Orally deliverable non-naturally occurring melanocortin analogs and uses thereof for modulating weight loss

Abstract

Provided herein are methods of treating, preventing, or reducing one or more symptoms or conditions associated with metabolic dysfunction, such as obesity, in a subject in need thereof using a non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is administered orally. In some embodiments, the method comprises suppressing appetite in a subject in need thereof using a non-naturally occurring melanocortin analog in accordance with the present technology.

Description

Docket No.: 146316.8023.WO00 ORALLY DELIVERABLE NON-NATURALLY OCCURRING MELANOCORTIN ANALOGS AND USES THEREOF FOR MODULATING WEIGHT LOSS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 554,944, filed February 16, 2024; U.S. Provisional Patent Application No.63 / 557,409, filed February 23, 2024; U.S. Provisional Patent Application No.63 / 572,896, filed April 1, 2024; U.S. Provisional Patent Application No. 63 / 573,433, filed April 2, 2024; U.S. Provisional Patent Application No.63 / 632,496, filed April 10, 2024; U.S. Provisional Patent Application No. 63 / 637,285, filed April 22, 2024; U.S. Provisional Patent Application No. 63 / 640,864, filed April 30, 2024; U.S. Provisional Patent Application No.63 / 647,545, filed May 14, 2024; U.S. Provisional Patent Application No.63 / 650,368, filed May 21, 2024; U.S. Provisional Patent Application No.63 / 654,876, filed May 31, 2024; U.S. Provisional Patent Application No. 63 / 656,579, field June 5, 2024; U.S. Provisional Patent Application No. 63 / 663,689, filed June 24, 2024; U.S. Provisional Patent Application No.63 / 675,219, filed July 24, 2024; U.S. Provisional Patent Application No.63 / 681,055, filed August 8, 2024; and of U.S. Provisional Patent Application No.63 / 692,605, filed September 9, 2024, all of which are incorporated herein by reference in their entirety. INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] This application contains an ST.26 compliant Sequence Listing, which is submitted concurrently in xml format and is hereby incorporated by reference in its entirety. The .xml copy, created on February 13, 2025, is titled “146316_8023_WO00_SL.xml” and is 490,839 bytes in size. BACKGROUND

[0003] The prevalence of obesity, diabetes, and metabolic syndrome has reached pandemic proportions, and is expected to continue to rise in the next two decades. These conditions place enormous stress on healthcare systems globally. Accordingly, various -1- 170456481.42Docket No.: 146316.8023.WO00 weight loss agents have been developed in an attempt to treat such conditions. Although some weight loss agents have been approved for ongoing use, many are not sufficiently effective in achieving desired amounts or types of weight loss. Further, commonly used weight loss agents are administered subcutaneously, requiring self-administered injections on a daily or weekly basis which may cause administration site irritation and discomfort.

[0004] Accordingly, despite recent advances treatment for obesity, diabetes, and metabolic syndrome, there is a demand for novel and effective weight loss agents that may be delivered via less invasive administration routes. SUMMARY

[0005] The present technology comprises methods of reducing body weight and / or fat mass in a subject in need thereof, comprising administering to the subject a non-naturally occurring melanocortin analog.

[0006] In some embodiments, the present technology comprises a non-naturally occurring melanocortin analog comprising a sequence according to Formula (IF), R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IF), wherein: R1is Nle; R2is Asp or Glu; R3is His; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg or His; R6is Trp; R7is Orn; Y1is dVal; Y2is dPro; and -2- 170456481.42Docket No.: 146316.8023.WO00 the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7.

[0007] In some embodiments, the present technology comprises a method of reducing body weight and / or fat mass in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4(I), wherein: X1is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is selected from the group consisting of Asp, D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of D-phenylalanine (dPhe), Pro, para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys) and lysine (Lys); R8is absent, Lys, or Trp; R9is absent or Lys; Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); -3- 170456481.42Docket No.: 146316.8023.WO00 Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7when R2is dCys, R4is p(Cl)dPhe, and R7is Cys; a lactam bridge between R1or R2and any one of R7-R9when R1or R2is Asp, R4is dPhe, or p(F)dPhe, and any one of R7-R9is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, provided that: when R3is Pro, then X1and Y3are present and R4is dPhe, when R4is p(Cl)dPhe, then the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Asp at R2and Lys at R7, when R2and / or R3is Phe, then R4is Pro and R6is dPhe, when R4is dPhe and R2is Pro, then X1is present and R5is Arg, and when R4is dPhe, R2is Ala, and R3is His, then R5is Arg.

[0008] In some embodiments, the present technology comprises a method of reducing body weight and / or fat mass in an obese subject, comprising orally administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I)

[0009] In some embodiments, the present technology comprises a method of treating, preventing, or reducing hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). -4- 170456481.42Docket No.: 146316.8023.WO00

[0010] In some embodiments, the present technology comprises a method of treating, preventing, or reducing hypothalamic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0011] In some embodiments, the present technology comprises a method of treating, preventing, or reducing a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0012] In some embodiments, the present technology comprises a method of treating, preventing, or reducing a leptin deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0013] In some embodiments, the present technology comprises a method of treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0014] In some embodiments, the present technology comprises a method of treating, preventing, or reducing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0015] In some embodiments, the present technology comprises a method of treating, preventing, or reducing hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0016] In some embodiments, the present technology comprises a method of treating, preventing, or reducing a cardiovascular disease in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). -5- 170456481.42Docket No.: 146316.8023.WO00

[0017] In some embodiments, the present technology comprises a method of treating, preventing, or reducing osteoarthritis in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0018] In some embodiments, the present technology comprises a method of treating, preventing, or reducing a cancer in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0019] In some embodiments, the present technology comprises a method of treating, preventing, or reducing erectile dysfunction in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0020] In some embodiments, the present technology comprises a method of treating, preventing, or reducing body weight gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0021] In some embodiments, the present technology comprises a method of maintaining body weight after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0022] In some embodiments, the present technology comprises a method of treating, preventing, or reducing fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0023] In some embodiments, the present technology comprises a method of treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). -6- 170456481.42Docket No.: 146316.8023.WO00

[0024] In some embodiments, the present technology comprises a method of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0025] In some embodiments, the present technology comprises a method of preserving or improving kidney function in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin 4 receptor agonist to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

[0026] In some embodiments, the present technology comprises a method of reducing body weight and / or fat mass in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IF).

[0027] In some embodiments, the present technology comprises a method of treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IF).

[0028] In some embodiments, the present technology comprises a method of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IF).

[0029] A method of preserving or improving kidney function in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IF). BRIEF DESCRIPTION OF THE DRAWINGS -7- 170456481.42Docket No.: 146316.8023.WO00

[0030] FIG. 1 illustrates 24-hour plasma concentrations of non-naturally occurring melanocortin analogs of the present technology following oral administration of Compound Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14; C2) to Cynomolgus Monkeys at 30.0 mg / kg.

[0031] FIGS. 2A-2F illustrates 24-hour plasma concentrations of non-naturally occurring melanocortin analogs of the present technology following PO administration of Compound E (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43; O10)) to Cynomolgus Monkeys at 3 mg / kg, 10.0 mg / kg, 30.0 mg / kg, or 60 mg / kg.

[0032] FIGS. 3A-3C illustrates 24-hour plasma and cerebrospinal fluid (CSF) concentrations of non-naturally occurring melanocortin analogs of the present technology following SC administration of Compound E of FIGS.2A-2F to Rats at 1.0 mg / kg, 3.0 mg / kg, and 10.0 mg / kg.

[0033] FIGS. 4A-4G illustrate plasma and CSF concentrations of non-naturally occurring melanocortin analogs of the present technology. FIGS. 4A-4G illustrate 24-hour plasma and CSF concentrations of non-naturally occurring melanocortin analogs following IP administration of Compound E of FIGS.2A-2I to Rats at 1.0 mg / kg, 3.0 mg / kg, and 10.0 mg / kg. FIGS.4H-4K illustrate 24-hour plasma and cerebrospinal fluid (CSF) concentrations of non-naturally occurring melanocortin analogs of the present technology following IP administration of Compound E (“O10”) at 10 mg / kg relative to setmelanotide. The shaded areas of 4D-4G represent the drug exposure at concentrations greater than the EC50. Area under the depicted lines represent the non-naturally occurring melanocortin analog exposure at concentrations greater than the EC50.

[0034] FIGS. 5A-5C illustrates 24-hour plasma and CSF concentrations of non- naturally occurring melanocortin analogs of the present technology following PO administration of Compound E of FIGS.2A-2I to Rats at 10.0 mg / kg and 30.0 mg / kg.

[0035] FIGS.6A and 6B show preliminary weight loss and daily food intake results in animals administered 3 mg / kg of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2; SEQ ID NO: 43). -8- 170456481.42Docket No.: 146316.8023.WO00

[0036] FIGS.7A-7D show food intake (g) at baseline in monkeys having diet-induced obesity (n=6) from 0.5 to 72 hours after saline administration at day 1 (D1). FIG.7A shows net weight of food intake among individual monkeys. FIG.7B shows net weight of food intake for each group average. FIG.7C shows cumulative food intake among individual monkeys. FIG.7D shows cumulative food intake for each group average.

[0037] FIGS. 8A-8H show food intake (g) in the same monkeys as FIGS. 7A-7D administered 1 mg / kg or 3 mg / kg of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2; SEQ ID NO: 43) on day 8 (D8). FIG.8A shows net weight of food intake among individual monkeys at day 8 (D8). FIG.8B shows net weight of food intake for each group average of monkeys administered the same compound at D8. FIG. 8C shows cumulative food intake among individual monkeys of FIG. 8A at D8. FIG. 8D shows cumulative food intake for each group average of monkeys of FIG.8C administered the same compound at D8. FIG. 8E shows net weight of food intake among individual monkeys at day 12 (D12). FIG.8F shows net weight of food intake for each group average of monkeys administered the same compound at D12. FIG. 8G shows cumulative food intake among individual monkeys at D12. FIG.8H shows cumulative food intake for each group average of monkeys administered the same compound at D12.

[0038] FIGS. 9A and 9B show food intake patterns in diet-induced obese monkeys administered saline, compared to the same monkeys administered 1mg / kg or 3 mg / kg of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43) in FIGS. 8A-8H.

[0039] FIGS. 10A-10C show changes in daily caloric intake (FIG. 10A), cumulative caloric intake (FIG.10B), percent change in caloric consumption from baseline through day 6 (FIG.10C) for diet-induced obese monkeys orally administered 10 mg / kg of or O10 (Ac- Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43) (QD: once daily).

[0040] FIGS. 11A-11P show changes in cumulative caloric intake, percent change in caloric consumption from baseline, food intake of a normal diet, food intake of a high fat diet, food intake in calories, and food preference for diet-induced obese monkeys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: -9- 170456481.42Docket No.: 146316.8023.WO00 43), saline, or semaglutide (sema) (PO: oral administration; SC: subcutaneous administration; QD: once daily; BID: twice daily; BIW: twice weekly).

[0041] FIG. 11Q shows normalized cumulative food consumption in rats subcutaneously administered 1 mg.kg or 3 mg / kg of MC4R selective agonists (A07D (Ac- Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2; SEQ ID NO: 48), O7 (Ac-Nle-c[Glu-Pro- p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 106), or O11 (Ac-Nle-c[Glu-Pro-dPhe- Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 62)) (n=5 per group) or MC3R / MC4R co-agonists (O10) (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43) (n=5) compared to saline controls (n=4).

[0042] FIG. 11R shows an average percent change in caloric consumption from baseline in moneys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]- dVal-dPro-NH2; SEQ ID NO: 43) at a starting dose of 10 mg / kg and increased to 20 mg / kg and 30 mg / kg.

[0043] FIGS.12A-12K show changes in body weight for diet included obese monkeys administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43) orally and / or subcutaneously. Shown are changes in daily body weight and percent change in body weight from baseline (FIGS. 12A and 12B) for the diet-induced obese monkeys of FIGS.11A-11P through day 8. FIGS.12C shows percent change in body weight as a percentage of initial weight for the monkeys of FIGS. 12A and 12B through day 15 compared to those administered semaglutide (sema) alone. FIG. 12D shows body weight change as a percentage of initial weight in diet induced obese monkeys orally administered O10 at increasing dosages or administered semaglutide. FIG. 12E shows body weight change in the monkeys of FIG.12D. FIG.12F shows body weight change as a percentage of initial weight in diet included obese monkeys administered O10 at changing doses and administration frequencies. FIG.12G shows body weight changes as a percentage of initial in monkeys orally administered O10 (PO) with dose changes or semaglutide. FIG. 12H shows body weight change after removal of O10 administration for the monkeys of FIG. 12G. FIG.12I shows percent change in body weight as a percentage of initial weight for diet induced obese monkeys orally administered O10 followed by subcutaneous administration. FIG. 12J shows body weight percent change after removal of O10 treatment in monkeys. -10- 170456481.42Docket No.: 146316.8023.WO00 FIG.12K shows body weight percent change at an oral O10 dosing regimen in accordance with the embodiments of the present technology.L(PO: oral administration; SC: subcutaneous administration; QD: once daily; BID: twice daily; BIW: twice weekly).

[0044] FIG. 12L shows changes in body weight as a percentage of day 1 in rats administered saline, a melanocortin 4 receptor (MC4R) selective agonist (A07D (Ac-Nle- c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2), O7 (Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp- Orn]-dVal-dPro-NH2; SEQ ID NO: 106), or O11 (Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal- dPro-NH2; SEQ ID NO: 62)), or an equal dose of a melanocortin 3 receptor (MC3R) / MC4R coagonist ((O10)(Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43)).

[0045] FIG. 12M shows an average percent change in normalized body weight from baseline in moneys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]- dVal-dPro-NH2; SEQ ID NO: 43) at a starting dose of 10 mg / kg and increased to 20 mg / kg and 30 mg / kg.

[0046] FIGS.13A-13N show changes in body composition for the diet-induced obese monkeys of FIGS.10A-10C.

[0047] FIGS. 14A-14D show blood chemistry levels in diet-induced obese monkeys orally administered 10 mg / kg O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2; SEQ ID NO: 43) once daily for week 1, 20mg / kg O10 once daily for week 2, and 15 mg / kg O10 twice daily weeks 3 and 4.

[0048] FIGS. 15A-15C show measurements of systolic blood pressure (FIG. 15A), diastolic blood pressure (FIG. 15B), and heart rate (FIG. 15C) in rats subcutaneously administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43) at 0.5 mg / kg, 1 mg / kg, or 3 mg / kg.

[0049] FIGS.16A-16D show measurements of diastolic blood pressure (DBP), systolic blood pressure (SBP), heart rate, and heart rate corrected QT interval (QTc) in rats administered setmelanotide at 0.5 mg / kg, 1.0 mg / kg, 3.0 mg / kg, or 6.0 mg / kg, relative to control rats administered saline. -11- 170456481.42Docket No.: 146316.8023.WO00

[0050] FIGS.17A-17H show measurements of normalized heart rate (FIG.17A), QTc (FIG. 17B), systolic blood pressure (FIG. 17C), diastolic blood pressure (FIG. 17D), mean blood pressure (FIG.17E), QT interval (FIG.17F), QRS internal (FIG.17G), and RR internal (FIG.17H) in male cynomolgus monkeys orally (PO) administered O10 (Ac-Nle-c[Glu-His- p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43) at 3, 10, 30, or 60 mg / kg, relative to those subcutaneously (SC) administered setmelanotide at 3 mg / kg or orally administered saline. (N = 3 to 5 animals per group).

[0051] FIG. 18 shows results of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2; SEQ ID NO: 43) screened for binding against a panel of 87 targets at 10µM. X- axis represents the percent inhibition of control at 10µM. (MC1R: melanocortin 1 receptor; MC4R: melanocortin 4 receptor).

[0052] FIG. 19 shows exemplary adipose tissue staining in diet-induced obese monkeys orally administered O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2; SEQ ID NO: 43) at 10 mg / kg.

[0053] FIG. 20 shows plasma concentration of O10 (Ac-Nle-c[Glu-His-p(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2; SEQ ID NO: 43) in monkeys orally (PO) administered 3mg / kg, 10 mg / kg, 30 mg / kg, or 60 mg / kg O10. DETAILED DESCRIPTION

[0054] The present technology comprises methods of treating, preventing, or reducing one or more symptoms or conditions associated with metabolic dysfunction in a subject in need thereof using a non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is administered orally. In some embodiments, the method comprises suppressing appetite in a subject in need thereof using a non-naturally occurring melanocortin analog in accordance with the present technology. In some embodiments, the method comprises promoting fat loss in a subject in need thereof using a non-naturally occurring melanocortin analog in accordance with the present technology. In some embodiments, the method comprises reducing body weight and / or fat mass in a subject in need thereof using a non-naturally occurring melanocortin analog, or a pharmaceutical composition thereof, of the present technology. -12- 170456481.42Docket No.: 146316.8023.WO00

[0055] 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 disclosed 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.

[0056] 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 any description, method, system, or process, may be executed in any order and are not limited to the order presented. Moreover, any of the steps or functions thereof may be outsourced to or performed by one or more third parties. Definitions

[0057] 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.

[0058] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., 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.

[0059] The term “about” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by acceptable levels in -13- 170456481.42Docket No.: 146316.8023.WO00 the art. Typically, such variation may be as much 10% above and below a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length and such variation may be influenced by standard applicable measurement practices. 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.

[0060] The terms “administering” or “administer” include delivery of therapies (e.g., combination therapies, non-naturally occurring melanocortin analogs (also referred to herein as peptides and synthetic peptides), 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.

[0061] 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.

[0062] 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.

[0063] As used herein, a “pharmaceutically acceptable carrier” of the first or the 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 -14- 170456481.42Docket No.: 146316.8023.WO00 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 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.

[0064] The term “weight loss agent” refers to a therapeutic agent useful for the treatment or prevention of metabolic dysfunction or one or more symptoms associated with metabolic dysfunction in a subject. In some embodiments, such weight loss agents may be effective to treat, reduce, prevent, or otherwise be useful for a subject having a disease or condition that is not metabolic dysfunction, or besides metabolic dysfunction. The present technology is expected to be useful for subjects that may receive, have received, or are receiving one or more doses of a weight loss agent regardless of the underlying disease or condition that the subject has or develops.

[0065] 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., metabolic dysfunction), 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 or reduction (e.g. by more than 10%, -15- 170456481.42Docket No.: 146316.8023.WO00 20%, 30%, 40%, 50%, or more than 60% of the baseline of glucose levels before administration) of circulating glucose levels (2) inhibiting or reducing rate of fat mass gain, (3) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with a pathology related to or caused in part by metabolic dysfunction, (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) an increase in the oxidation of lipids or carbohydrates by at least by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or at least 80% relative to the initial oxidation rate, (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 loss rate) in the rate of lean muscle mass loss, (9) an increase in lean muscle mass, (10) a reduction in mortality, (11) an increase in the response rate, the durability of response, or number of patients who respond, (12) ) a stabilization or reduction (e.g. by more than 10%, 20%, 30%, 40%, 50%, or more than 60% of the baseline of lactate levels before administration) of circulating lactate levels, (13) a decrease in the need for surgery (e.g. gastric bypass, liposuction, sleeve gastrectomy, bariatric surgery), and (14) preventing or reducing organ burden induced by metabolic dysfunction. 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.

[0066] As used herein, the term “prevent,” “preventing,” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

[0067] 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 -16- 170456481.42Docket No.: 146316.8023.WO00 from one individual to another. An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study.

[0068] The term “after administration” refers to any duration of time after the non- naturally occurring melanocortin analog or pharmaceutical composition thereof, and / or the weight loss 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 administration” refers to any duration of time before the non-naturally occurring melanocortin analog or pharmaceutical composition thereof, and / or the weight loss 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.

[0069] 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.

[0070] 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 metabolic dysfunction.

[0071] The term “control subject,” as used herein, refers to any subject used as a basis for comparison to the subject (e.g., test subject). A control subject includes, but is not limited to, 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. -17- 170456481.42Docket No.: 146316.8023.WO00

[0072] “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.

[0073] 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 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 -18- 170456481.42Docket No.: 146316.8023.WO00 appearance or function (including activation or deactivation of receptor activity) of the melanocortin pharmacophore core sequence peptide.

[0074] A “melanocortin receptor agonist” or “melanocortin agonist” is a naturally occurring substance or manufactured drug substance or composition that may interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor.

[0075] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating, and the like.

[0076] The “peptides” of the present technology 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.

[0077] 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.

[0078] 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- -19- 170456481.42Docket No.: 146316.8023.WO00 or C-terminus, and the like, thereby providing for improved stability and formulation, resistance to protease degradation, and the like.

[0079] “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 α-amino acids differ in the side-chain moiety that is attached to the α-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 Synthetic Peptides: 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 Synthetic Peptides: 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.

[0080] 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 disclosed 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. -20- 170456481.42Docket No.: 146316.8023.WO00

[0081] 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.

[0082] In the peptides of the present technology, 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; “Gln” is glutamine; “Glu” is glutamic acid; “His” is histidine; “Ile” is isoleucine; “Leu” is leucine; “Lys” is lysine; “Met” is methionine; “Phe” is phenylalanine; “Pro” is proline; “Ser” is serine; Thr is threonine; “Trp” is tryptophan; “Tyr” is tryosine; and “Val” 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 “lPhe” is L-phenylalanine; “D-Phe” or “dPhe” is D- phenylalanine; dVal is D-valine; dPro is D-proline; “D- / L-Phe” or “d / lPhe” is D-phenylalanine, L-phenylalanine, or combinations thereof; “Phe” is also D-phenylalanine, L-phenylalanine, or combinations thereof, and so on.

[0083] An alpha (α)-amino acid has the generic formula H2N—CαHR—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 α-carbon). Other types of amino acids exist when the amino group is attached to a different carbon atom. For example, beta (β)-amino acids, the carbon atom to which the amino group is attached is separated from the carboxylate group by one carbon atom, Cβ.

[0084] When β-amino acids are incorporated into peptides, two main types of β- peptides exist: those with the side chain residue, R, on the carbon next to the amine are called β3peptides and those with the side chain residue on the carbon next to the carbonyl group are called β2amino acids. Further, β-amino acids may adopt L- or D- stereochemistry. Unless otherwise indicated, all β-amino acid abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof. -21- 170456481.42Docket No.: 146316.8023.WO00

[0085] Gamma (γ)-amino acids are amino acids where the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms.

[0086] 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 as “c.” “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, i.e., —CO—NH2.

[0087] Additional abbreviations are used herein as follows: Nle is norleucine; Nal(2’) is 2′-naphthylalanine; Nal(1') is 1′-naphthylalanine; Tle is tert-leucine; Orn is ornithine; cisPro(guan) is cis-4-guanidyl-proline; transPro(guan) is trans-4-guanidyl-proline; p(Cl)dPhe is para-chloro-phenylalanine; and p(F)dPhe is para-fluoro-phenylalanine.

[0088] 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.”

[0089] 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.

[0090] An “amine” includes compounds that contain an amine group (—NH2).

[0091] 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.

[0092] 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.”

[0093] “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 -22- 170456481.42Docket No.: 146316.8023.WO00 of the melanocortin peptide by physiological enzymes and other factors, in such a manner or to a degree that side effects appear. According to one aspect, a 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 melanocortin analog that lacks a C-terminal extension.

[0094] As used herein, a “composition” refers to a mixture of the active ingredient with other chemical components.

[0095] 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

[0096] The non-naturally occurring melanocortin analogs of the present technology may comprise a non-naturally occurring melanocortin analog or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Non-naturally occurring melanocortin analogs of the present technology may be selective for the melanocortin 4 receptor (MC4R) and / or melanocortin 3 receptor (MC3R) over other melanocortin receptors, i.e., the melanocortin 1 receptor (MC1R), the melanocortin 2 receptor (MC2R), and the melanocortin 5 receptor (MC5R). Some of the non-naturally occurring melanocortin analogs may bind the MC4R with greater affinity than the MC3R. Alternatively, some melanocortin analogs may bind the MC3R with the same or generally similar affinity as the MC4R.

[0097] The non-naturally occurring melanocortin analogs of the present technology may be full agonists for one or more melanocortin receptors. A full agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect (Emax) agonist value of greater than or equal to 85%. -23- 170456481.42Docket No.: 146316.8023.WO00

[0098] The non-naturally occurring melanocortin analogs of the present technology may be partial agonists. A partial agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect Emax agonist value of less than 85%.

[0099] If a non-naturally occurring melanocortin analog’s Emax agonist value is greater than it’s Emax antagonist value, then the non-naturally occurring melanocortin analog may be classified as an agonist (e.g., a full agonist or a partial agonist).

[0100] The non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC4R agonist (ii) a full MC3R agonist; and (iii) a partial MC3R agonist with no MC3R antagonist activity. In some embodiments, the non-naturally occurring melanocortin is a full MC4R agonist. In some embodiments, the non-naturally occurring melanocortin agonist is a full MC3R agonist and a full MC3R agonist. In some embodiments, the non-naturally occurring melanocortin analog is a full MC4R agonist and partial MC3R agonist with no MC3R antagonist activity. In some embodiments, the non- naturally occurring melanocortin analogs of the present technology have an MC3R Emax agonist value of 50-84%. In some embodiments, the non-naturally occurring melanocortin analogs of the present technology have a MC3R:MC4R half maximal effective concentration (EC50) selectivity ratio of less than or equal to 49. In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise non-naturally occurring MC4R agonists or non-naturally occurring MC3R agonists.

[0101] The non-naturally occurring melanocortin analogs in accordance with the present technology may have structural features that impart specific properties on the analogs, such as, for example, degradation resistance, enhanced epithelial, gastrointestinal, and / or blood brain barrier transport, and binding affinity for the MC4R and / or MC3R. For example, in some embodiments, the non-naturally occurring melanocortin analogs comprise one or more of (i) blood brain barrier passage capabilities, (ii) one or more pharmaceutical- like pharmacokinetic measurements (e.g., a pharmacokinetic measurement of a weight loss agent pharmaceutical composition or an oral non-naturally occurring melanocortin analog pharmaceutical), (iii) degradation resistance; (iv) equipotency on MC3R and MC4R activity, or (v) oral potency. In some embodiments, the oral potency is greater than a subcutaneous administration potency for an equivalent dose. In some embodiments, the non-naturally -24- 170456481.42Docket No.: 146316.8023.WO00 occurring melanocortin analogs comprise two or more of (i)-(v). In some embodiments, he non-naturally occurring melanocortin analogs comprise each of (i)-(v). Accordingly, in some embodiments, the non-naturally occurring melanocortin analogs have one or more beta hairpin (β-hairpin) and / or beta turn (β-turn) structures. The presence of amino acids that are structurally rigid, such as, for example, Pro, dPro, transPro(guan), and cisPro(guan), may lead to formation of β-hairpin and / or β-turn structures in the non-naturally occurring melanocortin analog. Additionally, disulfide bridges (e.g., cyclization via disulfide bond) may induce and / or stabilize beta-turn structures of the non-naturally occurring melanocortin analogs. In general, cyclization and D-amino acids may induce and / or stabilize beta-turns. Further, in some embodiments, melanocortin analogs include a D-valine-D-proline (dVal- dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation.

[0102] The presence of certain structural features may impart the non-naturally occurring melanocortin analogs of the present technology with specific binding properties. For example, inclusion of p(F)dPhe or dPhe at the R4position may result in enhanced binding and activation of the melanocortin 4 receptor. Accordingly, melanocortin analogs having p(F)dPhe or dPhe at the R4position may be full agonists on MC4R. Further, inclusion of His at the R3position may result in full agonism on MC3R as well. By contrast, inclusion of His at the R3position may decrease activity on the melanocortin 3 receptor, resulting in only partial agonism on MC3R.

[0103] Non-naturally occurring melanocortin analogs in accordance with the present technology may induce or increase body weight and / or fat mass loss in a subject in need thereof while reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. Additionally, the non-naturally occurring melanocortin analogs of the present technology may avoid cardiac activation typically seen in conventional melanocortin peptide and small molecule agonists. For example, a subject may maintain a stable heart rate, systolic blood pressure, and / or diastolic blood pressure following administration of a melanocortin analog of the present technology.

[0104] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I): -25- 170456481.42Docket No.: 146316.8023.WO00 X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4(I), wherein: X1is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is selected from the group consisting of Asp, D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of D-phenylalanine (dPhe), Pro, para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys) and lysine (Lys); R8is absent, Lys, or Trp; R9is absent or Lys; Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: -26- 170456481.42Docket No.: 146316.8023.WO00 a disulfide bond between R2and R7when R2is dCys, R4is p(Cl)dPhe, and R7is Cys; a lactam bridge between R1or R2and any one of R7-R9when R1or R2is Asp, R4is dPhe, or p(F)dPhe, and any one of R7-R9is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, provided that: when R3is Pro, then X1and Y3are present and R4is dPhe, when R4is p(Cl)dPhe, then the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Asp at R2and Lys at R7, when R2and / or R3is Phe, then R4is Pro and R6is dPhe, when R4is dPhe and R2is Pro, then X1is present and R5is Arg, and when R4is dPhe, R2is Ala, and R3is His, then R5is Arg.

[0105] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I), wherein: X1is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is selected from the group consisting of Asp, D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of D-phenylalanine (dPhe), Pro, para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); -27- 170456481.42Docket No.: 146316.8023.WO00 R6is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys) and lysine (Lys); R8is absent, Lys, or Trp; R9is absent or Lys; Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7when R2is dCys, R4is p(Cl)dPhe, and R7is Cys; a lactam bridge between R1or R2and any one of R7-R9when R1or R2is Asp, R4is dPhe, or p(F)dPhe, and any one of R7-R9is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 50); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 51); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 52); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 53); -28- 170456481.42Docket No.: 146316.8023.WO00 Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 54); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 59); Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 60); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 65); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 67); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 70); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77); -29- 170456481.42Docket No.: 146316.8023.WO00 Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 81); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 83); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 87); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 88); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 89); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 90); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 91); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 92); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 95); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 96); Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 98); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 101); -30- 170456481.42Docket No.: 146316.8023.WO00 Ac-Nle-c[Asp-Pro-dPhe-Pro-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 103); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 105); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 106); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 107); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 109); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 111); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 112); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 113); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 114); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 115); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 116); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 117); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 123); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125); -31- 170456481.42Docket No.: 146316.8023.WO00 Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 126); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 127); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 128); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 129); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 130); Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 131); Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 132); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 133); Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 134); Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 135); Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 136); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 137); Ac-Nle-c[Asp-His-p(Cl)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 138); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 139); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 140); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 141); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 142); Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 143); Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 144); Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 145); Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 146); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 147); Ac-Nle-c[Asp-dHis-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 148); Ac-Nle-c[Asp-Phe-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 149); -32- 170456481.42Docket No.: 146316.8023.WO00 Ac-Nle-c[Asp-Gln-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 150); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 151); Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 152); Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 153); Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 154); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 155); Ac-Nle-c[Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 156); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 157); Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 158); Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 159); and Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 160).

[0106] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) wherein R4is dPhe or p(F)dPhe. When R4is dPhe or p(F)dPhe in the sequence of Formula (I), then R9is absent. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IA): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4(IA), wherein: X1is absent or is selected from the group consisting of Nle, Arg, and dArg; R1is selected from the group consisting of Nle, Arg, dArg, Asp, Ala, Lys, dLys, His, and dHis; R2is selected from the group consisting of Asp, Ala, dAla, Pro, and Glu R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); -33- 170456481.42Docket No.: 146316.8023.WO00 R6is Trp or dNal(2’); R7is selected from the group consisting of Pro, Orn, and Lys; R8is absent or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn.

[0107] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4(IA), wherein: X1is absent or is selected from the group consisting of Nle, Arg, and dArg; R1is selected from the group consisting of Nle, Arg, dArg, Asp, Ala, Lys, dLys, His, and dHis; R2is selected from the group consisting of Asp, Ala, dAla, Pro, and Glu R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp or dNal(2’); -34- 170456481.42Docket No.: 146316.8023.WO00 R7is selected from the group consisting of Pro, Orn, and Lys; R8is absent or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, provided that: when R3is Pro, then X1and Y3are present and R4is dPhe, when R4is dPhe and R2is Pro, then X1is present and R5is Arg, and when R4is dPhe, R2is Ala, and R3is His, then R5is Arg.

[0108] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA), wherein: X1is absent or is selected from the group consisting of Nle, Arg, and dArg; R1is selected from the group consisting of Nle, Arg, dArg, Asp, Ala, Lys, dLys, His, and dHis; R2is selected from the group consisting of Asp, Ala, dAla, Pro, and Glu R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); -35- 170456481.42Docket No.: 146316.8023.WO00 R6is Trp or dNal(2’); R7is selected from the group consisting of Pro, Orn, and Lys; R8is absent or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 50); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 51); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 52); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 54); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 58); -36- 170456481.42Docket No.: 146316.8023.WO00 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 67); Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 81); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 83); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 87); -37- 170456481.42Docket No.: 146316.8023.WO00 Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 88); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 89); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 90); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 91); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 92); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 95); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 96); Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[Asp-Pro-dPhe-Pro-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 106); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 107); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 109); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 111); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 112); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 113); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 114); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 115); -38- 170456481.42Docket No.: 146316.8023.WO00 Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 116); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 117); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 123); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125); Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 158); Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 159); and Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 160).

[0109] Further, when the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IA) wherein R4is dPhe or p(F)dPhe, then R8may also be absent. Additionally, the sequence of Formula (I) or (I) may be cyclized through a lactam bond between R2and R7. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IB), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2is Asp or Glu; R3is selected from the group consisting of His, dHis, Pro, and Gln; -39- 170456481.42Docket No.: 146316.8023.WO00 R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp or dNal(2’); R7is Orn or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R2and R7when R2is Asp and R7is Lys; and lactam bridge between Asp or Glu at R2and Orn or Lys at R7.

[0110] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IB), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2is Asp or Glu; R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); -40- 170456481.42Docket No.: 146316.8023.WO00 R6is Trp or dNal(2’); R7is Orn or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between Asp or Glu at R2and Orn or Lys at R7, provided that when R3is Pro, then X1and Y3are present and R4is dPhe,

[0111] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2is Asp or Glu; R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp or dNal(2’); R7is Orn or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; -41- 170456481.42Docket No.: 146316.8023.WO00 Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between Asp or Glu at R2and Orn or Lys at R7, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 50); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 51); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 52); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 54); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 67); -42- 170456481.42Docket No.: 146316.8023.WO00 Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 81); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 83); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 87); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 88); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 89); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 90); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 91); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 92); -43- 170456481.42Docket No.: 146316.8023.WO00 Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 95); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 96); Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[Asp-Pro-dPhe-Pro-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 106); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 107); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 109); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 111); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 112); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 113); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 114); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 115); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 116); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 117); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 120); -44- 170456481.42Docket No.: 146316.8023.WO00 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 123); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); and Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125),

[0112] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (I)-(IB) wherein R4is p(F)dPhe. In further embodiments, R3is His, R5is Arg, and R6is Trp. Accordingly, in some embodiments, the sequence of any one of Formulae (I)-(IB) is a sequence of Formula (IC): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IC), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2is Asp or Glu; R3is His; R4is p(F)dPhe; R5is Arg; R6is Trp; R7is Orn or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and -45- 170456481.42Docket No.: 146316.8023.WO00 the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between Asp or Glu at R2and Orn or Lys at R7.

[0113] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IC), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2is Asp or Glu; R3is His; R4is p(F)dPhe; R5is Arg; R6is Trp; R7is Orn or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R2and R7when R2is Asp and R7is Lys; and a lactam bridge between Asp or Glu at R2and Orn or Lys at R7. -46- 170456481.42Docket No.: 146316.8023.WO00

[0114] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of any one of Formulae (I)-(IB) wherein R4is dPhe. Accordingly, in some embodiments, the sequence of any one of Formulae (I)-(IB) is a sequence of Formula (ID): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3(ID), wherein: X1is absent or norleucine (Nle); R1is Nle or Asp; R2is selected from the group consisting of Asp, Glu, and Pro; R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp; R7is selected from the group consisting of Orn, Lys, and Pro; R8is absent or Lys; Y1is dVal or dPro; Y2is dVal or dPro; Y3is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn.

[0115] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID): -47- 170456481.42Docket No.: 146316.8023.WO00 X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3(ID), wherein: X1is absent or norleucine (Nle); R1is Nle or Asp; R2is selected from the group consisting of Asp, Glu, and Pro; R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp; R7is selected from the group consisting of Orn, Lys, and Pro; R8is absent or Lys; Y1is dVal or dPro; Y2is dVal or dPro; Y3is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, provided that: when R3is Pro, then X1and Y3are present, when R2is Pro, then X1is present and R5is Arg.

[0116] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID), wherein: -48- 170456481.42Docket No.: 146316.8023.WO00 X1is absent or norleucine (Nle); R1is Nle or Asp; R2is selected from the group consisting of Asp, Glu, and Pro; R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp; R7is selected from the group consisting of Orn, Lys, and Pro; R8is absent or Lys; Y1is dVal or dPro; Y2is dVal or dPro; Y3is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 67); -49- 170456481.42Docket No.: 146316.8023.WO00 Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 95); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 107); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 109); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 111); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); and Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125).

[0117] In some embodiments, when the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) or (IA) wherein R4is dPhe or p(F)dPhe, then R8is present. In further embodiments, R4is dPhe. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IE): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IE), wherein: X1is absent or selected from the group consisting of Nle, Arg, and dArg; R1is Asp; R2is dAla or Ala; R3is His; R4is dPhe; -50- 170456481.42Docket No.: 146316.8023.WO00 R5is Arg; R6is Trp; R7is Lys; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R1and Lys at R7.

[0118] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IE): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IE), wherein: X1is absent or selected from the group consisting of Nle, Arg, and dArg; R1is Asp; R2is dAla or Ala; R3is His; R4is dPhe; R5is Arg; R6is Trp; R7is Lys; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R1and Lys at R7.

[0119] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I) that is cyclized between Asp or Glu at R2and Orn at -51- 170456481.42Docket No.: 146316.8023.WO00 R7. In further embodiments, R3is His and R4is p(F)dPhe or p(Cl)dPhe. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IF): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IF), wherein: R1is Nle; R2is Asp or Glu; R3is His; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg or His; R6is Trp; R7is Orn; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7.

[0120] In some embodiments, the non-naturally occurring melanocortin analog compirses a sequence of Formula (IF): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IF), wherein: R1is Nle; R2is Asp or Glu; R3is His; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg or His; R6is Trp; -52- 170456481.42Docket No.: 146316.8023.WO00 R7is Orn; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7.

[0121] In some embodiments, the non-naturally occurring melanocortin analog of any one of Formulae (I)-(IF) has one or more beta hairpin (β-hairpin) and / or beta turn (β-turn) structures. In some embodiments, the presence of Pro, dPro, transPro(guan), and / or cisPro(guan), provides the β-hairpin and / or β-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 β-hairpin and / or β-turn structures of the non-naturally occurring melanocortin analog.

[0122] As will be appreciated by the skilled artisan, non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(IF), have an N- terminus and a C-terminus. The melanocortin analogs of the present technology are written beginning with the N-terminus at the left-most amino acid residue and ending with the C- terminus at the right most residue. Accordingly, the N-terminus of a non-naturally melanocortin analog comprising a sequence of any one of Formulae (I)-(IF) may be at X1or R1. Analogously, the C-terminus of a non-naturally occurring melanocortin analog comprising a sequence of any one of Formulae (I)-(IF) may be at any of R7, R8, R9, Y1, Y2, Y3, and Y4.

[0123] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group. In some embodiments, the acyl group is acetyl ).

[0124] In someof the non-naturally occurring melanocortin analog, if present, is not modified. -53- 170456481.42Docket No.: 146316.8023.WO00

[0125] In the sequence of any one of Formulae (I)-(IF), Y1Y2Y3Y4or a fragment thereof represents a C-terminus of the non-naturally occurring melanocortin analog. In some embodiments, Y1and Y2are present and Y3-Y4are absent. In some embodiments, Y3-Y4are absent, and Y1is D-valine and Y2is D-proline. In some embodiments, Y3-Y4are absent, and Y1is D-proline and Y2is D-valine. In some embodiments, Y3-Y4are absent, and Y1is D-tert-leucine and Y2is D-proline.

[0126] In some embodiments, Y1-Y3are present and Y4is absent. In some embodiments, Y4is absent and Y1is D-proline, Y2is D-valine, and Y3is D-proline. In some embodiments, Y4is absent, and Y1is D-tert-leucine, Y2is D-tert-leucine, and Y3is D-valine.

[0127] In some embodiments, Y1-Y4are present. In some embodiments, Y1-Y4are present and Y1is D-valine, Y2is D-valine, Y3is D-valine, and Y4is D-proline.

[0128] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide In the sequence of any one of Formulae (I)-(IF), a non-naturallywith a C- terminus modified by an amide may be represented by a terminal -NH2.

[0129] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of any one of Formulae (I)-(IF), a non- naturally occurring melanocortin analog with an unmodified C-terminus may be represented by -OH.

[0130] Non-naturally occurring melanocortin analogs comprising a sequence of any one of Formulae (I)-(IF) are 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 R2and R7when R2is dCys, R4is p(Cl)dPhe, and R7is Cys; a lactam bridge between R1or R2and any one of R7-R9when R1or R2is Asp, R4is dPhe, or p(F)dPhe, and any one of R7-R9is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn. -54- 170456481.42Docket No.: 146316.8023.WO00

[0131] In some embodiments of the sequence of any one of Formulae (I)-(IF), R3is His. In further embodiments, R3is His and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between the Asp at R2and the Lys at R7. In still further embodiments, R4is p(F)dPhe or dPhe.

[0132] In some embodiments, X1, Y3, and Y4are all absent. In further embodiments, R1is selected from Nle, Ala, Arg, dArg, Lys, dLys, His, and dHis and R4is p(F)dPhe. In still further embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 4); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 14); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 15); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 17); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 18); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19), wherein c represents cyclization through R2and R7via a lactam bond.

[0133] In other further embodiments, Y1is dTle, Y2is dPro. In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 7); Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 8); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 24); Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 27); Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 28); Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 29); Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 30); and -55- 170456481.42Docket No.: 146316.8023.WO00 Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 31), wherein c represents cyclization through R2and R7via a lactam bond.

[0134] In some embodiments, R1is Nle and R4is dPhe. In further embodiments, Y1is dVal or dPro, Y2is dPro or dVal. In some embodiments, the sequence of any one of Formulae (I)-(IF) is: Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 33); or Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 42), wherein c represents cyclization through R2and R7via a lactam bond.

[0135] Alternatively, in some embodiments, at least one of X1, Y3and Y4is present. In further embodiments, R1is Nle, and R4is p(F)dPhe. In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 6); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 22); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 23); Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 25); and Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 26), wherein c represents cyclization through R2and R7via a lactam bond

[0136] In some embodiments, when R3is His, R4is p(F)dPhe or dPhe, and the non- naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R2and Lys at R7, then R5is Arg. Alternatively, in some embodiments, R5is an amino acid other than Arg. In further embodiments, R5is selected from His, transPro(guan), cisPro(guan). In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 21); Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 46); and -56- 170456481.42Docket No.: 146316.8023.WO00 Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 47), wherein c represents cyclization through R2and R7via a lactam bond.

[0137] In some embodiments, when R3is His, R4is p(F)dPhe or dPhe, and the non- naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R2and Lys at R7, then R6is Trp. Alternatively, in some embodiments, R6is an amino acid other than Trp. In further embodiments, R6is dNal(2’). In some embodiments, the sequence of any one of Formulae (I)-(IF) is: Ac-Nle-c[Asp-His-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro- NH2 (SEQ ID NO: 5), wherein c represents cyclization through R2and R7via a lactam bond.

[0138] In some embodiments of the sequence of any one of Formulae (I)-(IF), R3is His and the non-naturally occurring melanocortin analog is cyclized through a bond other than a lactam bond between Asp at R2and Lys at R7. In some embodiments, the non-naturally occurring melanocortin analog is cyclized through R2and R7via a bond other than a lactam bond between Asp at and Lys. For example, the non-naturally occurring melanocortin analog may be cyclized through R2and R7via a disulfide bond or a lactam formed between amino acids other than Asp and Lys.

[0139] In some embodiments, the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp or Glu at R2and Orn at R7. In further embodiments, R4is selected from dPhe, p(Cl)dPhe, and p(F)dPhe. In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 11); and Ac-Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 12), wherein c represents cyclization through R2and R7via a lactam bond.

[0140] In other embodiments, the non-naturally occurring melanocortin analog is cyclized through a disulfide bond between dCys at R2and Cys at R7. In further embodiments, R4is p(Cl)dPhe. In some embodiments, the sequence of any one of -57- 170456481.42Docket No.: 146316.8023.WO00 Formulae (I)-(IF) is Ac-Nle-c[dCys-His-p(Cl)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization through R2and R7via a disulfide bond.

[0141] Alternatively, in some embodiments, the non-naturally occurring melanocortin analog is cyclized through Asp at a residue position other than R2and / or Lys at a residue position other than R7. For example, the non-naturally occurring melanocortin analog may be cyclized through Asp at R1and Lys at R7or through Asp at R2and Lys at R8.

[0142] In some embodiments, the non-naturally occurring melanocortin analog is cyclized through a lactam bond between Asp at R2and Lys at R8. In further embodiments, the sequence of any one of Formulae (I)-(IF) is: Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Pro-Lys]- dVal-dPro-NH2 (SEQ ID NO: 35), wherein c represents cyclization through R2and R8via a lactam bond.

[0143] In some embodiments, the non-naturally occurring melanocortin analog is cyclized between a lactam bond between Asp at R1and Lys at R7. In further embodiments, R2is Ala or dAla and R4is dPhe. In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 38); Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 39); Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 40); and Ac-Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 41), wherein c represents cyclization through R1and R7via a lactam bond.

[0144] In other further embodiments, R2is Pro, and R4is Phe. In some embodiments, the sequence of any one of Formulae (I)-(IF) is: Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]- dVal-dPro-NH2 (SEQ ID NO: 13), wherein c represents cyclization through R1and R7via a lactam bond.

[0145] In some embodiments of the sequence of any one of Formula (I)-(ID), R3is an amino acid other than His. In some embodiments, R3is selected from dHis, Gln and Pro. In further embodiments, R2is Asp, R4is dPhe or p(F)dPhe, R5is Arg, R6is Trp, and R7is Lys. -58- 170456481.42Docket No.: 146316.8023.WO00 In some embodiments, the sequence of any one of Formulae (I)-(IF) is selected from the group consisting of: Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 9); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 10); Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 32); Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 36); and Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 37), wherein c represents cyclization through R2and R7via a lactam bond.

[0146] In some embodiments of the sequence of Formula (I), R3is an amino acid other than His and R9is absent. Alternatively, in some embodiments, R9is present. In some embodiments, the sequence of any one of Formulae (I)-(IF) is: Ac-Nle-c[Asp-Phe-Phe-Pro- His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34), wherein c represents cyclization through R1and R9via a lactam bond.

[0147] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3-10, 13-33, and 35-47.

[0148] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3-10, 14-33, 36, 37, and 42-47.

[0149] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3-8, 14-31, 43, and 44.

[0150] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IC). In some embodiments, the non-naturally occurring -59- 170456481.42Docket No.: 146316.8023.WO00 melanocortin analog comprises any one of the sequences of SEQ ID NOs: 10, 13, 33, 35- 37, 42, and 45-47.

[0151] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (ID). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 38-41.

[0152] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IF). In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 11, 12, and 43- 45. In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 43-45.

[0153] Non-naturally occurring melanocortin analogs of any one of Formulae (I)-(IF) may be an agonist of the melanocortin 4 receptor and an agonist of the melanocortin 3 receptor. In some embodiments, non-naturally occurring melanocortin analogs of any one of Formulae (I)-(IF) are full agonists of the melanocortin 4 receptor and full agonists of the melanocortin 3 receptor. In other embodiments, non-naturally occurring melanocortin analogs of any one of Formulae (I)-(IF) are full agonists of the melanocortin 4 receptor and partial agonists of the melanocortin 3 receptor. Non-Naturally Occurring Melanocortin Analog Synthesis

[0154] The non-naturally occurring melanocortin analogs of the present technology may be readily synthesized by any known conventional procedure for the formation of a peptide linkage between amino acids. Such conventional procedures include, for example, any solution phase procedure permitting a condensation between the free alpha amino group of an amino acid or residue thereof having the carboxyl group or other reactive groups protected and the free primary carboxyl group of another amino acid or residue thereof having the amino group or other reactive groups protected. In an exemplary procedure, the peptides of the present technology may be synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare the peptides of the present technology. -60- 170456481.42Docket No.: 146316.8023.WO00

[0155] The process for synthesizing the peptides may be carried out by a procedure whereby each amino acid in the desired sequence is added one at a time in succession to another amino acid or residue thereof or by a procedure whereby peptide fragments with the desired amino acid sequence are first synthesized conventionally and then condensed to provide the desired peptide. The resulting peptide is then cyclized to yield a cyclic peptide.

[0156] Solid phase peptide synthesis methods are well known and practiced in the art. In such methods, the synthesis of peptides may be carried out by sequentially incorporating the desired amino acid residues one at a time into the growing peptide chain according to the general principles of solid phase methods. These methods are disclosed in numerous references, including Merrifield, Angew Chem.24:799-810 (1985) and Barany et al., The Peptides, Analysis, Synthesis and Biology, Vol. 2, Gross E. and Meienhofer J., Eds. Academic Press 1-284 (1980), the disclosure of which is incorporated herein by reference in its entirety.

[0157] In chemical syntheses of peptides, reactive side chain groups of the various amino acid residues are protected with suitable protecting groups, which prevent a chemical reaction from occurring at that site until the protecting group is removed. Also common is the protection of the alpha amino group of an amino acid residue or fragment while that entity reacts at the carboxyl group, followed by the selective removal of the alpha amino protecting group to allow a subsequent reaction to take place at that site. Specific protecting for solid phase synthesis methods and solution phase synthesis methods groups are known to those having ordinary skill in the art.

[0158] Alpha amino groups may be protected by a suitable protecting group, including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, p-biphenyl-isopropoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc) and p-methoxybenzyloxycarbonyl (Moz); aliphatic urethane-type protecting groups, such as t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc is useful for alpha amino protection.

[0159] Guanidino groups may be protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tosyl), Z, pentamethylchromanesulfonyl (Pmc), -61- 170456481.42Docket No.: 146316.8023.WO00 adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and Boc. Pmc is a useful protecting group for Arg.

[0160] Solid phase synthesis is commenced from the C-terminal end of the peptide by coupling a protected alpha amino acid to a suitable resin. Such starting material is prepared by attaching an alpha amino-protected amino acid by an ester linkage to a p- benzyloxybenzyl alcohol (Wang) resin or a 2-chlorotrityl chloride resin, by an amide bond between an Fmoc-Linker, such as p-[(R,S)-α-[1-(9H-fluor-en-9-yl)-methoxyformamido]-2,4- dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) to a benzhydrylamine (BHA) resin, or by other means well known in the art. Fmoc-Linker-BHA resin supports are commercially available and generally used when feasible. The resins are carried through repetitive cycles as necessary to add amino acids sequentially. The alpha amino Fmoc protecting groups are removed under basic conditions. Piperidine, piperazine, diethylamine, or morpholine (20- 40% v / v) in N,N-dimethylformamide (DMF) may be used for this purpose.

[0161] Following removal of the alpha amino protecting group, the subsequent protected amino acids are coupled stepwise in the desired order to obtain an intermediate, protected peptide-resin. The activating reagents used for coupling of the amino acids in the solid phase synthesis of the peptides are well known in the art. After the peptide is synthesized, if desired, the orthogonally protected side chain protecting groups may be removed using methods well known in the art for further derivatization of the peptide.

[0162] Reactive groups in a peptide may be selectively modified, either during solid phase synthesis or after removal from the resin. For example, peptides may be modified to obtain N-terminus modifications, such as acetylation, while on resin, or may be removed from the resin by use of a cleaving reagent and then modified. Methods for N-terminus modification, such as acetylation, and for C-terminus modification, such as amidation, are known in the art. Similarly, methods for modifying side chains of amino acids are well known to those skilled in the art of peptide synthesis. The choice of modifications made to reactive groups present on the peptide will be determined, in part, by the characteristics that are desired in the peptide.

[0163] The peptide may be cyclized prior to cleavage from the peptide resin. For cyclization through reactive side chain moieties, the desired side chains are deprotected, -62- 170456481.42Docket No.: 146316.8023.WO00 and the peptide suspended in a suitable solvent and a cyclic coupling agent added. Suitable solvents include, for example DMF, dichloromethane (DCM) or 1-methyl-2-pyrrolidone (NMP). Suitable cyclic coupling reagents include, for example, 2-(1H-benzotriazol-1-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1-yl-oxy- tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1-yl-oxy- tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1H-benzotriazol-1- yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1 (2H)-pyridyl)-1,1,3,3- tetramethyluronium tetrafluoroborate (TPTU) or N,N′-dicyclohexylcarbodiimide / 1- hydroxybenzotriazole (DCCl / HOBt). Coupling is convention initiated by use of a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine, or N-methylmorpholine (NMM).

[0164] Following cleavage of peptides from the solid phase following their synthesis, the peptide may be purified by any number of methods, such as reverse phase high performance liquid chromatography (RP-HPLC), using a suitable column, such as a C18 column. Other methods of separation or purification, such as methods based on the size or charge of the peptide, may also be employed. Once purified, the peptide may be characterized by any number of methods, such as high performance liquid chromatograph (HPLC), amino acid analysis, mass spectrometry, and the like. Salt Forms of Non-Naturally Occurring Melanocortin Analogs

[0165] The non-naturally occurring melanocortin analog peptides of the present technology may be in the form of any salt. The term “pharmaceutically acceptable salts” refers to salts prepared from non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Exemplary salts are the ammonium, calcium, lithium, magnesium, potassium, and sodium salts. Salts derived from organic non- toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, -63- 170456481.42Docket No.: 146316.8023.WO00 diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0166] When the non-naturally occurring melanocortin analogs of the present technology are basic, acid addition salts may be prepared from non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, carboxylic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like. Acid addition salts of the peptides of the present technology are prepared in a suitable solvent from the peptide and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, citric, tartaric, maleic, succinic or methanesulfonic acid. The acetate salt form is especially useful. Where the peptides of the present technology include an acidic moiety, suitable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts. Conjugates

[0167] The present technology further includes conjugates comprising a non-naturally occurring melanocortin analog. In some embodiments, the non-naturally melanocortin analog is conjugated to a pharmaceutical agent. Non-limiting examples of suitable pharmaceutical agents include peptides, monoclonal antibodies, and small molecules. In some embodiments, the non-naturally occurring melanocortin analog is conjugated to semaglutide. In other embodiments, the non-naturally occurring melanocortin analog is conjugated to setmelanotide. In yet other embodiments, the non-naturally occurring melanocortin analog is conjugated to a small molecule MCR agonist.

[0168] Conjugates of the present technology further comprise a linker connecting the non-naturally occurring melanocortin analog to the pharmaceutical agent. In some embodiments, the linker is rigid. In some embodiments, the linker is flexible. In some -64- 170456481.42Docket No.: 146316.8023.WO00 embodiments, the linker is a cleavable linker. In some embodiments, the linker comprises a glycine-serine (Gly / Ser) linker, a proline-threonine-glycine linker, an alanine linker, a lysine linker, a threonine linker, a valine-glycine-serine-threonine linker, an elastin-like peptide linker, a hexahistidine linker, a polyethylene glycol linker, a fatty acid linker, or a hydrocarbon linker.

[0169] In some embodiments, the linker is a peptide linker. The peptide linkers of the present technology may vary from 2 to 31 amino acids of any primary sequence in length and do not impose any constraints on the conformation or interactions of the linked partners. In some embodiments, the linkers vary from about 2-30, 2-29, 2-28, 2-27, 2-26, 2-25, 2-24, 2-23, 2-22, 2-21, 2-20, 2-19, 2-18, 2-17, 2-16, 2-15, 2- 14, 2-13, 2-12, 2-11, 2-10, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, 3-31, 3-30, 3-29, 3-28, 3-27, 3-26, 3-25, 3-24, 3-23, 3-22, 3-21, 3-20, 3-19, 3-18, 3-17, 3-16, 3-15, 3-14, 3-13, 3-12, 3-11, 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 3-4, 4-31, 4-30, 4-29, 4-28, 4-27, 4-26, 4-25, 4-24, 4-23, 4-22, 4-21, 4- 20, 4-19, 4-18, 4-17, 4-16, 4- 15, 4-14, 4-13, 4-12, 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 4-5, 5-31, 5- 30, 5-29, 5-28, 5-27, 5-26, 5-25, 5-24, 5-23, 5-22, 5-21, 5-20, 5-19, 5-18, 5-17, 5-16, 5-15, 5- 14, 5-13, 5-12, 5-11, 5- 10, 5-9, 5-8, 5-7, 5-6, 6-31, 6-30, 6-29, 6-28, 6-27, 6-26, 6-25, 6-24, 6-23, 6-22, 6-21, 6-20, 6-19, 6-18, 6-17, 6-16, 6-15, 6-14, 6-13, 6-12, 6-11, 6-10, 6-9, 6-8, 6- 7, 7-31, 7-30, 7-29, 7- 28, 7-27, 7-26, 7-25, 7-24, 7-23, 7-22, 7-21, 7-20, 7-19, 7-18, 7-17, 7- 16, 7-15, 7-14, 7-13, 7-12, 7-11, 7-10, 7-9, 7-8, 8-31, 8-30, 8-29, 8-28, 8-27, 8-26, 8-25, 8-24, 8-23, 8-22, 8-21, 8-20, 8-19, 8-18, 8-17, 8-16, 8-15, 8-14, 8-13, 8-12, 8-11, 8-10, 8-9, 9-31, 9-30, 9-29, 9-28, 9-27, 9-26, 9-25, 9-24, 9-23, 9-22, 9-21, 9-20, 9-19, 9-18, 9-17, 9-16, 9-15, 9-14, 9-13, 9-12, 9-11, 9-10, 10-31, 10-30, 10-29, 10-28, 10-27, 10-26, 10-25, 10-24, 10-23, 10-22, 10-21, 10- 20, 10-19, 10-18, 10-17, 10-16, 10-15, 10-14, 10-13, 10-12, 10-11, 11-31, 11-30, 11-29, 11- 28, 11-27, 11-26, 11-25, 11-24, 11-23, 11-22, 11-21, 11-20, 11-19, 11-18, 11-17, 11-16, 11- 15, 11-14, 11-13, 11-12, 12-31, 12-30, 12-29, 12-28, 12-27, 12-26, 12-25,12-24, 12-23, 12- 22, 12-21, 12-20, 12-19, 12-18, 12-17, 12-16, 12-15, 12-14, 12-13, 13-31, 13-30, 13-29, 13- 28, 13-27, 13-26, 13-25, 13-24, 13-23, 13-22, 13-21, 13-20, 13-19, 13-18, 13-17, 13-16, 13- 15, 13-14, 14-31, 14-30, 14-29, 14-28, 14-27, 14-26, 14-25, 14-24, 14-23, 14-22, 14-21, 14- 20, 14-19, 14-18, 14-17, 14-16, 14-15, 15-31, 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15- 24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 15-16, 16-31, 16-30, 16-29, 16-28, 16- 27, 16-26, 16-25, 16-24, 16-23, 16-22, 16-21, 16-20, 16-19, 16-18, 16-17, 17-31, 17-30, 17- -65- 170456481.42Docket No.: 146316.8023.WO00 29, 17-28, 17-27, 17-26, 17-25, 17-24, 17-23, 17-22, 17-21, 17-20, 17-19, 17-18, 18-31, 18- 30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 18-19, 19-31, 19- 30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-31, 20-30, 20- 29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-31, 21-30, 21-29, 21-28, 21- 27, 21-26, 21-25, 21-24, 21-23, 21-22, 22-31, 22-30, 22-29, 22-28, 22-27, 22-26, 22-25, 22- 24, 22-23, 23-31, 23-30, 23-29, 23-28, 23-27, 23-26, 23-25, 23-24, 24-31, 24-30, 24-29, 24- 28, 24-27, 24-26, 24-25, 25-31, 25-30, 25-29, 25-28, 25-27, 25-26, 26-31, 26-30, 26-29, 26- 28, 26-27, 27-31, 27-30, 27-29, 27-28, 28-31, 28-30, 28-29, 29-31, 29-30, or 30-31 amino acids of any primary sequence in length. The peptide linkers may be designed as appropriate for an intended use.

[0170] The peptide linkers may comprise one or more of a Gly-rich linker (e.g., a flexible linker connecting various domains in a single protein without interfering with the function of each domain; a linker forming stable covalently linked dimers; a linker to connect two independent domains that create a ligand-binding site or recognition sequence), a Serine linker (e.g., a coiled structure linker); a coiled structure linker comprising a Gln, Arg, Glu, Ser, and / or Pro amino acids; a rigid space linker comprising one or more of a Pro, Arg, Phe, Thr, Glu, and / or Gln residues; a linker comprising a flexible Gly-rich regions that may may generate loops connecting domains; or a linker comprising a Thr, Ser, Gly, and / or Ala residue.

[0171] In some embodiments, the linker comprises an amino acid sequence about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 100% identical to the amino acid sequence of any one of Linker A, Linker B, Linker C, Linker D, Linker E, Linker F, Linker G, Linker H, Linker I, Linker J, Linker K, Linker L, Linker M, Linker N, Linker O, Linker P, Linker Q, Linker R, or Linker S in Table 0.

[0172] In some embodiments, the linker comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 100% identical to the amino acid sequence of any one of Linker A, Linker B, Linker C, Linker D, Linker E, Linker F, Linker G, Linker H, Linker I, Linker J, Linker K, Linker L, Linker M, Linker N, Linker O, Linker P, Linker Q, Linker R, or Linker S in Table 0. -66- 170456481.42Docket No.: 146316.8023.WO00 In some embodiments, the linker comprises an amino acid sequence at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 100% identical to the amino acid sequence of any one of Linker A, Linker B, Linker C, Linker D, Linker E, Linker F, Linker G, Linker H, Linker I, Linker J, Linker K, Linker L, Linker M, Linker N, Linker O, Linker P, Linker Q, Linker R, or Linker S in Table 0. Table 0: Peptide Linker Amino Acid Sequences Name Amino Acid SEQ ID NO

[0173] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology are present in a pharmaceutical composition. -67- 170456481.42Docket No.: 146316.8023.WO00

[0174] 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 composition. For example, the non-naturally occurring melanocortin analog is present in the pharmaceutical 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 pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the pharmaceutical composition.

[0175] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IF), and 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. For example, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IF) is present in the pharmaceutical 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 pharmaceutical composition. In some embodiments, the non- naturally occurring melanocortin analog comprising a sequence of Formula (IF) is present in the pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the pharmaceutical composition.

[0176] In some embodiments, the composition 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 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 Formula (IF).

[0177] The non-naturally occurring melanocortin analogs may be formulated with one or more pharmaceutically acceptable carriers and / or excipients. The carriers and / or -68- 170456481.42Docket No.: 146316.8023.WO00 excipients of the present technology facilitate delivery of the non-naturally occurring melanocortin analog to a subject. Other pharmaceutically acceptable carriers and / or excipients may be included in the pharmaceutical composition to enhance dispersion, solubility, and / or stability of the non-naturally occurring melanocortin analog, and / or to reduce adverse injection site reactions.

[0178] In some embodiments, the pharmaceutical composition comprises 0.1 to 99.9999 wt.%, 1 to 99.999 wt.%, 5 to 99.99 wt.%, 10 to 99.9 wt.%, 15 to 99 wt.%, 20 to 90 wt.%, 30 to 85 wt.%, 40 to 80 wt.%, 50 to 75 wt.%, or 60 to 70 wt.% of the pharmaceutically acceptable carrier and / or excipient relative to a total weight of the pharmaceutical composition.

[0179] In some embodiments, the pharmaceutically acceptable carrier and / or excipient of the pharmaceutical composition is selected from the group consisting of water, a buffer, an inorganic salt, a fatty acid, a vegetable oil, a synthetic fatty ester, a surfactant, and a polymer.

[0180] In some embodiments, the pharmaceutically acceptable carrier and / or excipient of the pharmaceutical composition is water. In some embodiments, the pharmaceutically acceptable carrier and / or excipient of the pharmaceutical composition is a buffer.

[0181] In some embodiments, the pharmaceutical composition contains about 0.1 to about 99.9999 wt.%, about 1 to about 99.999 wt.%, about 5 to about 99.99 wt.%, about 10 to about 99.9 wt.%, about 15 to about 99 wt.%, about 20 to about 90 wt.%, about 30 to about 85 wt.%, about 40 to about 80 wt.%, about 50 to about 75 wt.%, or about 60 to about 70 wt.% of one or more pharmaceutically acceptable carriers and / or excipients relative to a total weight of the pharmaceutical composition.

[0182] In some embodiments, the pharmaceutical composition contains at least 0.1 to at least 99.9999 wt.%, at least 1 to at least 99.999 wt.%, at least 5 to at least 99.99 wt.%, at least 10 to at least 99.9 wt.%, at least 15 to at least 99 wt.%, at least 20 to at least 90 wt.%, at least 30 to at least 85 wt.%, at least 40 to at least 80 wt.%, at least 50 to at least 75 wt.%, or at least 60 to at least 70 wt.% of one or more pharmaceutically acceptable carriers and / or excipients relative to a total weight of the pharmaceutical composition. -69- 170456481.42Docket No.: 146316.8023.WO00

[0183] In some embodiments, the pharmaceutical composition contains at least about 0.1 to at least about 99.9999 wt.%, at least about 1 to at least about 99.999 wt.%, at least about 5 to at least about 99.99 wt.%, at least about 10 to at least about 99.9 wt.%, at least about 15 to at least about 99 wt.%, at least about 20 to at least about 90 wt.%, at least about 30 to at least about 85 wt.%, at least about 40 to at least about 80 wt.%, at least about 50 to at least about 75 wt.%, or at least about 60 to at least about 70 wt.% of one or more pharmaceutically acceptable carriers and / or excipients relative to a total weight of the pharmaceutical composition.

[0184] Any pharmaceutically acceptable carriers and / or excipients known in the art may be included in the pharmaceutical composition. Non-limiting examples of pharmaceutically acceptable carriers and / or excipients include buffers, binders, excipients, stabilizers, lubricants, oils, adjuvants, preservatives, lipids, and antioxidants. The pharmaceutical composition may comprise any combination of the one or more pharmaceutically acceptable carriers and / or excipients previously described in relation to the first and pharmaceutical compositions. In some embodiments, the one or more pharmaceutically acceptable carriers and / or excipients comprise water.

[0185] 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.

[0186] In some embodiments, the one or more pharmaceutically acceptable carriers and / or excipients are isotonic. In some embodiments, the carrier and / or excipient is isotonic to nasal fluids.

[0187] In some embodiments, the pharmaceutical composition further comprises a pharmaceutical salt. Any pharmaceutical salt known in the art may be included in the pharmaceutical composition. For examples, to achieve a desirable tonicity, the pharmaceutical composition may include a salt selected from the group consisting of sodium -70- 170456481.42Docket No.: 146316.8023.WO00 chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride.

[0188] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of about 0.1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 25 mg / mL, or about 5 mg / mL to about 10 mg / mL, relative to a total volume of the composition.

[0189] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of at least 0.1 mg / mL to at least 50 mg / mL, at least 1 mg / mL to at least 25 mg / mL, or at least 5 mg / mL to at least 10 mg / mL, relative to a total volume of the composition.

[0190] In some embodiments, the salt is present in the pharmaceutical composition in a concentration of at least about 0.1 mg / mL to at least about 50 mg / mL, at least about 1 mg / mL to at least about 25 mg / mL, or at least about 5 mg / mL to at least about 10 mg / mL, relative to a total volume of the composition.

[0191] Pharmaceutically acceptable carriers and / or excipients that may be included in the pharmaceutical composition generally include a pH buffered aqueous solution comprising one or more of the following components: (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.

[0192] In the pH buffered solution of the pharmaceutical composition, the water 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.

[0193] In some embodiments, the pharmaceutical 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. -71- 170456481.42Docket No.: 146316.8023.WO00

[0194] In some embodiments, the pharmaceutical composition includes water in an amount of at least 1 wt% to at least 90 wt%, at least 10 wt% to at least 75 wt%, or at least 25 wt% to at least 50 wt%, relative to a total weight of the composition.

[0195] In some embodiments, the pharmaceutical composition includes water in an amount of at least about 1 wt% to at least about 90 wt%, at least about 10 wt% to at least about 75 wt%, or at least about 25 wt% to at least about 50 wt%, relative to a total weight of the composition.

[0196] In some embodiments, sodium acetate is present in the pharmaceutical 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 may be present in the pharmaceutical 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.

[0197] In some embodiments, sodium acetate is present in the pharmaceutical 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 may be present in the pharmaceutical 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.

[0198] In some embodiments, sodium acetate is present in the pharmaceutical composition in a molar concentration of 5 mM to 700 mM, relative to a total volume of the composition. For example, sodium acetate may be present in the pharmaceutical 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.

[0199] In some embodiments, sodium acetate is present in the pharmaceutical 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 may be present in the pharmaceutical 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. -72- 170456481.42Docket No.: 146316.8023.WO00

[0200] The term “Tris” refers to tris(hydroxymethyl)aminomethane, which is also known as Tris buffer, Tris base, TRIS, tromethamine, tromethamine buffer, Trizma®, Trisamine, Trometamol, Tromethane, Trisaminol, or THAM. In some embodiments, Tris is present in the pharmaceutical composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical 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.

[0201] In some embodiments, Tris is present in the pharmaceutical 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 may be present in the pharmaceutical 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.

[0202] In some embodiments, Tris is present in the pharmaceutical composition in a molar concentration of 2 mM to 500 mM, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical 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.

[0203] In some embodiments, Tris is present in the pharmaceutical composition in a molar concentration of about 50 mM to about 70 mM, relative to a total volume of the composition. For example, Tris may be present in the pharmaceutical 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.

[0204] In some embodiments, the pH buffered aqueous solution provides the pharmaceutical 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. -73- 170456481.42Docket No.: 146316.8023.WO00

[0205] In some embodiments, a weight ratio of sodium acetate to Tris is about 1:4 to about 4:1, about 2:7 to about 7:2, about 1:3 to about 3:1, about 2:5 to about 5:2, about 1:2 to about 2:1, about 2:3 to about 3:2, or about 1:1. In some embodiments, the weight ratio of sodium acetate to Tris is about 1:1.

[0206] In some embodiments, a weight ratio of sodium acetate to Tris is at least 1:4 to at least 4:1, at least 2:7 to at least 7:2, at least 1:3 to at least 3:1, at least 2:5 to at least 5:2, at least 1:2 to at least 2:1, at least 2:3 to at least 3:2, or at least 1:1. In some embodiments, the weight ratio of sodium acetate to Tris is at least 1:1.

[0207] In some embodiments, a weight ratio of sodium acetate to Tris is at least about 1:4 to at least about 4:1, at least about 2:7 to at least about 7:2, at least about 1:3 to at least about 3:1, at least about 2:5 to at least about 5:2, at least about 1:2 to at least about 2:1, at least about 2:3 to at least about 3:2, or at least about 1:1. In some embodiments, the weight ratio of sodium acetate to Tris is at least about 1:1.

[0208] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is about 1:1 to about 20:1, about 3:2 to about 15:1, about 2:1 to about 12:1, about 3:1 to about 10:1, about 4:1 to about 9:1, about 5:1 to about 8:1, or about 6:1 to about 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is about 7:1.

[0209] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least 1:1 to at least 20:1, at least 3:2 to at least 15:1, at least 2:1 to at least 12:1, at least 3:1 to at least 10:1, at least 4:1 to at least 9:1, at least 5:1 to at least 8:1, or at least 6:1 to at least 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least 7:1.

[0210] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least about 1:1 to at least about 20:1, at least about 3:2 to at least about 15:1, at least about 2:1 to at least about 12:1, at least about 3:1 to at least about 10:1, at least about 4:1 to at least about 9:1, at least about 5:1 to at least about 8:1, or at least about 6:1 to at least about 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is at least about 7:1. -74- 170456481.42Docket No.: 146316.8023.WO00

[0211] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is about 1:1 to about 20:1, about 3:2 to about 15:1, about 2:1 to about 12:1, about 3:1 to about 10:1, about 4:1 to about 9:1, about 5:1 to about 8:1, or about 6:1 to about 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is about 7:1.

[0212] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is at least 1:1 to at least 20:1, at least 3:2 to at least 15:1, at least 2:1 to at least 12:1, at least 3:1 to at least 10:1, at least 4:1 to at least 9:1, at least 5:1 to at least 8:1, or at least 6:1 to at least 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is at least 7:1.

[0213] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is at least about 1:1 to at least about 20:1, at least about 3:2 to at least about 15:1, at least about 2:1 to at least about 12:1, at least about 3:1 to at least about 10:1, at least about 4:1 to at least about 9:1, at least about 5:1 to at least about 8:1, or at least about 6:1 to at least about 7:1. In some embodiments, the weight ratio of the non- naturally occurring melanocortin analog to Tris is at least about 7:1.

[0214] In addition to sodium acetate and Tris, the pharmaceutical 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 pharmaceutical composition comprises acetic acid as an additional buffering agent.

[0215] The pharmaceutical composition may further comprise one or more chelating agents. Suitable chelating agents include, but are not limited to edetate disodium dihydrate, calcium disodium edetate, sodium edetate, calcium versetamide sodium, calteridol, and diethylenetriaminepentaacetic acid. In some embodiments, the pharmaceutical composition further comprises edetate disodium dihydrate. -75- 170456481.42Docket No.: 146316.8023.WO00

[0216] The pharmaceutical composition may further 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. In some embodiments, when the pharmaceutical composition comprises a preservative agent, the preservative agent is phenol, benzyl alcohol, or a combination thereof.

[0217] If present in the pharmaceutical composition, 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.

[0218] The pharmaceutical composition may further comprise an emulsifier. Non- limiting examples of emulsifiers that may be included in the pharmaceutical composition include sodium carboxymethylcellulose, cetyl alcohol, glycerol monostearate, methylcellulose, and stearic acid. In some embodiments, when the pharmaceutical composition comprises an emulsifier, the emulsifier is sodium carboxymethylcellulose.

[0219] The pharmaceutical composition may further comprise a lipid. Lipids may enhance solubility and / or improve permeability of the non-naturally occurring melanocortin analog. In some embodiments, the lipid is a phospholipid. Non-limiting examples of phospholipids that may be included in the pharmaceutical composition include egg phosphatidylcholine, hydrogenated soybean phoshphaditylcholine, glycerophosphocholine, lecithin, and N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-glycero-3- phosphoethanolamine sodium salt. In some embodiments, when the pharmaceutical composition comprises a lipid, the lipid is N-(carbonyl-methoxypolyethylene glycol 2000)- 1,2-distearoyl-glycero-3-phosphoethanolamine sodium salt

[0220] The pharmaceutical composition may further comprise a bulking agent. Inclusion of a bulking agent may increase the stability of the pharmaceutical composition. Non-limiting examples of bulking agents that may be included in the pharmaceutical -76- 170456481.42Docket No.: 146316.8023.WO00 composition include sucrose, lactose, trehalose, mannitol, sorbitol, glucose, raffinose, glycine, histidine, and polyvinyl pyrrolidone. In some embodiments, when the pharmaceutical composition comprises a bulking agent, the bulking agent is mannitol.

[0221] In some embodiments, the pharmaceutical composition is in the form of an aqueous solution or a suspension. In some embodiments, the pharmaceutical composition is in the form of an emulsion. In some embodiments, the pharmaceutical composition is in the form of an aqueous solution. In some embodiments, the pharmaceutical composition is in the form of an aqueous solution which is clear, colorless, and / or free of visible foreign matter.

[0222] In some embodiments, the pharmaceutical composition has a pH ranging from about 6.5 to about 8.5. In some embodiments, the pharmaceutical 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, or 8.5.

[0223] In some embodiments, the pharmaceutical composition has a pH ranging from at least 6.5 to at least 8.5. In some embodiments, the pharmaceutical composition has a pH of at least 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, or 8.5.

[0224] In some embodiments, the pharmaceutical composition has a pH ranging from at least about 6.5 to at least about 8.5. In some embodiments, the pharmaceutical composition has a pH of at least 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, or 8.5.

[0225] In some embodiments, the pharmaceutical 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 pharmaceutical composition has a pH ranging from about 7.3 to about 7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or 7.4.

[0226] In some embodiments, the pharmaceutical composition is basic and has a pH of at least 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 pharmaceutical composition has a pH ranging from at least 7.3 to at least 7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or 7.4. -77- 170456481.42Docket No.: 146316.8023.WO00

[0227] In some embodiments, the pharmaceutical composition is basic and has a pH of at least 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 pharmaceutical composition has a pH ranging from at least about 7.3 to at least about 7.4. In some embodiments, the pharmaceutical composition has a pH of 7.3 or 7.4.

[0228] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the pharmaceutical composition may have 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 pharmaceutical 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 pharmaceutical composition has an osmolality ranging from about 275 mOsm / kg to about 330 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of about 279 mOsm / kg, about 314 mOsm / kg, or about 329 mOsm / kg.

[0229] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the pharmaceutical composition may have 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 at least 300 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolarity of at least 250 mOsm / kg, at least 260 mOsm / kg, at least 270 mOsm / kg, at least 280 mOsm / kg, at least 290 mOsm / kg, at least 300 mOsm / kg, at least 310 mOsm / kg, at least 320 mOsm / kg, at least 330 mOsm / kg, at least 340 mOsm / kg, at least 350 mOsm / kg, or at least 360 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality ranging from at least 275 mOsm / kg to at least 330 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least 279 mOsm / kg, at least 314 mOsm / kg, or at least 329 mOsm / kg. -78- 170456481.42Docket No.: 146316.8023.WO00

[0230] In some embodiments, the pharmaceutical composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the pharmaceutical composition may have 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 at least about 300 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolarity of at least about 250 mOsm / kg, at least about 260 mOsm / kg, at least about 270 mOsm / kg, at least about 280 mOsm / kg, at least about 290 mOsm / kg, at least about 300 mOsm / kg, at least about 310 mOsm / kg, at least about 320 mOsm / kg, at least about 330 mOsm / kg, at least about 340 mOsm / kg, at least about 350 mOsm / kg, or at least about 360 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality ranging from at least about 275 mOsm / kg to at least about 330 mOsm / kg. In some embodiments, the pharmaceutical composition has an osmolality of at least about 279 mOsm / kg, at least about 314 mOsm / kg, or at least about 329 mOsm / kg.

[0231] In some embodiments, the pharmaceutical composition has a viscosity ranging from about 0.5 cP to about 5 cP. For example, the pharmaceutical composition may have a viscosity ranging from about 0.5 cP to about 5 cP, about 0.75 cP to about 4.5 cP, about 1.0 cP to about 4 cP, about 1.2 cP to about 3.5 cP, about 1.3 cP to about 3 cP, about 1.4 cP to about 2.5 cP, about 1.5 cP to about 2 cP, or about 1.6 cP to about 1.8 cP. In some embodiments, the pharmaceutical 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 pharmaceutical composition has a viscosity of about 1.4 cP or about 1.6 cP.

[0232] In some embodiments, the pharmaceutical composition has a viscosity ranging from at least 0.5 cP to at least 5 cP. For example, the pharmaceutical composition may have a viscosity ranging from at least 0.5 cP to at least 5 cP, at least 0.75 cP to at least 4.5 cP, at least 1.0 cP to at least 4 cP, at least 1.2 cP to at least 3.5 cP, at least 1.3 cP to at least 3 cP, at least 1.4 cP to at least 2.5 cP, at least 1.5 cP to at least 2 cP, or at least 1.6 cP to at least 1.8 cP. In some embodiments, the pharmaceutical composition has a viscosity of at least 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, -79- 170456481.42Docket No.: 146316.8023.WO00 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, or 2.0 cP. In some embodiments, the pharmaceutical composition has a viscosity of at least 1.4 cP or at least 1.6 cP.

[0233] In some embodiments, the pharmaceutical composition has a viscosity ranging from at least about 0.5 cP to at least about 5 cP. For example, the pharmaceutical composition may have a viscosity ranging from at least about 0.5 cP to at least about 5 cP, at least about 0.75 cP to at least about 4.5 cP, at least about 1.0 cP to at least about 4 cP, at least about 1.2 cP to at least about 3.5 cP, at least about 1.3 cP to at least about 3 cP, at least about 1.4 cP to at least about 2.5 cP, at least about 1.5 cP to at least about 2 cP, or at least about 1.6 cP to at least about 1.8 cP. In some embodiments, the pharmaceutical composition has a viscosity of at least 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 pharmaceutical composition has a viscosity of at least about 1.4 cP or at least about 1.6 cP.

[0234] In some embodiments, the pharmaceutical composition disclosed is 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.

[0235] When the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration), 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.

[0236] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises a non-naturally occurring melanocortin analog in a concentration of 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 -80- 170456481.42Docket No.: 146316.8023.WO00 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.

[0237] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises sodium acetate in a concentration of 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.

[0238] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., subcutaneous administration) and comprises Tris in a concentration of about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35mM, 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.

[0239] In some embodiments, the pharmaceutical composition comprises one or more antioxidants. For example, the pharmaceutical composition may comprise ascorbic acid, cysteine, sodium metabisulfite, propyl gallate, butylated hydroxytoluene, and / or butylated hydroxyanisole.

[0240] In some embodiments, the pharmaceutical composition comprises a surfactant, such as a sorbitan ester.

[0241] In some embodiments, the pharmaceutical composition comprises a flavoring or scent, such as an aromatic oil.

[0242] In some embodiments, the non-naturally occurring melanocortin analog is solubilized or suspended in a solvent or vehicle. The solvent or vehicle may be purified water, ethyl alcohol, and / or propylene glycol. In some embodiments, the pharmaceutical composition comprises between 0.03 wt% and 1 wt% melanocortin analog solubilized or suspended in a solvent or vehicle. For example, the pharmaceutical composition may comprise the non-naturally occurring melanocortin analog in an amount of about 0.03 wt%, -81- 170456481.42Docket No.: 146316.8023.WO00 about 0.05 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt%, or about 1 wt%.

[0243] In some embodiments, the pharmaceutical composition may comprise the non- naturally occurring melanocortin analog in an amount of at least 0.03 wt%, at least 0.05 wt%, at least 0.1 wt%, at least 0.15 wt%, at least 0.2 wt%, at least 0.25 wt%, at least 0.3 wt%, at least 0.35 wt%, at least 0.4 wt%, at least 0.45 wt%, at least 0.5 wt%, at least 0.55 wt%, at least 0.6 wt%, at least 0.65 wt%, at least 0.7 wt%, at least 0.75 wt%, at least 0.8 wt%, at least 0.85 wt%, at least 0.9 wt%, at least 0.95 wt%, or at least 1 wt%.

[0244] In some embodiments, the pharmaceutical composition may comprise the non- naturally occurring melanocortin analog in an amount of at least about 0.03 wt%, at least about 0.05 wt%, at least about 0.1 wt%, at least about 0.15 wt%, at least about 0.2 wt%, at least about 0.25 wt%, at least about 0.3 wt%, at least about 0.35 wt%, at least about 0.4 wt%, at least about 0.45 wt%, at least about 0.5 wt%, at least about 0.55 wt%, at least about 0.6 wt%, at least about 0.65 wt%, at least about 0.7 wt%, at least about 0.75 wt%, at least about 0.8 wt%, at least about 0.85 wt%, at least about 0.9 wt%, at least about 0.95 wt%, or at least about 1 wt%.

[0245] The non-naturally occurring melanocortin analogs of the present technology may be formulated for administration using any means known in the art, including orally, rectally, vaginally, ocularly, intranasally, topically, parenterally, or by injection. If administered by injection, the peptide injection may be intravenous (IV), subcutaneous (SC), intramuscular (IM), intraperitoneal (IP), intracerebroventricular (ICV), or other means known in the art. The non-naturally occurring melanocortin analog of the combination therapy may be formulated by any means known in the art, including but not limited to formulation as tablets, capsules, caplets, suspensions, powders, lyophilized preparations, suppositories, pessaries, ocular drops, skin patches, orally soluble formulations, enteric formulations, solutions sprays, aerosols and the like, and may be mixed and formulated with buffers, binders, excipients, stabilizers, lubricants, oils, adjuvants, anti-oxidants and other agents known in the art. In general, any route of administration by which the peptides are introduced -82- 170456481.42Docket No.: 146316.8023.WO00 across an epidermal layer of cells may be employed. Administration includes topical delivery. Administration includes delivery across the blood brain barrier. Administration includes delivery through mucous membranes, buccal administration, ophthalmic administration, oral administration, dermal administration, inhalation administration, nasal administration, urethral administration, vaginal administration, rectal administration, and the like.

[0246] In some embodiments, the pharmaceutical 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 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.

[0247] In some embodiments, the pharmaceutical composition is formulated for oral administration. For example, the pharmaceutical composition may be in the form of a tablet, capsule, lozenge, pill, sachet, or any other orally deliverable form know in the art.

[0248] The composition may be formulated to be delivered by nose drop, spray device, or topical solution. In some embodiments, the pharmaceutical composition may be formulated as an aerosol, atomizer, inhalation, insufflation, metered-dose inhaler, or nebulizer. In some embodiments, the pharmaceutical composition includes a propellant, such as hydrofluoroalkane.

[0249] In some embodiments, the pharmaceutical 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 1ug to 100ug 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. Dosing

[0250] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered hourly (such as every hour, every 2 hours, every 4 hours, every 8 hours, etc.), once a day, -83- 170456481.42Docket No.: 146316.8023.WO00 or twice a day. In some embodiments, the non-naturally occurring melanocortin analog is administered every morning, every evening, or every afternoon. In some embodiments, the non-naturally occurring melanocortin analog is administered before a meal, after a meal, or with a meal.

[0251] In some embodiments, the non-naturally occurring melanocortin analog or pharmaceutical composition thereof may be administered as a dosing regimen comprising once, twice, or three times daily administration on a (i) weekly; (ii) every other week; (iii) one week of therapy followed by two, three or four weeks off; (iv) two weeks of therapy followed by one, two, three or four weeks off; (v) three weeks of therapy followed by one, two, three, four or five week off; (vi) four weeks of therapy followed by one, two, three, four or five week off; (vii) five weeks of therapy followed by one, two, three, four or five week off; or (viii) monthly schedule. The (i)-(viii) schedules may be repeated 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times or more. In some embodiments, the non-naturally occurring melanocortin analog or pharmaceutical composition thereof is administered at various dosages during the dosing regimen (e.g., a first dose with an effective amount of 10 mg / kg and a second dose with an effective amount of 5 mg / kg).

[0252] In some embodiments, the non-naturally occurring melanocortin analog or pharmaceutical composition thereof is administered once every other day, once every 2 or 3 days, once every third day, once per week, once every other week, once every third week, once every month, once every six weeks, once every other month, once every three months, once every six months, or once per year.

[0253] Administration of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof at any of the dosing frequencies of the present technology may be repeated for a total of about 2 dosages, about 3 dosages, about 4 dosages, about 5 dosages, about 10 dosages, about 15 dosages, about 20 dosages, about 30 dosages, about 40 dosages, about 50 dosages or more.

[0254] Administration of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof at any of the dosing frequencies of the present technology may be repeated for a total of at least 2 dosages, at least 3 dosages, at least 4 -84- 170456481.42Docket No.: 146316.8023.WO00 dosages, at least 5 dosages, at least 10 dosages, at least 15 dosages, at least 20 dosages, at least 30 dosages, at least 40 dosages, at least 50 dosages or more.

[0255] Administration of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof at any of the dosing frequencies of the present technology may be repeated for a total of at least about 2 dosages, at least about 3 dosages, at least about 4 dosages, at least about 5 dosages, at least about 10 dosages, at least about 15 dosages, at least about 20 dosages, at least about 30 dosages, at least about 40 dosages, at least about 50 dosages or more.

[0256] In some embodiments, the frequency of dosages of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof is the same during a treatment regimen. In other embodiments, the frequency of dosages of the non-naturally occurring melanocortin analog or pharmaceutical composition thereof is different during a treatment regimen. The non-naturally occurring melanocortin analog or the pharmaceutical composition thereof may be administered even less frequently. Alternatively, the dosage regimen may be decreased or increased from an initial dosing regimen for days, weeks, months, or years. In some embodiments, the dosing regimen is repeated at other intervals.

[0257] 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, 0.01 mg / kg to 20 mg / kg, 0.05 mg / kg to 15 mg / kg, 0.075 mg / kg to 10 mg / kg, 0.1 mg / kg to 8 mg / kg, 0.2 mg / kg to 6 mg / kg, 0.3 mg / kg to 4 mg / kg, 0.4 mg / kg to 2 mg / kg, or 0.5 mg / kg to 1 mg / kg per body weight of the subject. 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, about 1 mg / kg to about 7.5 mg / kg, or about 2.5 mg / kg to about 5 mg / kg per body weight of the subject.

[0258] The methods disclosed herein may be performed on the subject for about 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years. In some embodiments, the combination therapy (i.e., pharmaceutical combination) is administered to the subject for about 1 day, about 2 days, about 5 days, about 6 days, about 1 week, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 1 year, about 2 years, about 3 years, about 4 years, or about 5 years. -85- 170456481.42Docket No.: 146316.8023.WO00

[0259] The methods disclosed herein may be performed on the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years. In some embodiments, the combination therapy (i.e., pharmaceutical combination) is administered to the subject for at least 1 day, at least 2 days, at least 5 days, at least 6 days, at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years.

[0260] The methods disclosed herein may be performed on the subject for at least about 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years. In some embodiments, the combination therapy (i.e., pharmaceutical combination) is administered to the subject for at least about 1 day, at least about 2 days, at least about 5 days, at least about 6 days, at least about 1 week, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, or at least about 5 years.

[0261] In some embodiments, a method disclosed herein is performed on the subject for 1 day, 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.

[0262] In some embodiments, at least one active ingredient of the combination therapy is administered to a subject in a continuous doing schedule. As used herein, a “continuous dosing schedule” is an administration or dosing regimen without dose interruptions, e.g., without days off treatment. Repetition of 21-day or 28-day treatment cycles without dose interruptions is an exemplary continuous dosing schedule.

[0263] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg / kg to about 100 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg / kg or 60 mg / kg per body weight of the subject once daily. -86- 170456481.42Docket No.: 146316.8023.WO00

[0264] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.

[0265] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg / kg to about 1000 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg / kg to about 550 mg / kg per body weight of the subject once daily. In some embodiments, non-naturally occurring melanocortin analog is administered at a dose of about 15 mg / kg to about 100 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 20 mg / kg to about 75 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg / kg or 60 mg / kg per body weight of the subject once daily.

[0266] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg / kg to at least 1000 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 10 mg / kg to at least 550 mg / kg per body weight of the subject once daily. In some embodiments, non-naturally occurring melanocortin analog is administered at a dose of at least 15 mg / kg to at least 100 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 20 mg / kg to at least 75 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 30 mg / kg or 60 mg / kg per body weight of the subject once daily.

[0267] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 5 mg / kg to at least about 1000 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 10 mg / kg to at least about -87- 170456481.42Docket No.: 146316.8023.WO00 550 mg / kg per body weight of the subject once daily. In some embodiments, non-naturally occurring melanocortin analog is administered at a dose of at least about 15 mg / kg to at least about 100 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 20 mg / kg to at least about 75 mg / kg per body weight of the subject once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 30 mg / kg or 60 mg / kg per body weight of the subject once daily.

[0268] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 50 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, or about 500 mg / kg, about 550 mg / kg, about 600 mg / kg, about 650 mg / kg, about 700 mg / kg, about 750 mg / kg, about 800 mg / kg, about 850 mg / kg, about 900 mg / kg, about 950 mg / kg, or about 1000 mg / kg per body weight of the subject once daily.

[0269] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, at least 30 mg / kg, at least 35 mg / kg, at least 40 mg / kg, at least 50 mg / kg, at least 65 mg / kg, at least 70 mg / kg, at least 75 mg / kg, at least 80 mg / kg, at least 85 mg / kg, at least 90 mg / kg, at least 95 mg / kg, at least 100 mg / kg, at least 125 mg / kg, at least 150 mg / kg, at least 175 mg / kg, at least 200 mg / kg, at least 250 mg / kg, at least 300 mg / kg, at least 350 mg / kg, at least 400 mg / kg, at least 450 mg / kg, or at least 500 mg / kg, at least 550 mg / kg, at least 600 mg / kg, at least 650 mg / kg, at least 700 mg / kg, at least 750 mg / kg, at least 800 mg / kg, at least 850 mg / kg, at least 900 mg / kg, at least 950 mg / kg, or at least 1000 mg / kg per body weight of the subject once daily.

[0270] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 5 mg / kg, at least about 10 mg / kg, at least about 15 mg / kg, at least about 20 mg / kg, at least about 25 mg / kg, at least about 30 mg / kg, at least about 35 mg / kg, at least about 40 mg / kg, at least about 50 mg / kg, at least about 65 mg / kg, -88- 170456481.42Docket No.: 146316.8023.WO00 at least about 70 mg / kg, at least about 75 mg / kg, at least about 80 mg / kg, at least about 85 mg / kg, at least about 90 mg / kg, at least about 95 mg / kg, at least about 100 mg / kg, at least about 125 mg / kg, at least about 150 mg / kg, at least about 175 mg / kg, at least about 200 mg / kg, at least about 250 mg / kg, at least about 300 mg / kg, at least about 350 mg / kg, at least about 400 mg / kg, at least about 450 mg / kg, or at least about 500 mg / kg, at least about 550 mg / kg, at least about 600 mg / kg, at least about 650 mg / kg, at least about 700 mg / kg, at least about 750 mg / kg, at least about 800 mg / kg, at least about 850 mg / kg, at least about 900 mg / kg, at least about 950 mg / kg, or at least about 1000 mg / kg per body weight of the subject once daily.

[0271] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg / kg per body weight of the subject once daily.

[0272] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg / kg per body weight of the subject once daily.

[0273] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg / kg per body weight of the subject once daily.

[0274] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 20 mg / kg per body weight of the subject once daily.

[0275] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 25 mg / kg per body weight of the subject once daily.

[0276] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg / kg per body weight of the subject once daily.

[0277] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 35 mg / kg per body weight of the subject once daily.

[0278] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 40 mg / kg per body weight of the subject once daily.

[0279] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 50 mg / kg per body weight of the subject once daily. -89- 170456481.42Docket No.: 146316.8023.WO00

[0280] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 5 mg / kg per body weight of the subject once daily.

[0281] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 10 mg / kg per body weight of the subject once daily.

[0282] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 15 mg / kg per body weight of the subject once daily.

[0283] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 20 mg / kg per body weight of the subject once daily.

[0284] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 25 mg / kg per body weight of the subject once daily.

[0285] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 30 mg / kg per body weight of the subject once daily.

[0286] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 35 mg / kg per body weight of the subject once daily.

[0287] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 40 mg / kg per body weight of the subject once daily.

[0288] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least 50 mg / kg per body weight of the subject once daily.

[0289] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 5 mg / kg per body weight of the subject once daily.

[0290] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 10 mg / kg per body weight of the subject once daily.

[0291] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 15 mg / kg per body weight of the subject once daily.

[0292] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 20 mg / kg per body weight of the subject once daily. -90- 170456481.42Docket No.: 146316.8023.WO00

[0293] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 25 mg / kg per body weight of the subject once daily.

[0294] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 30 mg / kg per body weight of the subject once daily.

[0295] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 35 mg / kg per body weight of the subject once daily.

[0296] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 40 mg / kg per body weight of the subject once daily.

[0297] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of at least about 50 mg / kg per body weight of the subject once daily.

[0298] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 50 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, about 550 mg / kg, about 600 mg / kg, about 650 mg / kg, about 700 mg / kg, about 750 mg / kg, about 800 mg / kg, about 850 mg / kg, about 900 mg / kg, about 950 mg / kg, or about 1000 mg / kg per body weight of the subject twice daily.

[0299] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg / kg per body weight of the subject twice daily.

[0300] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg / kg per body weight of the subject twice daily.

[0301] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg / kg per body weight of the subject twice daily.

[0302] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 20 mg / kg per body weight of the subject twice daily. -91- 170456481.42Docket No.: 146316.8023.WO00

[0303] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 25 mg / kg per body weight of the subject twice daily.

[0304] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg / kg per body weight of the subject twice daily.

[0305] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 35 mg / kg per body weight of the subject twice daily.

[0306] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 40 mg / kg per body weight of the subject twice daily.

[0307] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 50 mg / kg per body weight of the subject twice daily.

[0308] In some embodiments, the non-naturally occurring melanocortin analog is administered at one or more doses. In some embodiments, the non-naturally occurring melanocortin analog is administered at two or more doses.

[0309] In some embodiments, the non-naturally occurring melanocortin analog is administered at a first dose once daily or twice daily. In some embodiments, the non- naturally occurring melanocortin analog is administered at a second dose once daily or twice daily.

[0310] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose that is a projected human equivalent dose (HED) based on a nonhuman primate dose. In some embodiments, the HED based on a 10 mg / kg nonhuman primate dose ranges from about 300 mg to about 550 mg.

[0311] In some embodiments, the non-naturally occurring melanocortin analog is administered at a first dose once daily for about 5 days to about 10 days. In some embodiments, the non-naturally occurring melanocortin analog is administered at a second dose once daily for about 5 days to about 10 days, after administration of the first dose. In some embodiments, the non-naturally occurring melanocortin analog is administered at a third dose twice daily for about 7 days to about 21 days, after administration of the second dose. In some embodiments, the second dose is greater than the first dose. In some -92- 170456481.42Docket No.: 146316.8023.WO00 embodiments, the third dose comprises a cumulative dose that is greater than the second dose.

[0312] In some embodiments, the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at a second dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose.

[0313] In some embodiments, the non-naturally occurring melanocortin analogs or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at a third dose that is at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% greater than the first dose and / or the second dose.

[0314] In some embodiments, the dosage of the second dose is greater than the dosage of the first dose. In some embodiments, the first dose is administered about once a day and the second dose is administered about twice a day.

[0315] In some embodiments, the dosage of the third dose is greater than the dosage of the first dose and / or the second dose. In some embodiments, the first dose and / or the second dose is administered about once a day, and the third dose is administered about twice a day.

[0316] In some embodiments, the non-naturally occurring melanocortin analog is administered using two or more different administration routes. The two or more different administration routes may comprise an oral administration and a subcutaneous administration. The oral administration may occur before, during, or after the subcutaneous administration.

[0317] In some embodiments, the first dose and the second dose comprise different routes of administration. In some embodiments, the first dose comprises an oral dose and the second dose comprises a subcutaneous dose. In some embodiments, the first dose and / or second dose and the third dose comprise different routes of administration. In some -93- 170456481.42Docket No.: 146316.8023.WO00 embodiments, the first dose and / or the second dose comprises an oral dose and the third dose comprises a subcutaneous dose.

[0318] In some embodiments, the second dose is administered at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after the first dose.

[0319] In some embodiments, the third dose is administered at least about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, or about 6 weeks after the first dose and / or the second dose.

[0320] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at two or more dosage amounts, each dosage amount differing from the other. The first dosage amount, the second dosage amount, and the third dosage amount may each be greater than, less than, equal to, or substantially equivalent to another dosage amount. For example, the first dosage amount is less than a second dosage amount which is greater than a third dosage amount also greater than the first dosage amount. The dosage amounts refer to doses administered more than once over a period of time, such as a first dosage amount administered daily, BID, TID, or weekly, a second dosage amount administered daily, BID, TID, or weekly, and a third dosage amount administered daily, BID, TID, or weekly. In some embodiments, the first dosage amount, the second dosage amount, or the third dosage amount may be administered every other day, every second day, every third day, twice per week, or twice per month. For example, the first dosage amount of 10 mg / kg may be administered once a day for 7 days, followed by the second dosage amount of 20 mg / kg once a day for 7 days, followed by the third dosage amount of 15 mg / kg twice a day for at least about 7 days. In some embodiments, the third dosage amount is administered for at least about 7 days, at least about 14 days, or at least about 21 days.

[0321] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) may be administered using more than one route of administration. For example, the first dosage -94- 170456481.42Docket No.: 146316.8023.WO00 amount and the second dosage amount may be administered by two different routes of administration. In addition, the first dosage amount and the second dosage amount administered via different routes of administration may be the same or different dosage amounts. In some embodiments, the first dosage amount is administered orally and the second dosage amount is administered subcutaneously. The dosage frequency and / or duration of the dosage amounts may be the same or may be different. For example, the frequency of each dosage amount may be more than once per day, once per day, once every other day, once per week, or once every other week, or once per month. As another example, the duration of each dosage amount may be one day, two days, three days, more than three days, one week, more than one week, two weeks, more than two weeks, one month, or more than one month. For example, a dosing regimen may comprise a first dosage amount administered once a day or twice a day for about 5 weeks, and a second dosage amount administered subcutaneously once a day or twice a day for about 1 week. In some embodiments, the second dosage amount is administered the day after the duration of the first dosage amount is complete, or two days, three days, more than three days, one week, more than one week, two weeks, more than two weeks, one month, or more than one month after the first dosage amount is complete. In some embodiments, the second dosage amount is administered at least about 1 week after administration of the first dosage is complete.

[0322] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) is administered at a dose of (i) 10 mg / kg once a day for 7 days, followed by (ii) 20 mg / kg once a day for 7 days, followed by (iii) 15 mg / kg twice a day for at least about 7 days. In some embodiments, (iii) is administered for at least about 7 days, at least about 14 days, or at least about 21 days.

[0323] In some embodiments, the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof (e.g., the pharmaceutical composition) comprises a (i) first dose administered orally once a day or twice a day for about 5 weeks, and (ii) second dose administered subcutaneously once a day or twice a day for about 1 week. In some embodiments, the second dose is administered at least about 1 week after administration of the first dose is complete. -95- 170456481.42Docket No.: 146316.8023.WO00

[0324] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg / kg to about 20 mg / kg administered once a day for about 5 days to about 10 days; (ii) at a second dose of about 10 mg / kg to about 40 mg / kg administered once a day after administration of the first dose for about 5 days to about 10 days; (iii) at a third dose of about 5 mg / kg to about 30 mg / kg administered twice a day after administration of the second dose for at least about 5 days to about 10 days. In some embodiments, the third dose is administered twice a day for at least about 7 days or more.

[0325] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, or about 20 mg / kg administered once a day for about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days; (ii) at a second dose of about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, or about 40 mg / kg administered once a day after administration of the first dose about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, or about 10 days; (iii) at a third dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, or about 30 mg / kg administered twice a day after administration of the second dose for at least about 5 days, about, 6 days, about 7 days, about 8 days, about 9 days, or about 10 days. In some embodiments, the third dose is administered twice a day for at least about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days or more.

[0326] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg / kg administered once a day for about 7 days; (ii) at a second dose of about 15 mg / kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 10 mg / kg administered twice a day after administration of the second dose for at least about 7 days. In some embodiments, the third dose is administered twice a day for at least about 14 days or more.

[0327] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 10 mg / kg administered once a day for about 7 days; (ii) at a second dose of about 20 mg / kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 15 mg / kg administered twice a day -96- 170456481.42Docket No.: 146316.8023.WO00 after administration of the second dose for at least about 7 days. In some embodiments, the third dose is administered twice a day for at least about 14 days or more.

[0328] In some embodiments, the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 15 mg / kg administered once a day for about 7 days; (ii) at a second dose of about 25 mg / kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 20 mg / kg administered twice a day after administration of the second dose for at least about 7 days. In some embodiments, the third dose is administered twice a day for at least about 14 days or more.

[0329] In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 0.5 mg to about 75 mg once daily. In some embodiments, the non-naturally occurring melanocortin analog is administered at a dose of about 5 mg to about 60 mg once daily. In some embodiments, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.

[0330] In some embodiments, the non-naturally occurring melanocortin analog is administered as a single dosage unit. In some embodiments, the non-naturally occurring melanocortin analog dose is administered as multiple dosage units. In some embodiments, the multiple dosage units individually comprise about 2.5 mg / mL to about 100 mg / mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise about 2.5 mg / mL to about 10 mg / mL of the non-naturally occurring melanocortin analog. In some embodiments, the multiple dosage units individually comprise about 6 mg / mL of the non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is administered as about 5 dosage units to about 10 dosage units. In some embodiments, the non-naturally occurring melanocortin analog is administered as 5 dosage units. In some embodiments, the non- naturally occurring melanocortin analog is administered as 10 dosage units.

[0331] In some embodiments, 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. In some embodiments, the non- -97- 170456481.42Docket No.: 146316.8023.WO00 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. 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.

[0332] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition at a dose of about 5 mg to about 1000 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. In some embodiments, the non-naturally occurring melanocortin analog is present in the 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. In some embodiments, the non-naturally occurring melanocortin analog is present in the 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. In some embodiments, the administration is performed once per day. Methods

[0333] The present technology also provides methods of treating, preventing, reducing, or otherwise ameliorating one or more symptoms or conditions associated with metabolic dysfunction comprising administering a non-naturally occurring melanocortin analog to a subject in need thereof. The methods of the present technology may promote fat loss, prevent muscle loss, decrease body weight, accelerate weight loss, decrease fat mass to lean mass ratio, improve body composition and / or BMI, reduce waist circumference, or any combination thereof.

[0334] The present technology comprises methods of reducing body weight and / or fat mass in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog of the present technology to the subject. -98- 170456481.42Docket No.: 146316.8023.WO00

[0335] In some embodiments, the present technology comprises methods of reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. In some embodiments, the lean mass is lean muscle mass.

[0336] In some embodiments, the present technology comprises methods of treating, preventing, reducing, or otherwise ameliorating glucose intolerance and / or diabetes mellitus in the subject.

[0337] In some embodiments, the present technology comprises a method of reducing body weight and / or fat mass in an obese subject (e.g., an obese subject without diabetes mellitus or an obese subject having diabetes mellitus), comprising administering a non- naturally occurring melanocortin analog to the subject.

[0338] In some embodiments, the methods of the present technology (i) reduce a lipid droplets size (e.g., an average lipid droplet size); (ii) increase an adipose tissue mitochondrial number or adipose tissue mitochondrial concentration; (iii) increase an adipose tissue vascularization level; (iv) increase, maintain, or prevent reduction of a beige or brown adipocyte level; (v) increase a metabolic rate; (vi) increase a calorie burn level; and / or (vii) increase, maintain, or prevent reduction of an insulin sensitivity level, relative to a control.

[0339] In some embodiments, the methods of the present technology comprise reducing a lipid droplet, or an average lipid droplet, size by about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or 95%, relative to a control.

[0340] In some embodiments, the methods of the present technology comprise reducing a lipid droplet, or an average lipid droplet, size by at least 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or 95%, relative to a control.

[0341] In some embodiments, the methods of the present technology comprise reducing a lipid droplet, or an average lipid droplet, size by at least about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or 95%, relative to a control.

[0342] In some embodiments, the methods of the present technology comprise one or more of (i) increasing an adipose tissue mitochondrial number; (ii) increasing an adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; -99- 170456481.42Docket No.: 146316.8023.WO00 increasing a beige adipocyte level; (iv) increasing a brown adipocyte level; (v) increasing a metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing an insulin sensitivity level, by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more, relative to a control.

[0343] In some embodiments, the methods of the present technology comprise one or more of (i) increasing an adipose tissue mitochondrial number; (ii) increasing an adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; increasing a beige adipocyte level; (iv) increasing a brown adipocyte level; (v) increasing a metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing an insulin sensitivity level, by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more, relative to a control.

[0344] In some embodiments, the methods of the present technology comprise one or more of (i) increasing an adipose tissue mitochondrial number; (ii) increasing an adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; increasing a beige adipocyte level; (iv) increasing a brown adipocyte level; (v) increasing a metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing an insulin sensitivity level, by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, or 500% or more, relative to a control.

[0345] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0346] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating hypothalamic obesity (e.g., congenital hypothalamic damage and / or or damage from tumors or trauma) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0347] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. -100- 170456481.42Docket No.: 146316.8023.WO00

[0348] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a leptin deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0349] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. Nonlimiting examples of syndromic obesity include Prader–Willi syndrome, Wilms tumor, Aniridia, Genitourinary, Range of Developmental Delays (WAGR) syndrome, Bardet- Biedl syndrome, Fragile X syndrome, Cohen syndrome, Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, Alstrom syndrome, MC4 haploinsufficiency, 17p11.2 deletion syndrome, and 2q37 deletion syndrome.

[0350] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating non-alcoholic steatohepatitis (NASH) (i.e., metabolic dysfunction-associated steatohepatitis (MASH)), in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0351] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0352] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating Type 2 Diabetes in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0353] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a cardiovascular disease (e.g., stroke and / or heart attack) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0354] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating osteoarthritis in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. -101- 170456481.42Docket No.: 146316.8023.WO00

[0355] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a cancer (e.g., decreasing a risk of cancer) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0356] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating erectile dysfunction in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0357] In some embodiments, the method further comprises reducing obesity-related inflammation in the subject.

[0358] In some embodiments, method further comprises preserving or improving kidney function in the subject.

[0359] The present technology also provides methods of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject.

[0360] The present technology further provides methods of preserving or improving kidney function in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject.

[0361] In some embodiments, the method comprises orally administering a non- naturally occurring melanocortin analog comprising a sequence of Formula (I) to the subject. Any of the sequences of Formula (I) listed above may be used in the methods of the present technology. In some embodiments, the method comprises orally administering a non- naturally occurring melanocortin analog comprising a sequence of Formula (IA) to the subject. Any of the sequences of Formula (IA) listed above may be used in the methods of the present technology.

[0362] The present technology also provides methods of reducing body weight and / or fat mass in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of -102- 170456481.42Docket No.: 146316.8023.WO00 Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA).

[0363] The present technology also provides methods of treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA).

[0364] The present technology also provides methods of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IF).

[0365] The present technology also provides methods of preserving or improving kidney function in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I). In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IF).

[0366] The present technology also provides methods of reducing body weight and / or fat mass in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog having a sequence selected from the group consisting of SEQ ID NOs: 11, 12, and 43-45 to the subject.

[0367] In some embodiments, the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. In some embodiments, the lean mass is lean muscle mass.

[0368] In some embodiments, wherein the method further comprises treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in the subject. -103- 170456481.42Docket No.: 146316.8023.WO00

[0369] The present technology also provides methods of treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog having a sequence selected from the group consisting of SEQ ID NOs: 11, 12, and 43-45 to the subject.

[0370] In some embodiments, the method further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. In some embodiments, the lean mass is lean muscle mass. In some embodiments, the method further comprises reducing body weight and / or fat mass in the subject.

[0371] In some embodiments, the method further comprises reducing obesity-related inflammation in the subject. In some embodiments, the method further comprises preserving or improving kidney function in the subject.

[0372] The present technology also provides methods of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject.

[0373] The present technology also provides methods of preserving or improving kidney function in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject.

[0374] In some embodiments of the methods, after administration of the non-naturally occurring melanocortin analog, the subject’s body weight is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.

[0375] In some embodiments of the methods after administration of the non-naturally occurring melanocortin analog, the subject’s fat mass is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog. -104- 170456481.42Docket No.: 146316.8023.WO00

[0376] In some embodiments of the methods of the present technology, the subject exhibits about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% reduction in body weight about 10 days, about 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0377] In some embodiments of the methods of the present technology, the subject exhibits at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, or at least a 10% reduction in body weight at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0378] In some embodiments of the methods of the present technology, the subject exhibits at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, or at least about a 10% reduction in body weight at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0379] In some embodiments of the methods of the present technology, the subject exhibits about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 12.5%, about a 15%, about a 17.5%, about a 20%, about a 25%, or about a 30% reduction in fat mass about 10 days, about 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0380] In some embodiments of the methods of the present technology, the subject exhibits at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 12.5%, at least a 15%, at least a 17.5%, at least a 20%, at least a 25%, or at least a 30% reduction in fat mass at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. -105- 170456481.42Docket No.: 146316.8023.WO00

[0381] In some embodiments of the methods of the present technology, the subject exhibits at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 12.5%, at least about a 15%, at least about a 17.5%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in fat mass at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0382] In some embodiments of the methods of the present technology, the subject exhibits no change, about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% reduction in lean mass loss about 10 days, about 20 days, or about 30 days after administration of a first dose of a non- naturally occurring melanocortin analog of the present technology.

[0383] In some embodiments of the methods of the present technology, the subject exhibits no change, at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, or at least a 10% reduction in lean mass loss at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0384] In some embodiments of the methods of the present technology, the subject exhibits no change, at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, or at least about a 10% reduction in lean mass loss at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0385] In some embodiments of the method of the present technology, the subject exhibits no change, about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, or about a 10% increase in lean mass about 10 days, about 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology. -106- 170456481.42Docket No.: 146316.8023.WO00

[0386] In some embodiments of the method of the present technology, the subject exhibits no change, at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, or at least a 10% increase in lean mass at least 10 days, at least 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0387] In some embodiments of the method of the present technology, the subject exhibits no change, at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, or at least about a 10% increase in lean mass at least about 10 days, at least about 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0388] In some embodiments, the subject exhibits about a 5%, about a 10%, about a 12.5%, about a 15%, about a 17.5%, about a 20%, about a 25%, about a 30%, about a 35%, about a 40%, about a 45%, about a 50%, about a 60%, or about a 70% reduction in food intake per day about 10 days, about 20 days, or about 30 days after administration of a first dose of the combination therapy. In some embodiments, the reduction in food intake occurs about 0.5 hours, about 1 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 4 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, or about 6 weeks after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology.

[0389] Food intake may reflect cumulative food intake, net food intake, or both. Cumulative food intake may represent total food intake. Net food intake may represent the difference between total food intake and energy expenditure. Cumulative and net food intake may represent a food intake measurement from start to end of dosing, from start to an intermediate time point of dosing (i.e., a time point after the start of dosing but prior to the end of dosing), from an intermediate time point to end of dosing, or between two or more intermediate time points. -107- 170456481.42Docket No.: 146316.8023.WO00

[0390] The methods of the present technology alter a subject’s preference for food having high-fat content or low-fat content or is otherwise calorically dense or less calorically dense. In some embodiments, the methods of the present technology increase a subject’s preference for one or more of a lower-fat food or a less calorically dense food relative to the food preference of the subject at baseline or of a control. In some embodiments, the methods of the present technology decrease the subject’s preference for one or more of a higher-fat food or a more calorically dense food relative to the food preference of the subject at baseline or of a control.

[0391] In some embodiments of the methods of the present technology, the blood glucose level of the subject is decreased following administration of the combination therapy. In some embodiments, the blood glucose level of the subject is decreased following administration of a first dose of the combination therapy.

[0392] In some embodiments, the subject exhibits at least about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 15%, about a 20%, about a 25%, or about a 30% reduction in a blood glucose level about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control.

[0393] In some embodiments, the subject exhibits at least at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, or at least a 30% reduction in a blood glucose level at least 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control.

[0394] In some embodiments, the subject exhibits at least about at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in a blood glucose level at least about 1 day, 2 days, 3 days, 4 days, 8 days, -108- 170456481.42Docket No.: 146316.8023.WO00 10 days, 12 days, 14 days, 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control.

[0395] In some embodiments, the subject of the methods of the present technology may experience no change in or a reduction in one or more of an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a gamma-glutamyl transferase (GGT), a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in a biological sample from the subject. Nonlimiting examples of biological samples include a circulatory fluid sample (e.g., blood, serum, lymphatic fluid), a urine sample, or a tissue sample.

[0396] In some embodiments, the subject exhibits at least about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 15%, about a 20%, about a 25%, or about a 30% reduction in an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a GGT, a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in the biological sample about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control.

[0397] In some embodiments, the subject exhibits at least at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, or at least a 30% reduction in an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a GGT, a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in the biological sample at least 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control.

[0398] In some embodiments, the subject exhibits at least about at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, or at least about a -109- 170456481.42Docket No.: 146316.8023.WO00 30% reduction in an alkaline phosphatase level, a total protein level, an albumin level, a globulin level, a GGT, a glucose level, a urea nitrogen level, a creatine level, a urea acid level, or a C-reactive protein level in the biological sample at least about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control.

[0399] In some embodiments, the subject of the methods of the present technology experiences no change or a reduction in one or more of a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject.

[0400] In some embodiments, the subject exhibits at least about a 1%, about a 2%, about a 3%, about a 4%, about a 5%, about a 6%, about a 7%, about an 8%, about a 9%, about a 10%, about a 15%, about a 20%, about a 25%, or about a 30% reduction in a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject. In some embodiments, the reduction occurs about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control.

[0401] In some embodiments, the subject exhibits at least at least a 1%, at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 7%, at least an 8%, at least a 9%, at least a 10%, at least a 15%, at least a 20%, at least a 25%, or at least a 30% reduction in a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject. In some embodiments, the reduction occurs at least 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least 30 days after administration of a first dose of a non- naturally occurring melanocortin analog of the present technology, relative to a control. -110- 170456481.42Docket No.: 146316.8023.WO00

[0402] In some embodiments, the subject exhibits at least about at least about a 1%, at least about a 2%, at least about a 3%, at least about a 4%, at least about a 5%, at least about a 6%, at least about a 7%, at least about an 8%, at least about a 9%, at least about a 10%, at least about a 15%, at least about a 20%, at least about a 25%, or at least about a 30% reduction in a total white blood cell count level, a neutrophil level, a lymphocyte level, a monocyte level, an eosinophil level, a basophil level, a red cell distribution width level, a platelet count level, a mean platelet volume in a biological sample from the subject. In some embodiments, the reduction occurs at least about 1 day, 2 days, 3 days, 4 days, 8 days, 10 days, 12 days, 14 days, 20 days, or at least about 30 days after administration of a first dose of a non-naturally occurring melanocortin analog of the present technology, relative to a control.

[0403] In some embodiments, the subject of the methods of the present technology experiences no change or an increase in one or more of a red blood cell count, a hemoglobin level, a hematocrit level, a mean corpuscular volume level, a mean corpuscular hemoglobin level, or a mean corpuscular hemoglobin concentration level in a biological sample from the subject, relative to a control. In some embodiments, the red blood cell count, a hemoglobin level, the hematocrit level, the mean corpuscular volume level, the mean corpuscular hemoglobin level, or the mean corpuscular hemoglobin concentration level is increased in the biological sample by at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 300%, after administration of a first dose of a non- naturally occurring melanocortin analog, relative to a control.

[0404] In some embodiments, the subject of the methods of the present technology may experience no change in or an increase in an albumin to globulin ratio in a biological sample from the subject, relative to a control. In some embodiments, the albumin to globulin ratio is increased in the biological sample by at least about 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 300%, after administration of a first dose of a non-naturally occurring melanocortin analog, relative to a control.

[0405] In some embodiments, the subject administered a non-naturally occurring melanocortin analog of the present technology exhibits one or more of: -111- 170456481.42Docket No.: 146316.8023.WO00 (a) a reduction in fat mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (b) a reduction in epididymal fat mass at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (c) a reduction in perirenal fat mass at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (d) a reduction in body weight at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (e) a reduction in body mass at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (f) an increase in lean mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, or 500% relative to baseline or a control; (g) an increase in muscle mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, or 500% relative to baseline or a control; (h) an increase in glucose tolerance by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, or 500% relative to baseline or a control; (i) a reduction in a fat mass to lean mass ratio at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (j) a reduction in BMI by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; -112- 170456481.42Docket No.: 146316.8023.WO00 (k) a reduction in waist circumference at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% relative to baseline or a control; (l) a reduction in an adverse cardiovascular event by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (m) a reduction in brain mass loss by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (n) a reduction in a hemoglobin A1c level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (o) a reduction in nausea by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (p) a reduction in vomiting by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (q) a reduction in diarrhea by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (r) a reduction in inflammation by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (s) a reduction in obesity-related inflammation by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; -113- 170456481.42Docket No.: 146316.8023.WO00 (t) an increase in kidney function by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250%, 300%, 400%, or 500% relative to baseline or a control; (u) a reduction in hyperplasia by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (v) a reduction in alcohol use by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (w) a reduction in metabolic dysfunction by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (x) a reduction in a symptom associated with metabolic dysfunction by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (y) a reduction in blood sugar by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (z) a reduction in weight gain after treatment with a weight loss agent or a non-naturally occurring melanocortin analog is terminated by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to baseline or a control; (aa) a reduction in body weight measured in kg by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (bb) a reduction in BMI by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; -114- 170456481.42Docket No.: 146316.8023.WO00 (cc) a reduction in trunk fat mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (dd) an increase in a bone mineral content level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (ee) an increase in a whole-body bone mineral content level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (ff) an increase in a trunk bone mineral content level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (gg) an increase in a bone density level by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (hh) an increase in a trunk muscle mass by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, or 300%, relative to baseline or a control; (ii) a reduction in food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (jj) a reduction in caloric intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (kk) a reduction in a high-fat food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; -115- 170456481.42Docket No.: 146316.8023.WO00 (ll) a reduction in a calorically dense food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; (mm) an increase in a low-fat food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control; or (nn) an increase in a less calorically dense food intake by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, relative to baseline or a control.

[0406] In some embodiments, any one of (a)-(nn) is maintained for at about 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after administration of the non-naturally occurring melanocortin analog.

[0407] In some embodiments, any one of (a)-(nn) is maintained for at least 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after administration of the non-naturally occurring melanocortin analog.

[0408] In some embodiments, any one of (a)-(nn) is maintained for at least about 2 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, 1 year, or 5 years, after administration of the non-naturally occurring melanocortin analog.

[0409] In some embodiments, any one of (a)-(nn) occurs during or after administration of a first, a second, and / or a third dose of the non-naturally occurring melanocortin analog. In some embodiments, any one of (a)-(nn) is greater during or after administration the second dose relative to during or after administration of the first dose. In some embodiments, any one of (a)-(nn) is greater during or after administration the third dose relative to during or after administration of the first dose or the second dose.

[0410] In some embodiments, the muscle mass is cardiac muscle mass, skeletal muscle mass, or both. In some embodiments, the cardiac muscle mass is determined by measuring change in heart weight. In some embodiments, the skeletal muscle mass is determined by measuring change in gastrocnemius tissue weight. In related embodiments, the muscle mass change is cardiac muscle mass change, skeletal muscle mass change, or -116- 170456481.42Docket No.: 146316.8023.WO00 both. In some embodiments, cardiac muscle is determined by heart weight. In some embodiments, skeletal muscle mass is determined by gastrocnemius tissue weight. In some embodiments, the muscle mass changes may be assessed by using magnetic resonance imaging (MRI) and / or or nuclear magnetic resonance (NMR). Weight Loss Agents

[0411] Administration of the non-naturally occurring melanocortin analogs of the present technology may comprise rebound-resistant weight loss (i.e., prevention of weight gain after treatment completion) and / or increased muscle retention, relative to a control (e.g., administration of a conventional weight loss agent alone). The rebound resistant weight loss may comprise a prevention or a reduction in fat mass gain and / or BMI increase, relative to the control. In some embodiments, the non-naturally occurring melanocortin analog is administered as a combination therapy with a weight loss agent, where the combination therapy achieves the same weight loss as administration of the weight loss agent alone, but at a reduced dose or dosing frequency relative to the weight loss agent.

[0412] In some embodiments, the rebound-resistant weight loss is maintained for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and / or discontinued.

[0413] In some embodiments, the rebound-resistant weight loss is maintained for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and / or discontinued.

[0414] In some embodiments, the rebound-resistant weight loss is maintained for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and / or discontinued.

[0415] In other embodiments, the subject’s weight increases no more than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less than about 1%. -117- 170456481.42Docket No.: 146316.8023.WO00

[0416] In some embodiments, the present technology comprises a method of suppressing appetite in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the weight loss agent. Administration of the non-naturally occurring melanocortin analog prior to, during, and / or after administration of the weight loss agent may produce an additive or synergistic effect on suppressing the subject’s appetite. In some embodiments, the weight loss agent is a GLP-1 receptor agonist and the non-naturally occurring melanocortin analog is a melanocortin agonist and administration of the combination therapy produces an additive effect on suppressing the subject’s appetite. In some embodiments, the weight loss agent is a dual GLP-1 / GIP receptor agonist and the non-naturally occurring melanocortin analog is a melanocortin agonist and administration of the combination therapy produces a synergistic effect on suppressing the subject’s appetite.

[0417] In some embodiments, the method reduces food intake of the subject. Administration of the non-naturally occurring melanocortin analog prior to, during, and / or after administration of the weight loss agent may produce an additive or synergistic effect on reducing the subject’s food intake. In some embodiments, the method reduces fat body mass and / or body weight of the subject. In some embodiments, the reduction in food intake is a reduction in caloric intake.

[0418] In other embodiments, the subject’s weight increases no more than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less than about 1% at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the non-naturally occurring melanocortin analog is complete and / or discontinued.

[0419] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating body weight gain a during or after use of a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0420] In some embodiments, the present technology comprises a method of maintaining body weight after use of a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject. -118- 170456481.42Docket No.: 146316.8023.WO00

[0421] In some embodiments, the present technology comprises a method of preventing, reducing, or otherwise ameliorating a fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0422] The methods of the present technology may decrease the risk and / or incidence of adverse cardiovascular events associated with the use of a weight loss agent including, but not limited to, cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, angina, sinus tachycardia, sinus bradycardia, coronary artery bypass grafting, percutaneous coronary intervention, heart failure, carotid endarterectomy, peripheral vascular disease, or any combination thereof. Cardiac Effects

[0423] The methods of the present technology may prevent or decrease the risk and / or incidence of adverse cardiac effects associated with the use of conventional melanocortin analogs, melanocortin peptides, and / or melanocortin receptor agonists. In some embodiments, the subject of the present technology experiences no or substantially no adverse cardiac effects and / or no change in cardiac outcomes during or after administration of a non-naturally occurring melanocortin analog of the present technology, relative to a control (e.g., a subject administered conventional melanocortin analogs, melanocortin peptides, and / or melanocortin receptor agonists). In some embodiments, the adverse cardiac effect and / or change in cardiac outcomes comprises one or more of a change in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, mean arterial blood pressure), heart rate, QT interval, QRS interval, RR interval, or QTc, relative to a control. In some embodiments, the adverse cardiac effect and / or change in cardiac outcomes is a transient change in blood pressure (e.g., systolic blood pressure, diastolic blood pressure, mean arterial blood pressure), heart rate, QT interval, QRS interval, RR interval, or QTc, relative to a control. In some embodiments, the transient change in blood pressure comprises an increase in blood pressure in the evening, at night, during a sleep cycle, or during a dark cycle after administration of the conventional melanocortin analogs, melanocortin peptides, and / or melanocortin receptor agonists. Tanning and Hyperpigmentation -119- 170456481.42Docket No.: 146316.8023.WO00

[0424] The present technology comprises a method of inducing a tanning effect in a subject during or after administration of a non-naturally occurring melanocortin analog. In some embodiments, the tanning effect comprises skin darkening without hyperpigmentation (e.g., an uneven distribution of melanin) compared to subjects who have not received the non-naturally occurring melanocortin analog or compared to the same subject at baseline (e.g., prior to receiving a dose of the non-naturally occurring melanocortin analog). In some embodiments, the tanning effect is not clinically significant, occurs in response to UV or sun exposure, and / or is not substantially ectopic. The tanning effect may occur in combination with weight loss. The weight loss may comprise a retention in muscle mass (e.g., lean muscle mass) and a loss of fat mass. In some embodiments, the tanning effect is observed about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 20 days after administration of a non- naturally occurring melanocortin analog. In some embodiments, the tanning effect occurs at a dose of greater than 100 mg or at least about 200 mg.

[0425] In some embodiments, the tanning effect is reduced after completion and / or discontinuation of the non-naturally occurring melanocortin analog dosing. In some embodiments, the tanning effect is reduced at least about 1 day, 2 days, 3 days, 4 days, 5 days, 1 week, 2 weeks, 3 week, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, 15 weeks, or 20 weeks after completion and / or discontinuation of the non-naturally occurring melanocortin analog dosing.

[0426] In some embodiments the reduced tanning effect comprises reversal of about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% 90%, 95%, 99%, or 100% of the total area of skin darkening. In some embodiments, the tanning effect does not comprise ectopic skin hyperpigmentation and / or tanning effects (e.g., of the palms or gums).

[0427] In some embodiments the reduced tanning effect comprises reversal of at least 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% 90%, 95%, 99%, or 100% of the total area of skin darkening. In some embodiments, the tanning effect does not comprise ectopic skin hyperpigmentation and / or tanning effects (e.g., of the palms or gums).

[0428] In some embodiments the reduced tanning effect comprises reversal of at least about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80% 90%, 95%, 99%, or 100% of -120- 170456481.42Docket No.: 146316.8023.WO00 the total area of skin darkening. In some embodiments, the tanning effect does not comprise ectopic skin hyperpigmentation and / or tanning effects (e.g., of the palms or gums).

[0429] The non-naturally occurring melanocortin analog may be useful in treating, preventing, or otherwise ameliorating one or more hypopigmentation diseases. Nonlimiting examples of hypopigmentation disease include albinism (e.g., oculocutaneous albinism), vitiligo, piebaldism, nevus depigmentosus, hypomelanosis of Ito, phenylketonuria, tuberous sclerosis, dyschromatosis symmetrica hereditaria, Waardenburg syndrome, Hermansky- Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome, and Tietz syndrome, and acquired hypopigmentary diseases such as leukoderma Sutton, Vogt-Koyanagi Harada syndrome, leukoderma senile, leukoderma after sea bathing, and leukoderma syphiliticum.

[0430] The methods of the present technology may prevent or decrease the risk and / or incidence of hyperpigmentation associated with the use of conventional melanocortin analogs, melanocortin peptides, and / or melanocortin receptor agonists. In some embodiments, the subject of the present technology experiences no or substantially no hyperpigmentation during or after administration of a non-naturally occurring melanocortin analog of the present technology, relative to a control (e.g., a subject administered conventional melanocortin analogs, melanocortin peptides, and / or melanocortin receptor agonists). In some embodiments, the hyperpigmentation comprises one or more of hyperpigmentation of the skin, nose, cheeks, or site of administration of the non-naturally occurring melanocortin analog. Subjects

[0431] In some embodiments, the subject has a body mass index (BMI) of 18.5 kg / m2to 35 kg / m2. In some embodiments, the subject has a BMI of less than 20 kg / m2. In some embodiments, the subject has a BMI of less than 18.5 kg / m2.

[0432] In some embodiments, the subject has a BMI of greater than 24.9 kg / m2. In some embodiments, the subject has a BMI of 25 kg / m2to 29.9 kg / m2. In some embodiments, the subject has a BMI of greater than or equal to 30 kg / m2. -121- 170456481.42Docket No.: 146316.8023.WO00

[0433] In some embodiments, the subject is an overweight subject. Overweight subjects include those having a body weight about 3% or more, 5% or more, 10% or more, 20% or more, or 30% or less, than the upper end of "normal" BMI (e.g., 24.9 kg / m2).

[0434] In some embodiments, the subject is an obese subject. Obese subjects include those having a BMI of greater than or equal to 30 kg / m2.

[0435] In some embodiments, the subject has a metabolic dysfunction. In some embodiments, the metabolic dysfunction is selected from the group consisting of obesity, diabetes mellitus, metabolic syndrome, insulin resistance, non-alcoholic fatty liver disease, polycystic ovarian syndrome, metabolic acidosis, hypothyroidism, hyperlipidemia, Cushing Syndrome, and metabolic myopathies. In other embodiments, the subject has another condition which is not metabolic dysfunction, but administration of the weight loss agent provides therapeutic benefit to the non-metabolic dysfunction condition.

[0436] In some embodiments, the subject with a metabolic dysfunction has previously received treatment with the weight loss agent. A subject who has previously received treatment with the weight loss agent has completed at least one full treatment cycle with the weight loss agent. In other embodiments, the subject with a metabolic dysfunction is currently receiving treatment with the weight loss agent. A subject who is currently receiving treatment with the weight loss has received at least one dose of the weight loss agent. In still other embodiments, the subject with a metabolic dysfunction has not received any treatment with the weight loss agent. A subject who has not received any treatment with the weight loss agent has not received even a single dose of the weight loss agent.

[0437] In accordance with the present technology, a subject who has been treated with a weight loss agent has received a weight loss agent in an amount sufficient to induce at least minimum weight loss. Likewise, a subject how is currently undergoing treatment with a weight loss agent is receiving a weight loss agent in an amount sufficient to induce at least minimum weight loss.

[0438] In some embodiments, the subject has previously received treatment with the weight loss agent and has not lost body weight and / or fat mass. Alternatively, in some embodiments, the subject has previously received treatment with the weight loss agent and -122- 170456481.42Docket No.: 146316.8023.WO00 has lost body weight and / or fat mass. In such embodiments, the subject may still be overweight or obese. The subject may have stopped treatment with the weight loss agent because they were unable to continue losing body weight and / or fat mass with the weight loss agent.

[0439] In embodiments in which the subject has previously received treatment with the weight loss agent, the subject’s body weight may be more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.

[0440] In embodiments in which the subject has previously received treatment with the weight loss agent, the subject’s fat mass may be more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.

[0441] In some embodiments, the subject is currently receiving treatment with the weight loss agent and has not lost any body weight. Alternatively, in some embodiments, the subject is currently receiving treatment with the weight loss agent and has lost body weight and / or fat mass. In some embodiments, the subject is currently receiving treatment with the weight loss agent, has lost body weight and / or fat mass, and has failed to lose sufficient body weight and / or fat mass following administration of the weight loss agent. The subject who is currently receiving treatment with the weight loss agent may still be overweight or obese.

[0442] In embodiments in which the subject is currently receiving treatment with the weight loss agent, the subject’s body weight may be more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.

[0443] In embodiments in which the subject is currently receiving treatment with the weight loss agent, the subject’s fat mass may be more than 5%, more than 10%, more than -123- 170456481.42Docket No.: 146316.8023.WO00 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.

[0444] In some embodiments, the subject has not received any treatment with the weight loss agent and has failed to lose sufficient or any weight using other weight loss methods. In some embodiments, the subject has not received any treatment with the weight loss agent and has not attempted to lose weight using any other methods. In such embodiments, the subject may begin treatment with non-naturally occurring melanocortin analog and the weight loss agent at the same time. A subject who begins administration of the weight loss agent and the non-naturally occurring melanocortin analog at the same time, and continues with concurrent administration of the two therapies, may experience greater body weight and / or fat mass loss compared to a subject who is administered only one of the therapies, e.g., only the weight loss agent or only the non-naturally occurring melanocortin analog.

[0445] In embodiments in which the subject begins treatment with the non-naturally occurring melanocortin analog and the weight loss agent at the same time, the subject’s body weight may be more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, or more than 55% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.

[0446] In embodiments in which the subject begins treatment with the non-naturally occurring melanocortin analog and the weight loss agent at the same time, the subject’s fat mass may be more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, or more than 55% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.

[0447] In some embodiments, the method prevents or reduces muscle mass loss (e.g., involuntary muscle mass loss) in the subject. In some embodiments, the subject’s muscle mass is not more than 5%, not more than 10%, not more than 15%, not more than 20%, not -124- 170456481.42Docket No.: 146316.8023.WO00 more than 25%, or not more than 30% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the weight loss agent.

[0448] In some embodiments, the weight loss agent is administered to the subject for treating or preventing one of one or more metabolic dysfunctions. Nonlimiting examples of metabolic dysfunctions include obesity, diabetes mellitus, metabolic syndrome, insulin resistance, non-alcoholic fatty liver disease, polycystic ovarian syndrome, metabolic acidosis, hypothyroidism, hyperlipidemia, Cushing Syndrome, and metabolic myopathies.

[0449] The subject of the present technology may be 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. Pharmacokinetics and Pharmacodynamics

[0450] 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.

[0451] 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., Tfinal, Cmax, T ½ (h)), AUC, or Tmax. 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

[0452] “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 -125- 170456481.42Docket No.: 146316.8023.WO00 over time (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 (λz) or an inter-compartmental clearance (Q).

[0453] 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. In some embodiments, the reduced clearance comprises an intestinal fluid clearance, a gastric fluid clearance, a liver clearance, or a liver microsome clearance.

[0454] 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

[0455] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise an increased tissue, plasma, serum, or aqueous 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. The aqueous concentration may comprise an intestinal fluid concentration or a gastric fluid concentration.

[0456] 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 -126- 170456481.42Docket No.: 146316.8023.WO00 trough concentration (Ctrough), or a concentration at the end of administration (e.g., infusion) time (CT).

[0457] 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).

[0458] 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).

[0459] 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.

[0460] In some embodiments, the increased concentration is reflected by a final measurable concentration (Tfinal). An increased Tfinal may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control.

[0461] 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).

[0462] In some embodiments, the increased concentration is reflected by a reduction in a partition coefficient or an increase in a partition coefficient, relative to a control. The reduced partition coefficient may reflect an increase in aqueous solubility (e.g., an intestinal -127- 170456481.42Docket No.: 146316.8023.WO00 fluid or a gastric fluid), relative to the control. In some embodiments, the increased partition coefficient may reflect an increase in membrane permeability, relative to the control.

[0463] 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.

[0464] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement at least 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.

[0465] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement at least 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.

[0466] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement during administration of the non-naturally occurring melanocortin analogs.

[0467] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement at the completion of administration of the non- naturally occurring melanocortin analogs.

[0468] In some embodiments, the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng / mL to at least about 2000 ng / mL about 24 hours after administration of the non-naturally occurring melanocortin analog.

[0469] In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject until the concentration of the non-naturally occurring -128- 170456481.42Docket No.: 146316.8023.WO00 melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng / mL to at least about 2000 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 5 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 10 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 50 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 100 ng / mL after administration of the non- naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 200 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 300 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 400 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 500 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the wherein concentration is at least about 750 ng / mL after administration of the non- naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 1000 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the is at least about 1500 ng / mL after administration of the non- naturally occurring melanocortin analog. In some embodiments, the concentration is at least about 2000 ng / mL after administration of the non-naturally occurring melanocortin analog. In some embodiments, the concentration is a Cmax. Distribution

[0470] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise an increased distribution relative to a control. The increased distribution may be an increase in distribution 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 distribution may be measured at an intermediate time point or a final time point. -129- 170456481.42Docket No.: 146316.8023.WO00

[0471] In some embodiments, the measurement of distribution comprises measuring a volume of distribution at the terminal phase (Vd or Vdß), a central volume of distribution (V), a peripheral volume of distribution (V2), an apparent volume of distribution (Vz), or a measurement of distribution comprises measuring a volume of distribution at steady state (Vss). A high or increased Vd, Vdß, Vz, and / or Vss may suggest large distribution beyond the tissue, plasma, and / or serum compartment, relative to the control.

[0472] In some embodiments, the increase in distribution 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.

[0473] In some embodiments, the increase in distribution comprises a measurement at least 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.

[0474] In some embodiments, the increase in distribution comprises a measurement at least 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.

[0475] In some embodiments, the increase in distribution comprises a measurement during administration of the non-naturally occurring melanocortin analogs.

[0476] In some embodiments, the increase in distribution comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs. Additional pD and pK Embodiments

[0477] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following: (a) an increase in half-life relative to a control; (b) a reduction in clearance relative to a control; (c) an increase in tissue concentration relative to a control; -130- 170456481.42Docket No.: 146316.8023.WO00 (d) an increase in plasma concentration relative to a control; (e) an increase in serum concentration relative to a control; (f) an increase in distribution relative to a control; (g) an increase in an AUC measurement relative to a control; (h) an increase in a DNAUC measurement relative to a control; (i) an increase in Tfinal relative to a control; (j) an increase in Cmax relative to a control; (k) an increase in Cmin relative to a control; (l) an increase in DNCmin relative to a control; (m) an increase in MRT relative to a control; (n) an increase in Cavg relative to a control; (o) an increase in Ctrough relative to a control; (p) an increase in CT relative to a control; (q) an increase in Vd relative to a control; (r) a reduction in Tmax relative to a control; or (s) a reduction in Q relative to a control.

[0478] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following, relative to a control: (a) an increase in half-life by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (b) a reduction in clearance by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control; -131- 170456481.42Docket No.: 146316.8023.WO00 (c) an increase in tissue concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (d) an increase in plasma concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (e) an increase in serum concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (f) an increase in distribution by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (g) an increase in an AUC by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% measurement relative to a control; (h) an increase in a DNAUC measurement by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (i) an increase in Tfinal by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (j) an increase in Cmax by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (k) an increase in Cmin by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; -132- 170456481.42Docket No.: 146316.8023.WO00 (l) an increase in DNCmin by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (m) an increase in MRT by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (n) an increase in Cavg by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (o) an increase in Ctrough by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (p) an increase in CT by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (q) an increase in Vd by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control; (r) a reduction in Tmax by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control; or (s) a reduction in Q by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control. EXAMPLES

[0479] The following examples are intended to illustrate various embodiments of the present technology. As such, the specific embodiments discussed are not to be construed as limitations on the scope of the present technology. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of present technology, and it is understood that such equivalent -133- 170456481.42Docket No.: 146316.8023.WO00 embodiments, are to be included herein. Further, all references cited herein are hereby incorporated by reference in their entirety, as if fully set forth herein. Example 1: Peptide Synthesis-Generic

[0480] The non-naturally occurring melanocortin analogs of the present technology were synthesized by conventional procedures (e.g., solution-phase procedure, solid-phase synthesis) for the formation of a peptide linkage between amino acids. The solution-phase procedure involved a condensation between the free alpha amino group of an amino acid or derivative thereof having the carboxyl group or other reactive groups protected and the free primary carboxyl group of another amino acid or derivative thereof having the amino group or other reactive groups protected. The solid-phase synthesis utilized a variety of resins and reagents and may involve additional purification steps.

[0481] The process for synthesizing the non-naturally occurring melanocortin analogs was generally performed by a procedure as follows. Each amino acid in the desired sequence of the non-naturally occurring melanocortin analogs was added one at a time in succession to another amino acid or derivative thereof or by a procedure whereby peptide fragments with the desired amino acid sequence were first synthesized conventionally and then condensed to provide the desired peptide. In most cases, the resulting peptide was then cyclized to yield a cyclic peptide.

[0482] Solid-phase peptide synthesis was carried out by sequentially incorporating the desired amino acid residues one at a time into the growing peptide chain coupled to a solid- phase support according to the general principles of solid phase methods (see Merrifield, Angew Chem.24:799-810 (1985) and Barany et al., The Peptides, Analysis, Synthesis and Biology, Vol. 2, Gross E. and Meienhofer J., Eds. Academic Press 1-284 (1980)). An exemplary solid-phase synthesis of non-naturally occurring melanocortin analogs is provided below.

[0483] Initially, the C-terminal amino acid residue of the non-naturally occurring melanocortin analog was coupled to a solid-phase support, e.g., a solid-phase resin. Coupling of the C-terminal amino acid residue and the solid-phase support may be carried out according to any method know in the art. Depending on the coupling method, the alpha- -134- 170456481.42Docket No.: 146316.8023.WO00 amine of the C-terminal amino acid residue may or may not be protected with an amine protecting group, as described below. Likewise, the carboxyl group of the amino acid residue may or may not be activated prior to coupling to the solid-phase support in order to increase its electrophilicity. Some methods of coupling rely on the formation of an ester bond between the carboxyl group of the amino acid and a reactive handle on the solid-phase resin. For example, an amino acid residue may be coupled to a p-benzyloxybenzyl alcohol resin (Wang) or a 2-chlorotrityl chloride resin via an ester linkage. Some methods of coupling rely on the formation of an aminde bond between the carboxyl group of the amino acid and a reactive handle on the solid-phase resin For example, an amino acid residue may be coupled to a benzhydrylamine (BHA) resin through an Fmoc-linker such as, for example, p- [(R,S)-α-[1-(9H-fluor-en-9-yl)-methoxyformamido]-2,4-dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) via an amide linkage.

[0484] The non-naturally occurring melanocortin analog was then synthesized by sequential amino acid addition or combination of peptide fragments. Subsequently, the peptide was cleaved from the solid-phase support and purified by methods known in the art, such as, for example, reverse phase high performance liquid chromatography (RP-HPLC) using a suitable column, such as a C18 column. Additionally, or alternatively, other methods of separation or purification were employed, including, but not limited to, methods based on the size or charge of the peptide. Once purified, the peptide was characterized by methods such as high-performance liquid chromatograph (HPLC), amino acid analysis, mass spectrometry, and the like. Example 2: Peptide Synthesis-Protecting Groups

[0485] During synthesis of the non-naturally occurring melanocortin analogs, reactive side chain groups of the various amino acid residues were protected with suitable protecting groups, which prevented undesirable chemical reaction from occurring at that site until the protecting group was removed.

[0486] Additionally, protection of the alpha amino group of an amino acid residue or fragment was performed while that entity reacting with the carboxyl group, followed by the selective removal of the alpha amino protecting group to allow a subsequent reaction to take place at that site. Specific protecting groups for solid phase synthesis methods and solution -135- 170456481.42Docket No.: 146316.8023.WO00 phase synthesis methods are known to those having ordinary skill in the art. Alpha amino groups were protected by a suitable protecting group, including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p- chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p- biphenyl-isopropoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc) and p- methoxybenzyloxycarbonyl (Moz); aliphatic urethane-type protecting groups, such as t- butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc was also used for alpha amino protection. Guanidino groups, if present, were protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tos), Z, pentamethylchromanesulfonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and Boc. Pmc was used as a protecting group for Arg.

[0487] Alpha aminoprotecting groups may be removed under basic conditions, such as, for example, using a solution of piperidine, piperazine, diethylamine, or morpholine (20- 40% v / v) in N,N-dimethylformamide (DMF). In synthesis methods in which alpha amino protecting groups were used, protecting groups were removed after synthesis of the peptide and before or after cleavage of the solid-phase support. Example 3: Peptide Synthesis-Additional Modifications

[0488] If necessary, the peptides were further modified to obtain N-terminus modifications, such as acetylation, while on resin, or were removed from the resin by use of a cleaving reagent and then modified. Likewise, C-terminus modification (e.g., amidation), was performed if needed.

[0489] Additionally, the cyclized peptide structures were obtained prior to cleavage from the peptide resin. For cyclization through reactive side chain moieties, the desired side chains were deprotected, and the peptide suspended in a suitable solvent and a cyclic coupling agent added. Suitable solvents, for example DMF, dichloromethane (DCM) or 1- methyl-2-pyrrolidone (NMP), were used for the cyclization. Suitable cyclic coupling reagents (e.g., 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H- benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), benzotriazole- 1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1-yl- -136- 170456481.42Docket No.: 146316.8023.WO00 oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1H-benzotriazol- 1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1 (2H)-pyridyl)-1,1,3,3- tetramethyluronium tetrafluoroborate (TPTU), N,N′-dicyclohexylcarbodiimide / 1- hydroxybenzotriazole (DCCl / HOBt)) were also used for the cyclization. Coupling was initiated by a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N- methylmorpholine (NMM). Example 4: Biological Data

[0490] The agonist and antagonist activity of exemplary non-naturally occurring melanocortin analogs at the melanocortin receptors (e.g., MC1R, MC3R, MC4R, and MC5R) were measured via cAMP accumulation assay, according to the following procedure. Experimental design and execution were conducted by Epics Therapeutics S.A. EuroscreenFast (Bruxelles, Belgium). Compound Handing

[0491] Compounds were delivered as powder (1 mg) or 10 mM solutions (100 μl) in 100% DMSO. Powders were solubilized in 100% DMSO at a concentration of 10 mM (master solution) in a solvent volume defined. Serial dilutions were performed from master solution in 100% DMSO to obtain intermediate concentrations 200-, 300- or 400-fold higher than the concentrations to be tested, depending on the assay. Each sample was diluted 100- fold in the assay buffer and dispensed in a test plate. Amounts, solvents, and dilutions were estimated based on standard small-molecule drugs. Cell lines used for functional assays are shown in Table 1. Table 1. Cell lines Receptor Cell Line Reference agonist Reference t Compound-137- 170456481.42Docket No.: 146316.8023.WO00

[0492] Compounds were tested for (i) agonist and / or antagonist activity at the human MC3 (FAST-0232C) and MC4 (FAST-0233C) receptors, (ii) agonist activity at the human MC1 (FAST-0230C) receptor, and / or (iii) agonist activity at the human MC5 (FAST-0233C) receptor at the following nanomolar concentrations, in duplicate: 0.0001, 0.001, 0.01, 0.03, 0.1, 0.3, 1, 10, 100, and 1,000. Testing Protocol

[0493] Cyclic AMP (cAMP) Homogenous Time-Resolved Fluorescence (HTRF) assay for Gs coupled receptor:

[0494] CHO-K1 cells expressing recombinant human receptor grown prior to the test in media without antibiotic were detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in assay buffer (KRH: 5 mM KCl, 1.25 mM MgSO4, 124 mM NaCl, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1.45 mM CaCl2, 0.5 g / l BSA, supplemented with 1mM IBMX or 25μM Rolipram).

[0495] Dose response curves were performed in parallel with the reference compounds.

[0496] For agonist test (384well): 5 μl of cells were mixed with 5 μl of the test compound at increasing concentrations and then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1-hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit.

[0497] For antagonist test (384well): 5 μl of cells were mixed in the wells of an assay plate with 5 μl of a mix of test compound at increasing concentrations and reference agonist for a final concentration corresponding to the historical EC80. The plates were then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1-hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit. Quality Control for Compound Testing -138- 170456481.42Docket No.: 146316.8023.WO00

[0498] On each day of experimentation and prior to the testing of compounds, reference compounds were tested at several concentrations in duplicate (n=2) to obtain a dose-response curve and an estimated EC50 and / or IC50 values.

[0499] Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session.

[0500] A session was considered as valid only if the reference value was found to be within a 0.5 logs interval from the historical value.

[0501] For replicate determinations, the maximum variability tolerated in the test was of + / -20% around the average of the replicates. Non-naturally occurring melanocortin analog grouping

[0502] Group A included non-naturally occurring melanocortin analogs A1 to A4, all of which are cyclic peptides comprising the motif c[Asp-His-p(F)dPhe-Arg-Trp-Lys] (SEQ ID NO: 161). Group A melanocortin analogs also comprise Ala or dArg at the N-terminus and dVal-dPro or dTle-dPro at the C-terminus. Group A non-naturally occurring melanocortin analogs are provided in Table 2. Table 2. Group A non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analo NOp y g g , all of which are cyclic peptides comprising the motif c[Asp-His-p(F)dPhe-Arg-Trp-Lys] (SEQ ID NO: 161). Group B melanocortin analogs also comprise Arg, Lys, dLys, His, or dHis at the N-terminus and dVal-dPro or dTle-dPro at the C-terminus. Group B non-naturally occurring melanocortin analogs are provided in Table 3. -139- 170456481.42Docket No.: 146316.8023.WO00 Table 3. Group B non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO 2 2 2 2l of which are cyclic peptides comprising the motif c[Asp-His-p(F)dPhe-Arg-Trp-Lys] (SEQ ID NO: 161). Group C melanocortin analogs also comprise Nle at the N-terminus. Group C non-naturally occurring melanocortin analogs are provided in Table 4. Table 4. Group C non-naturally occurring melanocortin analogs Melanocortin SEQ ID n l NO Formula 2 2 2 2 o--140- 170456481.42Docket No.: 146316.8023.WO00

[0505] Group D included non-naturally occurring melanocortin analogs D1 to D4, all of which are cyclic peptides comprising a derivative of the motif c[Asp-His-p(F)dPhe-Arg-Trp- Lys] (SEQ ID NO: 161). Derivatives of the motif of SEQ ID NO: 161 may include substitution of His with another amino acid, for example, Gln or dHis, substitution of Arg with another amino acid, for example, His, or substitution of Trp with another amino acid, for example, dNal(2’). Group D non-naturally occurring melanocortin analogs are provided in Table 5. Table 5. Group D non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO H2l of which are cyclic peptides comprising the motif c[Asp-His-dPhe-Arg-Trp-Lys] (SEQ ID NO: 164) or a derivative thereof. Derivatives of the motif of SEQ ID NO: 164 included in Group E melanocortin analogs include insertions of a Pro between Asp and His or between Trp and Lys. Group E non-naturally occurring melanocortin analogs are provided in Table 6. Table 6. Group E non-naturally occurring melanocortin analogs Melanocortin SEQ ID l NO Formula

[0050] Group ncuded non-naura y occurrng meanocor n anaogs o , al of which are cyclic peptides comprising a derivative of the motif c[Asp-His-dPhe-Arg-Trp-Lys] (SEQ ID NO: 164). Derivatives of the motif of SEQ ID NO: 164 may include substitution of His with another amino acid, for example, Gln, Pro or dHis, or substitution of Arg with another -141- 170456481.42Docket No.: 146316.8023.WO00 amino acid, for example, cisPro(guan) or transPro(guan). Group F non-naturally occurring melanocortin analogs are provided in Table 7. Table 7. Group F non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula analog NO 2 2s a cyclic peptide comprising a derivative of the motif c[Asp-His-dPhe-Arg-Trp-Lys] (SEQ ID NO: 164). The derivative of the motif of SEQ ID NO: 164 included in the Group G melanocortin analog includes at least one insertion between Asp and His. The Group G non-naturally occurring melanocortin analog is provided in Table 8. Table 8. Group G non-naturally occurring melanocortin analog Melanocortin SEQ ID Formula analo NO, l of which are cyclic peptides comprising the motif dAla-His-dPhe-Arg-Trp (SEQ ID NO: 163), or a derivative thereof. Derivatives of the motif of SEQ ID NO: 163 may include substitution of dAla with a similar amino acid, for example, Ala. Group H non-naturally occurring melanocortin analogs are provided in Table 9. Table 9. Group H non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula 2 2-142- 170456481.42Docket No.: 146316.8023.WO00 H3 40 Ac-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 ofwhich are cyclic peptides comprising the motif His-p(Cl)dPhe-Arg-Trp (SEQ ID NO: 165). Group I melanocortin analogs also comprise Nle at the N-terminus. Group I non-naturally occurring melanocortin analogs are provided in Table 10. Table 10. Group I non-naturally occurring melanocortin analogs Melanocortin SEQ ID analog NO Formula 2 2 2nd O10, all of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp-Orn (SEQ ID NO: 162), or a derivative thereof. Derivatives of SEQ ID NO: 162 may include substitution of Arg with a similar amino acid, for example, His. Group O non-naturally occurring melanocortin analogs are provided in Table 11. Table 11. Group O non-naturally occurring melanocortin analogs Melanocortin SEQ ID Formula l NO 2 2go s ac y o ea oco a aogs o ea oco ecepo a ea oco n 5 receptor

[0512] Administration of some non-naturally occurring melanocortin analogs activated melanocortin 1 receptor (MC1R) and melanocortin 5 receptor (MC5R) activity, as measured by cAMP levels (Table 12). -143- 170456481.42Docket No.: 146316.8023.WO00 Table 12. Dose-response results of melanocortin analogs and control against the melanocortin 1 receptor (MC1R) and the melanocortin 5 receptor MC1R MC5R Compound Max Max n-144- 170456481.42Docket No.: 146316.8023.WO00 23 C5 0.01 102.78 0.41 101.46 24 C6 0.00 99.42 0.02 102.04rtin 4 receptor

[0513] Administration of all the non-naturally occurring melanocortin analogs activated melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels (Table 13). -145- 170456481.42Docket No.: 146316.8023.WO00 Table 13. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) in agonist mode MC3R MC4R Compound Max Max n-146- 170456481.42Docket No.: 146316.8023.WO00 24 C6 0.33 87.59 0.24 100.29 25 C7 0.36 88.52 0.33 99.69ortin 4 receptor

[0514] Administration of none of the non-naturally occurring melanocortin analogs substantially inhibited melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels (Table 14). -147- 170456481.42Docket No.: 146316.8023.WO00 Table 14. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) in antagonist mode MC3R MC4R Compound Max Max n-148- 170456481.42Docket No.: 146316.8023.WO00 24 C6 >1000 nd >1000 nd 25 C7 >1000 nd >1000 ndComparison of agonist activity of O10 and similar melanocortin analogs

[0515] To determine the impact that certain features of the melanocortin analogs of the present technology had on agonist activity at the different melanocortin receptors, the agonist activity of O10 was compared to the agonist activity of similar sequences. Specifically, O10 was compared to sequences with different lactam cyclization types, different residues at the R4and R3positions, and different C-terminal residues. The agonist activity of O10 and comparative sequences is provided in Table 15, below. -149- 170456481.42Docket No.: 146316.8023.WO00 Table 15. Agonist activity of O10 and melanocortin analogs with point mutations relative to O10 MC3R MC4R Feature Sequence SEQ ID Max Max o-150- 170456481.42Docket No.: 146316.8023.WO00

[0516] As shown in Table 15, the specific cyclization residues have a minor effect on agonist activity, when the His-p(F)dPhe-Arg-Trp (SEQ ID NO: 162) is conserved. On the other hand, a substantial change in agonist ac...

Claims

Docket No.: 146316.8023.WO00 CLAIMS I / We claim:

1. A non-naturally occurring melanocortin analog comprising a sequence according to Formula (IF), R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IF), wherein: R1is Nle; R2is Asp or Glu; R3is His; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg or His; R6is Trp; R7is Orn; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7.

2. The non-naturally occurring melanocortin analog of claim 1, comprising a sequence selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 11); and -284- 170456481.42Docket No.: 146316.8023.WO00 Ac-Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 12), wherein c represents cyclization through R2and R7via a lactam bond.

3. The non-naturally occurring melanocortin analog of claim 1 or 2, wherein the non-naturally occurring melanocortin analog is cyclized between Glu at R2and and Orn at R7.

4. The non-naturally occurring melanocortin analog of claim 3, comprising a sequence selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45); and Ac-Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 12), wherein c represents cyclization through R2and R7via a lactam bond.

5. The non-naturally occurring melanocortin analog of claim 1 or 2, wherein R4is p(F)dPhe or dPhe.

6. The non-naturally occurring melanocortin analog of claim 5, comprising a sequence selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); and Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45), wherein c represents cyclization through R2and R7via a lactam bond.

7. The non-naturally occurring melanocortin analog of claim 5, comprising a sequence of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); or -285- 170456481.42Docket No.: 146316.8023.WO00 Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44), wherein c represents cyclization through R2and R7via a lactam bond.

8. The non-naturally occurring melanocortin analog of claim 5, comprising a sequence of: Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45), wherein c represents cyclization through R2and R7via a lactam bond.

9. The non-naturally occurring melanocortin analog of claim 1 or 2, wherein R4is p(F)dPhe or p(Cl)dPhe.

10. The non-naturally occurring melanocortin analog of claim 9, comprising a sequence selected from the group consisting of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43); Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 44); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 11); and Ac-Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 12), wherein c represents cyclization through R2and R7via a lactam bond.

11. The non-naturally occurring melanocortin analog of claim 1 or 2, wherein R4is para-fluoro-D-phenylalanine (p(F)dPhe).

12. The non-naturally occurring melanocortin analog of any one of claims 1-11, comprising a sequence of: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43), wherein c represents cyclization through R2and R7via a lactam bond.

13. A method of reducing body weight and / or fat mass in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I): X1-R1-R2-R3-R4-R5-R6-R7-R8-R9-Y1-Y2-Y3-Y4(I), -286- 170456481.42Docket No.: 146316.8023.WO00 wherein: X1is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is selected from the group consisting of Asp, D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of D-phenylalanine (dPhe), Pro, para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys) and lysine (Lys); R8is absent, Lys, or Trp; R9is absent or Lys; Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: -287- 170456481.42Docket No.: 146316.8023.WO00 a disulfide bond between R2and R7when R2is dCys, R4is p(Cl)dPhe, and R7is Cys; a lactam bridge between R1or R2and any one of R7-R9when R1or R2is Asp, R4is dPhe, or p(F)dPhe, and any one of R7-R9is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn, provided that: when R3is Pro, then X1and Y3are present and R4is dPhe, when R4is p(Cl)dPhe, then the non-naturally occurring melanocortin analog is not cyclized through a lactam bond between Asp at R2and Lys at R7, when R2and / or R3is Phe, then R4is Pro and R6is dPhe, when R4is dPhe and R2is Pro, then X1is present and R5is Arg, and when R4is dPhe, R2is Ala, and R3is His, then R5is Arg.

14. Use of a non-naturally occurring melanocortin analog for reducing body weight and / or fat mass in a subject in need thereof, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

15. A method of reducing body weight and / or fat mass in an obese subject, comprising orally administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

16. Use of a non-naturally occurring melanocortin analog for reducing body weight and / or fat mass in an obese subject, comprising orally administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). -288- 170456481.42Docket No.: 146316.8023.WO00 17. The method or the use of any one of claims 13-16, wherein the method or the use further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.

18. The method or the use of claim 17, wherein the lean mass is lean muscle mass.

19. The method or the use of any one of claims 13-18, wherein the method or the use further comprises treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in the subject.

20. A method of treating, preventing, or reducing hyperplasia in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

21. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing hyperplasia in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

22. A method of treating, preventing, or reducing hypothalamic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

23. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing hypothalamic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). -289- 170456481.42Docket No.: 146316.8023.WO00 24. The method or the use of claim 22 or 23, wherein the hypothalamic obesity comprises congenital hypothalamic damage, damage from tumors, or damage from trauma.

25. A method of treating, preventing, or reducing a proopiomelanocortin (POMC) deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

26. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a POMC deficiency in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

27. A method of treating, preventing, or reducing a leptin deficiency in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

28. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a leptin deficiency in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

29. A method of treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

30. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a syndromic obesity in a subject in need thereof, comprising administering a -290- 170456481.42Docket No.: 146316.8023.WO00 non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

31. The method or the use of claim 29 or 30, wherein the syndromic obesity is selected from the group consisting of Prader–Willi syndrome, Wilms tumor, Aniridia, Genitourinary, Range of Developmental Delays (WAGR) syndrome, Bardet-Biedl syndrome, Fragile X syndrome, Cohen syndrome, Proprotein Convertase Subtilisin / Kexin Type 1 (PCSK1) deficiency, Alstrom syndrome, MC4 haploinsufficiency, 17p11.2 deletion syndrome, and 2q37 deletion syndrome.

32. A method of treating, preventing, or reducing non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

33. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing NASH in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

34. A method of treating, preventing, or reducing hyperinsulinism in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

35. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing hyperinsulinism in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). -291- 170456481.42Docket No.: 146316.8023.WO00 36. A method of treating, preventing, or reducing a cardiovascular disease in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

37. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing a cardiovascular disease in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

38. The method or the use of claim 36 of 451, wherein the cardiovascular disease comprises a stroke or a heart attack.

39. A method of treating, preventing, or reducing osteoarthritis in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

40. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing osteoarthritis in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

41. A method of treating, preventing, or reducing a cancer in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

42. Use of non-naturally occurring melanocortin analog for treating, preventing, or reducing a cancer in a subject in need thereof, comprising administering a non-naturally -292- 170456481.42Docket No.: 146316.8023.WO00 occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

43. The method or the use of claim 41 or 42, wherein the method or the use further comprises reducing a risk of the cancer.

44. A method of treating, preventing, or reducing erectile dysfunction in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

45. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing erectile dysfunction in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

46. A method of treating, preventing, or reducing body weight gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

47. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing body weight gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

48. A method of maintaining body weight after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I). -293- 170456481.42Docket No.: 146316.8023.WO00 49. Use of a non-naturally occurring melanocortin analog for maintaining body weight after a weight loss in a subject in need thereof, comprising administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

50. A method of treating, preventing, or reducing fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

51. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing fat mass gain after a weight loss in a subject in need thereof, comprising administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

52. A method of treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

53. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

54. The method or the use of claim 52 or 53, wherein the method or the use further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.

55. The method or the use of claim 54, wherein the lean mass is lean muscle mass. -294- 170456481.42Docket No.: 146316.8023.WO00 56. The method or the use of any one of claims 52-55, wherein the method or the use further comprises reducing body weight and / or fat mass in the subject.

57. The method or the use of any one of claims 13-56, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg / kg to about 1000 mg / kg per body weight of the subject once daily.

58. The method or the use of any one of claims 13-27, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg / kg to about 550 mg / kg per body weight of the subject once daily.

59. The method or the use of any one of claims 13-29, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg / kg to about 100 mg / kg per body weight of the subject once daily.

60. The method or the use of any one of claims 13-31, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg / kg to about 75 mg / kg per body weight of the subject once daily.

61. The method or the use of claim 60, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg / kg or 60 mg / kg per body weight of the subject once daily.

62. The method or the use of any one of claims 13-56, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.

63. The method or the use of any one of claims 13-56, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily. -295- 170456481.42Docket No.: 146316.8023.WO00 64. The method or the use of any one of claims 13-63, wherein the method or the use further comprises reducing obesity-related inflammation in the subject.

65. The method or the use of any one of claims 13-64, wherein the method or the use further comprises preserving or improving kidney function in the subject.

66. A method of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

67. Use of a non-naturally occurring melanocortin analog for reducing obesity- related inflammation in a subject in need thereof, comprising orally administering a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

68. A method of preserving or improving kidney function in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin 4 receptor agonist to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

69. Use of a non-naturally occurring melanocortin analog for preserving or improving kidney function in a subject in need thereof, comprising orally administering a non- naturally occurring melanocortin 4 receptor agonist to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (I).

70. The method or the use of any one of claims 13-68, wherein the subject has a metabolic dysfunction selected from the group consisting of obesity, diabetes mellitus, metabolic syndrome, insulin resistance, non-alcoholic fatty liver disease, polycystic ovarian syndrome, metabolic acidosis, hypothyroidism, hyperlipidemia, Cushing Syndrome, and metabolic myopathies. -296- 170456481.42Docket No.: 146316.8023.WO00 71. The method or the use of any one of claims 1-70, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg / kg to about 20 mg / kg administered once a day for about 5 days to about 10 days; (ii) at a second dose of about 10 mg / kg to about 40 mg / kg administered once a day after administration of the first dose for about 5 days to about 10 days; (iii) at a third dose of about 5 mg / kg to about 30 mg / kg administered twice a day after administration of the second dose for at least about 5 days to about 10 days.

72. The method or the use of any one of claims 1-70, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 5 mg / kg administered once a day for about 7 days; (ii) at a second dose of about 15 mg / kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 10 mg / kg administered twice a day after administration of the second dose for at least about 7 days.

73. The method or the use of any one of claims 1-70, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 10 mg / kg administered once a day for about 7 days; (ii) at a second dose of about 20 mg / kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 15 mg / kg administered twice a day after administration of the second dose for at least about 7 days.

74. The method or the use of any one of claims 1-70, wherein the non-naturally occurring melanocortin analog is administered (i) at a first dose of about 15 mg / kg administered once a day for about 7 days; (ii) at a second dose of about 25 mg / kg administered once a day after administration of the first dose for about 7 days; (iii) at a third dose of about 20 mg / kg administered twice a day after administration of the second dose for at least about 7 days.

75. The method or the use of any one of claims 13-74, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein: -297- 170456481.42Docket No.: 146316.8023.WO00 X1is absent or is selected from the group consisting of norleucine (Nle), arginine (Arg), and D-arginine (dArg); R1is selected from the group consisting of Nle, Arg, dArg, aspartic acid (Asp), alanine (Ala), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis); R2is selected from the group consisting of Asp, D-cysteine (dCys), Ala, D-alanine (dAla), proline (Pro), glutamic acid (Glu), and phenylalanine (Phe); R3is selected from the group consisting of His, dHis, Pro, Phe, and glutamine (Gln); R4is selected from the group consisting of D-phenylalanine (dPhe), Pro, para-fluoro- D-phenylalanine (p(F)dPhe), and para-chloro-D-phenylalanine (p(Cl)dPhe); R5is selected from the group consisting of Arg, His, cis-4-guanidyl-proline (cisPro(guan)), and trans-4-guanidyl-proline (transPro(guan)); R6is selected from the group consisting of dPhe, tryptophan (Trp), and 2’-D- naphthylalanine (dNal(2’)); R7is selected from the group consisting of Arg, Pro, ornithine (Orn), cysteine (Cys) and lysine (Lys); R8is absent, Lys, or Trp; R9is absent or Lys; Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tert-leucine (dTle); Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a disulfide bond between R2and R7when R2is dCys, R4is p(Cl)dPhe, and R7is Cys; -298- 170456481.42Docket No.: 146316.8023.WO00 a lactam bridge between R1or R2and any one of R7-R9when R1or R2is Asp, R4is dPhe, or p(F)dPhe, and any one of R7-R9is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn; provided that the non-naturally occurring melanocortin analog does not comprise a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 48); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 49); Ac-dNle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 50); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 51); His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 52); dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 53); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 54); Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 55); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 56); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 57); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 58); Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 59); Ac-Nle-c[dCys-Pro-dPhe-Arg-Trp-dCys]-dVal-dPro-NH2 (SEQ ID NO: 60); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 61); Ac-Nle-c[Glu-Pro-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 62); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Gly-Lys]-dVal-dPro-NH2 (SEQ ID NO: 63); Ac-Nle-c[Asp-Phe-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 64); Ac-Nle-c[Asp-His-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 65); Ac-Nle-c[Asp-Pro-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 66); Ac-Nle-c[Asp-Pro-dPhe-Lys-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 67); -299- 170456481.42Docket No.: 146316.8023.WO00 Ac-Nle-c[Asp-Pro-dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 68); Ac-Nle-c[Asp-Pro-dPhe-Arg-Nal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69); Ac-Nle-c[dCys-Pro-p(F)dPhe-Arg-Trp-Cys]-dVal-dPro-NH2 (SEQ ID NO: 70); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 72); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 73); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 74); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 75); Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 76); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 77); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 78); Ac-Nle-c[Asp-Pro-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 79); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 80); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 81); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 82); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 83); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 84); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 85); Ac-Nle-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 86); Ac-Ala-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 87); Ac-dArg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 88); Ac-Arg-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 89); Ac-Lys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 90); Ac-dLys-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 91); -300- 170456481.42Docket No.: 146316.8023.WO00 Ac-His-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 92); Ac-dHis-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 93); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 94); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dTle-NH2 (SEQ ID NO: 95); Ac-dHis-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 96); Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 97); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 98); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 99); Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 100); Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 101); Ac-Nle-c[Asp-Pro-dPhe-Pro-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 102); Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 103); Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 104); Ac-Nle-c[Glu-Pro-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 105); Ac-Nle-c[Glu-Pro-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 106); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 107); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2 (SEQ ID NO: 108); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 109); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 110); Ac-Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 111); Ac-Ala-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 112); Ac-dArg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 113); Ac-Arg-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 114); Ac-Lys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 115); -301- 170456481.42Docket No.: 146316.8023.WO00 Ac-dLys-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 116); Ac-His-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 117); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dPro-NH2 (SEQ ID NO: 118); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 119); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dPro-NH2 (SEQ ID NO: 120); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 121); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 122); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 123); Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 124); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 125); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2 (SEQ ID NO: 126); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 127); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 128); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2 (SEQ ID NO: 129); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 130); Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 131); Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 132); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 133); Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 134); Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 135); Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 136); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 137); Ac-Nle-c[Asp-His-p(Cl)dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 138); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-dNal(2')-Lys]-dVal-dPro-NH2 (SEQ ID NO: 139); -302- 170456481.42Docket No.: 146316.8023.WO00 Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 140); Ac-Nle-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 141); Ac-Ala-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 142); Ac-dArg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 143); Ac-Arg-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 144); Ac-dLys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 145); Ac-dHis-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 146); Ac-Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 147); Ac-Nle-c[Asp-dHis-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 148); Ac-Nle-c[Asp-Phe-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 149); Ac-Nle-c[Asp-Gln-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 150); Ac-Lys-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 151); Ac-His-c[Asp-His-p(Cl)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 152); Ac-Nle-c[Asp-Phe-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 153); Ac-Nle-c[Asp-Phe-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 154); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 155); Ac-Nle-c[Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 156); Ac-Nle-c[Asp-Phe-His-dPhe-Arg-Trp-Lys]-dTle-dPro-NH2 (SEQ ID NO: 157); Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 158); Ac-Arg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 159); and Ac-dArg-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 160).

76. The method or the use of any one of claims 13-75, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IA): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3-Y4(IA), -303- 170456481.42Docket No.: 146316.8023.WO00 wherein: X1is absent or is selected from the group consisting of Nle, Arg, and dArg; R1is selected from the group consisting of Nle, Arg, dArg, Asp, Ala, Lys, dLys, His, and dHis; R2is selected from the group consisting of Asp, Ala, dAla, Pro, and Glu R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp or dNal(2’); R7is selected from the group consisting of Pro, Orn, and Lys; R8is absent or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn.

77. The method or the use of any one of claims 13-76, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IB): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IB), wherein: -304- 170456481.42Docket No.: 146316.8023.WO00 X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; R2is Asp or Glu; R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe or p(F)dPhe; R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp or dNal(2’); R7is Orn or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R2and R7when R2is Asp and R7is Lys; and lactam bridge between Asp or Glu at R2and Orn or Lys at R7.

78. The method or the use of any one of claims 13-77, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IC): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IC), wherein: X1is absent or Nle; R1is selected from the group consisting of Nle, Arg, dArg, Ala, Lys, dLys, His, and dHis; -305- 170456481.42Docket No.: 146316.8023.WO00 R2is Asp or Glu; R3is His; R4is p(F)dPhe; R5is Arg; R6is Trp; R7is Orn or Lys; Y1is selected from the group consisting of dVal, dPro, and dTle; Y2is selected from the group consisting of dVal, dPro, and dTle; Y3is absent, dVal, or dPro; Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R2and R7when R2is Asp and R7is Lys; and lactam bridge between Asp or Glu at R2and Orn or Lys at R7.

79. The method or the use of any one of claims 13-77, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (ID): X1-R1-R2-R3-R4-R5-R6-R7-R8-Y1-Y2-Y3(ID), wherein: X1is absent or norleucine (Nle); R1is Nle or Asp; R2is selected from the group consisting of Asp, Glu, and Pro; R3is selected from the group consisting of His, dHis, Pro, and Gln; R4is dPhe; -306- 170456481.42Docket No.: 146316.8023.WO00 R5is selected from the group consisting of Arg, His, cisPro(guan), and transPro(guan); R6is Trp; R7is selected from the group consisting of Orn, Lys, and Pro; R8is absent or Lys; Y1is dVal or dPro; Y2is dVal or dPro; Y3is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized through a moiety selected from the group consisting of: a lactam bridge between R1or R2and R7or R8when R1or R2is Asp and R7or R8is Lys; and a lactam bridge between R2and R7when R2is Asp or Glu and R7is Orn.

80. The method or the use of any one of claims 13-76, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IE): X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IE), wherein: X1is absent or selected from the group consisting of Nle, Arg, and dArg; R1is Asp; R2is dAla or Ala; R3is His; R4is dPhe; R5is Arg; R6is Trp; R7is Lys; -307- 170456481.42Docket No.: 146316.8023.WO00 Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp at R1and Lys at R7.

81. The method or the use of any one of claims 13-75, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (IF): R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IF), wherein: R1is Nle; R2is Asp or Glu; R3is His; R4is selected from dPhe, p(F)dPhe, and p(Cl)dPhe; R5is Arg or His; R6is Trp; R7is Orn; Y1is dVal; Y2is dPro; and the non-naturally occurring melanocortin analog is cyclized through a lactam bridge between Asp or Glu at R2and Orn at R7.

82. The method or the use of any one of claims 13-81, wherein R3is His and R4is p(F)dPhe or dPhe.

83. The method or the use of any one of claims 13-82, wherein R1is selected from Nle, Ala, Arg, dArg, Lys, dLys, His, and dHis and R4is p(F)dPhe. -308- 170456481.42Docket No.: 146316.8023.WO00 84. The method or the use of any one of claims 13-83, wherein the sequence according to any one of Formulae (I)-(IF) is selected from the group consisting of: Ac—Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 3); Ac—dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 4); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 14); Ac—Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 15); Ac—Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 16); Ac—dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 17); Ac—His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 18); and Ac—dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 19), wherein c represents cyclization through R2and R7via a lactam bond.

85. The method or the use of any one of claims 13-83, wherein the sequence according to any one of Formulae (I)-(IF) is selected from the group consisting of: Ac—Ala-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 7); Ac—dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 8); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 24); Ac—Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 27); Ac—Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 28); Ac—dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 29); Ac—His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 30); and Ac—dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 31), wherein c represents cyclization through R2and R7via a lactam bond.

86. The method or the use of any one of claims 13-82, wherein R1is Nle and R4is dPhe. -309- 170456481.42Docket No.: 146316.8023.WO00 87. The method or the use of claim any one of claims 13-82 and 79, wherein the sequence according to any one of Formulae (I)-(IF) is: Ac—Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal—NH2 (SEQ ID NO: 33); or Ac—Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 42), wherein c represents cyclization through R2and R7via a lactam bond.

88. The method or the use of any one of claims 13-82, wherein R1is Nle and R4is p(F)dPhe.

89. The method or the use of claim any one of claims 13-82 and 81, wherein the sequence according to any one of Formulae (I)-(IF) is selected from the group consisting of: Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal—NH2 (SEQ ID NO: 6); Ac—Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 20); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro—NH2 (SEQ ID NO: 22); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro—NH2 (SEQ ID NO: 23); Ac—Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro—NH2 (SEQ ID NO: 25); and Ac—Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro—NH2 (SEQ ID NO: 26), wherein c represents cyclization through R2and R7via a lactam bond.

90. The method or the use of any one of claims 13-82, wherein R1is Nle and R4is dPhe or p(F)dPhe.

91. The method or the use of claim any one of claims 13-82 and 83, wherein the sequence according to any one of Formulae (I)-(IF) is selected from the group consisting of: Ac—Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 21); Ac—Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 46); and -310- 170456481.42Docket No.: 146316.8023.WO00 Ac—Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 47), wherein c represents cyclization through R2and R7via a lactam bond.

92. The method or the use of claim any one of claims 13-82 and 83, wherein the sequence according to any one of Formulae (I)-(IF) is: Ac—Nle-c[Asp-His-p(F)dPhe-Arg- dNal(2')-Lys]-dVal-dPro—NH2 (SEQ ID NO: 5), wherein c represents cyclization through R2and R7via a lactam bond.

93. The method or the use of any one of claims 13-78, wherein the sequence of any one of Formulae (I)-(IF) is cyclized through a lactam bond between Asp or Glu at R2and Orn at R7.

94. The method or the use of claim any one of claims 13-78 and 86, wherein the sequence according to any one of Formulae (I)-(IF) is selected from the group consisting of: Ac—Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 43); Ac—Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 44); Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 45); Ac—Nle-c[Asp-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 11); and Ac—Nle-c[Glu-His-p(Cl)dPhe-Arg-Trp-Orn]-dVal-dPro—NH2 (SEQ ID NO: 12), wherein c represents cyclization through R2and R7via a lactam bond.

95. The method or the use of any one of claims 13-78, wherein the sequence of any one of Formulae (I)-(IF) is cyclized through a lactam bond between dCys at R2and Cys at R7.

96. The method or the use of claim any one of claims 13-78 and 88, wherein the sequence according to any one of Formulae (I)-(IF) is: Ac—Nle-c[dCys-His-p(Cl)dPhe-Arg- Trp-Cys]-dVal-dPro—NH2 (SEQ ID NO: 5), wherein c represents cyclization through R2and R7via a disulfide bond. -311- 170456481.42Docket No.: 146316.8023.WO00 97. The method or the use of any one of claims 13-82, wherein the sequence of any one of Formulae (I)-(IF) is cyclized through a lactam bond between Asp at R2and Lys at R8.

98. The method or the use of claim any one of claims 13-82 and 90, wherein the sequence according to any one of Formulae (I)-(IF) is: Ac—Nle-c[Asp-His-dPhe-Arg-Trp- Pro-Lys]-dVal-dPro—NH2 (SEQ ID NO: 35), wherein c represents cyclization through R2and R8via a lactam bond.

99. The method or the use of any one of claims 13-82, wherein the sequence of any one of Formulae (I)-(IF) is cyclized through a lactam bond between Asp at R1and Lys at R7.

100. The method or the use of claim any one of claims 13-82 and 92, wherein the sequence according to any one of Formulae (I)-(IF) is selected from the group consisting of: Ac—Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 38); Ac—Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 39); Ac—dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 40); and Ac—Nle-c[Asp-Ala-His-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 41), wherein c represents cyclization through R1and R7via a lactam bond.

101. The method or the use of claim any one of claims 13-82 and 93, wherein the sequence according to any one of Formulae (I)-(IF) is: Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp- Lys]-dVal-dPro-NH2 (SEQ ID NO: 13), wherein c represents cyclization through R1and R7via a lactam bond.

102. The method or the use of claim any one of claims 13-78, wherein R3is selected from dHis, Gln and Pro and R4is dPhe or p(F)dPhe. -312- 170456481.42Docket No.: 146316.8023.WO00 103. The method or the use of claim any one of claims 13-78 and 95, wherein the sequence according to any one of Formulae (I)-(IF) is selected from the group consisting of: Ac—Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 9); Ac—Nle-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-dPro—NH2 (SEQ ID NO: 10); Ac—Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 32); Ac—Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 36); and Ac—Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro—NH2 (SEQ ID NO: 37), wherein c represents cyclization through R2and R7via a lactam bond.

104. The method or the use of claim any one of claims 13-78 and 95, wherein the sequence according to any one of Formulae (I)-(IF) is: Ac-Nle-c[Asp-Phe-Phe-Pro-His- dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 34), wherein c represents cyclization through R1and R9via a lactam bond.

105. The method or the use of claim any one of claims 13-104, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 2-47.

106. The method or the use of claim any one of claims 13-105, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 3-10, 13-33, and 35-47.

107. The method or the use of claim any one of claims 13-105, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 3-10, 14-33, 36, 37, and 42-47. -313- 170456481.42Docket No.: 146316.8023.WO00 108. The method or the use of claim any one of claims 13-105, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 3-8, 14-31, 43, and 44.

109. The method or the use of claim any one of claims 13-105, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 10, 13, 33, 35-37, 42, and 45-47.

110. The method or the use of claim any one of claims 13-105, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 38-41.

111. The method or the use of claim any one of claims 13-105, wherein the non- naturally occurring melanocortin analog comprises a sequence of any of one SEQ ID NOs: 11, 12, and 43-45.

112. A method of reducing body weight and / or fat mass in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IF).

113. Use of a non-naturally occurring melanocortin analog for reducing body weight and / or fat mass in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IF). -314- 170456481.42Docket No.: 146316.8023.WO00 114. A method of treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IF).

115. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IF).

116. A method of reducing obesity-related inflammation in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IF).

117. A method of preserving or improving kidney function in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non- naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IF).

118. Use of a non-naturally occurring melanocortin analog for preserving or improving kidney function in a subject in need thereof, comprising orally administering about 15 mg / kg to about 100 mg / kg of a non-naturally occurring melanocortin analog to the subject, the non-naturally occurring melanocortin analog comprising a sequence of Formula (IF).

119. The method or use of any one of claims 112-118, wherein the sequence of -315- 170456481.42Docket No.: 146316.8023.WO00 Formula (IF) is: Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43), wherein c represents cyclization through R2and R7via a lactam bond.

120. The method or the use of any one of claims 13-119, wherein, after administration of the non-naturally occurring melanocortin analog, the subject’s body weight is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.

121. The method or the use of any one of claims 13-120, wherein, after administration of the non-naturally occurring melanocortin analog, the subject’s fat mass is more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, or more than 40% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog.

122. A non-naturally occurring melanocortin analog comprising a sequence of: Ac- Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 43), wherein c represents cyclization through R2and R7via a lactam bond.

123. A method of reducing body weight and / or fat mass in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog comprising a sequence of SEQ ID NO: 43 to the subject.

124. Use of a non-naturally occurring melanocortin analog for reducing body weight and / or fat mass in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog comprising a sequence of SEQ ID NO: 43 to the subject.

125. The method or the use of claim 123 or 124, wherein the method or the use further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject. -316- 170456481.42Docket No.: 146316.8023.WO00 126. The method or the use of claim 125, wherein the lean mass is lean muscle mass.

127. The method or the use of any one of claims 123-126, wherein the method or the use further comprises treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in the subject.

128. A method of treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog comprising a sequence of SEQ ID NO: 43 to the subject.

129. Use of a non-naturally occurring melanocortin analog for treating, preventing, or reducing glucose intolerance and / or diabetes mellitus in a subject in need thereof, comprising orally administering a non-naturally occurring melanocortin analog comprising a sequence of SEQ ID NO: 43 to the subject.

130. The method or the use of claim 128 or 129, wherein the method or the use further comprises reducing lean mass loss, maintaining lean mass, or promoting lean mass gain in the subject.

131. The method or the use of claim 130, wherein the lean mass is lean muscle mass.

132. The method or the use of any one of claims 128-131, wherein the method or the use further comprises reducing body weight and / or fat mass in the subject.

133. The method or the use of any one of claims 128-132, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 15 mg / kg to about 100 mg / kg per body weight of the subject once daily. -317- 170456481.42Docket No.: 146316.8023.WO00 134. The method or the use of claim 133, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 30 mg / kg or 60 mg / kg per body weight of the subject once daily.

135. The method or the use of any one of claims 128-134, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 0.1 mg to about 100 mg once daily.

136. The method or the use of any one of claims 128-135, wherein the non-naturally occurring melanocortin analog is administered at a dose of about 10 mg or about 50 mg once daily.

137. The method or the use of any one of claims 128-136, wherein the method or the use further comprises reducing obesity-related inflammation in the subject.

138. The method or the use of any one of claims 128-137, wherein the method or the use further comprises preserving or improving kidney function in the subject.

139. The method or the use of any one of claims 13-138, wherein the method of the use further comprises one or more of (i) reducing a lipid droplets size (e.g., an average lipid droplet size); (ii) increasing an adipose tissue mitochondrial number or adipose tissue mitochondrial concentration; (iii) increasing an adipose tissue vascularization level; (iv) increasing, maintaining, or preventing a reduction of a beige or brown adipocyte level; (v) increasing a metabolic rate; (vi) increasing a calorie burn level; or (vii) increasing, maintaining, or preventing reduction of an insulin sensitivity level, relative to a control.

140. The method or the use of any one of claims 13-139, wherein the subject has a metabolic dysfunction selected from the group consisting of obesity, diabetes mellitus, metabolic syndrome, insulin resistance, non-alcoholic fatty liver disease, polycystic ovarian syndrome, metabolic acidosis, hypothyroidism, hyperlipidemia, Cushing Syndrome, and metabolic myopathies. -318- 170456481.42Docket No.: 146316.8023.WO00 141. The method or the use of any one of claims 13-140, wherein the non-naturally occurring melanocortin analog comprises a reduced clearance, and increased concentration, or an increased distribution during or after administration to the subject, relative to a control.

142. The method or the use of claim 141, wherein the clearance is a liver or a liver microsome clearance.

143. The method or the use of claim 141, wherein the concentration is an aqueous concentration.

144. The method or the use of claim 143, wherein the aqueous concentration comprises an intestinal fluid concentration or a gastric fluid concentration.

145. The method or the use of any one of claims 13-144, wherein the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng / mL to at least about 2000 ng / mL about 24 hours after administration of the non-naturally occurring melanocortin analog.

146. The method or the use of any one of claims 13-144, wherein the non-naturally occurring melanocortin analog is administered to the subject until the concentration of the non-naturally occurring melanocortin analog in the plasma or a tissue of the subject is at least about 5 ng / mL to at least about 2000 ng / mL after administration of the non-naturally occurring melanocortin analog.

147. The method or the use of claim 145 or 146, wherein concentration is at least about 5 ng / mL after administration of the non-naturally occurring melanocortin analog.

148. The method or the use of claim 145 or 146, wherein concentration is at least about 10 ng / mL after administration of the non-naturally occurring melanocortin analog. -319- 170456481.42Docket No.: 146316.8023.WO00 149. The method or the use of claim 145 or 146, wherein concentration is at least about 50 ng / mL after administration of the non-naturally occurring melanocortin analog.

150. The method or the use of claim 145 or 146, wherein concentration is at least about 100 ng / mL after administration of the non-naturally occurring melanocortin analog.

151. The method or the use of claim 145 or 146, wherein concentration is at least about 200 ng / mL after administration of the non-naturally occurring melanocortin analog.

152. The method or the use of claim 145 or 146, wherein concentration is at least about 300 ng / mL after administration of the non-naturally occurring melanocortin analog.

153. The method or the use of claim 145 or 146, wherein concentration is at least about 400 ng / mL after administration of the non-naturally occurring melanocortin analog.

154. The method or the use of claim 145 or 146, wherein concentration is at least about 500 ng / mL after administration of the non-naturally occurring melanocortin analog.

155. The method or the use of claim 145 or 146, wherein concentration is at least about 750 ng / mL after administration of the non-naturally occurring melanocortin analog.

156. The method or the use of claim 145 or 146, wherein concentration is at least about 1000 ng / mL after administration of the non-naturally occurring melanocortin analog.

157. The method or the use of claim 145 or 146, wherein concentration is at least about 1500 ng / mL after administration of the non-naturally occurring melanocortin analog.

158. The method or the use of claim 145 or 146, wherein concentration is at least about 2000 ng / mL after administration of the non-naturally occurring melanocortin analog. -320- 170456481.42Docket No.: 146316.8023.WO00 159. The method or the use of any one of claims 145-158, wherein the concentration is a maximum concentration (Cmax).

160. The method or the use of any one of claims 18-159, wherein the non-naturally occurring melanocortin analog is administered as a single dosage unit.

161. The method or the use of any one of claims 13-159, wherein the non-naturally occurring melanocortin analog dose is administered as multiple dosage units.

162. The method or the use of claim 161, wherein the multiple dosage units individually comprise about 2.5 mg / mL to about 100 mg / mL of the non-naturally occurring melanocortin analog.

163. The method or the use of claim 162, wherein the multiple dosage units individually comprise about 2.5 mg / mL to about 10 mg / mL of the non-naturally occurring melanocortin analog.

164. The method or the use of claim 161, wherein the multiple dosage units individually comprise about 6 mg / mL of the non-naturally occurring melanocortin analog.

165. The method or the use of claim 161, wherein the non-naturally occurring melanocortin analog is administered as about 5 dosage units to about 10 dosage units.

166. The method or the use of claim 161, wherein the non-naturally occurring melanocortin analog is administered as 5 dosage units.

167. The method or the use of claim 161, wherein the non-naturally occurring melanocortin analog is administered as 10 dosage units. -321- 170456481.42Docket No.: 146316.8023.WO00 168. The method or the use of any one of claims 13-167, wherein the dosage unit is a capsule.

169. The method or the use of claim 168, wherein the capsule comprises the non- naturally occurring melanocortin analog suspended in a saline solution.

170. The method or the use of claim 169, wherein the saline solution is about 100% saline.

171. The method or the use of claim 169, wherein the saline solution is about 95% saline.

172. The method or the use of claim 169, wherein the saline solution is about 90% saline.

173. The method or the use of claim 171 or 172, wherein the saline solution comprises dimethyl sulfoxide (DMSO). -322- 170456481.42

Images