycine, lysine, alanine, D-alanine, cysteine, norleucine, arginine, succinic acid, glutaric acid, methionine, and phenylalanine;R3 is absent or is selected from the group consisting of histidine, L-proline, transPro(guan), c / sPro(guan), D-valine, glutamic acid, tryptylarginine (Trp-Arg), glycine, D-leucine, D-isoleucine, tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2 / - / )-one (Aia), octohydroindole-2-carboxylic acid (Oic), 1-amino-1-cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), and indoline-2-carboxylic acid (loc),R4 is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);R5 is absent or is selected from the group consisting of arginine, homoarginine, proline, transPro(guan), c / sPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), D-histidine, D-alanine, D-aspartic acid, D-glutamic acid, cysteine, and p(l)dPhe;R6 is absent or is selected from the group consisting of L-tryptophan, D-phenylalanine, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, D-histidine, cysteine, D-Nal(1’), Aba, Ata, D-tyrosine, Pen, dPen, and D-alanine;R7 is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, ornithine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), and tetrahydro-isoquinoline-3-carboxylic acid (Tic);R8 is absent or is lysine;R9-R20 are absent;X1 is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, p-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine;X2 is absent or is D-proline;X3 is absent;Y1 is absent or is selected from the group consisting of D-valine, D-tert-leucine, L-tert-leucine, norleucine, and D-proline;Y2 is absent or is selected from the group consisting of D-proline, L-proline, Hyp, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, and glycine;Y3 is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;Y4 is absent or is D-aspartic acid or aspartic acid;Y5-Y8 are absent;the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:a disulfide bond between R1 and R7 when R1 is cysteine and R7 is cysteine;a lactam bridge between R1 and R7 when R1 is norleucine and R7 is glutamic acid;a side-chain lactam bridge between R1 or R2 and R7 when R1 or R2 is glutamic acid or aspartic acid, and R7 is lysine, Dap, or ornithine;a side-chain lactam bridge between R2 and R7 when R2 is lysine, and R7 is glutamic acid or aspartic acid;a side-chain lactam bridge between R1 or R2 and R8 when R1 or R2 is glutamic acid or aspartic acid, R8 is lysine, and R7 is proline, glycine or tryptophan;provided that:when R2 is dAsp, then R7 is not dLys;when R2-R4 is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7 is not Arg-Trp-Lys;when Y1 is dPro, Y2 is dVal, and Y3-Y8 are absent, then R4 is not dNal(2’) or R4 is dNal(2’) and the C-terminus is not modified;when R3 is Aba, Ata, or Aia, R6 is Aia, or R7 is Orn, then R4 is not dNal(2’), or R4 is dNal(2’) and R5 is not Arg;when R4 is p(CI)dPhe, then R3 is not Pro or His;when R4 is p(l)dPhe then the non-naturally occurring melanocortin analog is cyclized through a side-chain lactam bridge between R1 and R7 and at least one of R2 and R3 is Pro;when Y2-Y4 are absent, then Y1 is absent or is norleucine;when R2 is Pro or Y2 is Hyp, then R3 is not Pro;when R3, R5, or R6 is absent, then the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R1 and R7 or X1-X2 are present and are Ac-dVal-dPro;when R2-R7 is Asp-Pro-dNal(2’)-Arg-Trp-Lys (SEQ ID NO: 526) or Cys-Pro-dNal(2’)-Arg-Trp-Cys (SEQ ID NO: 527), then R1 is not Ac-Nle or Y1-Y2 is not dVal-dPro, dVal-dVal, dPro-dPro; andwhen the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between R2 and R8, then R3 is not His or Y1 is not dVal.

313. The use of any one of claims 219-236 and 373, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 10, 14, 33-39, 82-96, 108-111, 119-124, 126-135, 138, 192-199, 222-295, 408 and 413.

314. The use of any one of claims 219-236 and 373-374, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 3).

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