Methods and compositions

Abstract

The present disclosure relates to, inter alia, MC4R agonists and enhanced selectivity of MC4R over MC1R. Furthermore, the present disclosure relates to methods of treating metabolic disorders or diseases.

Description

123828-02-5133-WO METHODS AND COMPOSITIONS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This disclosure claims priority to and benefit from U.S. Provisional Patent Application Nos.63 / 651,487,filed May 24, 2024, 63 / 651,488, filed May 24, 2024, 63 / 651,491, filed May 24, 2024, 63 / 651,492, filed May 24, 2024, 63 / 651,493, filed May 24, 2024, 63 / 651,498, filed May 24, 2024, 63 / 726,988, filed December 2, 2024, 63 / 726,993, filed December 2, 2024, and 63 / 726,999, filed December 2, 2024, all of which are incorporated by reference herein in their entireties. FIELD

[0002] This disclosure provides compositions and methods for treating diseases and disorders related tomelanocortin 4 receptor (MC4R). BACKGROUND

[0003] The melanocortin-4 receptor (MC4R) regulates adipose tissue formation and energy homeostasis andthus may be targeted for anti-obesity intervention. Treatments of MC4R-related diseases and disorders due to malfunctions or absence of signaling cascades entailing MC4R signaling, such as genetic and / or hypothalamic obesity, may be treated by administration of pan-melanocortin receptor activating peptides. Additionally, it is possible that overactivation of the MC4R signaling cascades in patients suffering from general obesity may provide anti-obesity benefits to those patients. While MC4R agonists have been characterized in vitro, undesirable side effects frequently appeared during clinical trials and in real world use, including, but not limited to hyperpigmentation due, it is believed, to cross-activation of other melanocortin receptors, such as MC1R.

[0004] Accordingly, there is a need for compositions and methods for treating diseases and disorders thatcould benefit from pharmacologically-induced melanocortin 4 receptor (MC4R) activity, preferably with reduced undesirable side effects. SUMMARY

[0005] In aspects and embodiments, there is provided a method of treating diseases and disorders related tomelanocortin 4 receptor (MC4R), including, but not limited to, reducing undesirable side effects of cross-activation of other melanocortin receptors, such as hyperpigmentation, by administering a peptide of the present disclosure alone or in combination with a therapeutical agent.

[0006] In aspects and embodiments, there is provided a peptide comprising the amino acid sequence offormula (I): X1-X2-X3-X4-X5-X6-X7-X8 formula (I) wherein in formula (I): 1123828-02-5133-WO X3is 3-aminooxetane-3-carboxylic acid (Aib(O-cyclic)); X4is glutamine (Gln), homocitrulline (hCit), citrulline (Cit), 3-(3-pyridyl)-L-alanine (3-Pal), L-homoglutamine (hGln), histidine (His), or L-ornithine (Orn); andX1, X2, X5, X6, X7, and X8 are each independently a canonical or non-canonical amino acid.

[0007] In embodiments, the peptide of formula (I) is a peptide of any one of formula (Ia): X-4-X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8, formula (Ib): X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8, formula (Ic): X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8, formula (Id): X-1-X1-X2-X3-X4-X5-X6-X7-X8, formula (Ie): X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10, or formula (If): X-1- X1-X2-X3-X4-X5-X6-X7-X8-X9-X10, wherein X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and Table A2A or a linker.

[0008] In embodiments, X4 is Gln.

[0009] In embodiments, X4 is Cit.

[0010] In embodiments, X4 is hCit.

[0011] In embodiments, X4 is 3-Pal.

[0012] In embodiments, X4 is hGln.

[0013] In embodiments, X4 is His.

[0014] In embodiments, X4 is Orn.

[0015] In embodiments, X5 is selected from 4-fluoro-D-phenylalanine (D-Phe(4-F)), D-phenylalanine (D-Phe),and 4-methyl-D-phenylalanine (D-Phe(4-Me)).

[0016] In embodiments, X5 is D-Phe(4-F).

[0017] In embodiments, X5 is D-Phe.

[0018] In embodiments, X5 is D-Phe(4-Me).

[0019] In embodiments, X6 is arginine (Arg).

[0020] In embodiments, X7 is 6-fluoro-L-tryptophan (Trp(6-F)).

[0021] In embodiments, X8 is cysteine (Cys).

[0022] In embodiments, X8 is penicillamine (Pen).

[0023] In embodiments, X1 is selected from D-norarginine (D-Nar) and beta-homo-L-arginine (Beta-homoArg).

[0024] In embodiments, X1 is D-Nar.

[0025] In embodiments, X2 is Cys.

[0026] In embodiments, the peptide of formula (I) is selected from Table 1, Table 2, Table A1, Table A1A,Table A2, and Table A2A. 2123828-02-5133-WO

[0027] In embodiments, the peptide is a cyclic peptide.

[0028] In embodiments, the cyclic peptide comprises a disulfide bridge or a lactam bridge.

[0029] In embodiments, the cyclic peptide is a peptide of formula (II):

[0030] In embodiments, the cyclic peptide of formula (II) is a cyclic peptide of any one of formula (IIa)-(IIf):formula (IIe), orformula (IIf) wherein X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10are each independently an amino acid selected from Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and Table A2A or a linker.

[0031] In embodiments, the peptide further comprises one or more amino acids conjugated to X1 and / or X8,optionally wherein the one or more amino acids are selected from D-arginine (D-Arg), glycine (Gly), gamma-Glu 3123828-02-5133-WO

[0032] In embodiments, the peptide further comprises one or more lipids conjugated to X1 and / or X8.

[0033] In embodiments, the peptide further comprises one or more PEG linkers conjugated to X1 and / or X8.

[0034] In embodiments, the peptide is capped with N-terminal acetyl and / or C-terminal amide groups.

[0035] In embodiments, the peptide is selected from Table 1, Table 2, Table A1, Table A1A, Table A2, andTable A2A.

[0036] In aspects and embodiments, there is provided a peptide of formula (III):X1-X2-X3-X4-X5-X6-X7-X8 formula (III) wherein in formula (III): X1 is D-norarginine (D-Nar); X2is cysteine (Cys); X3is 3-Aminooxetane-3-carboxylic acid (Aib(O-cyclic)); X4 is glutamine (Gln); X5is 4-fluoro-D-phenylalanine (D-Phe(4-F)); X6 is arginine (Arg); X7 is 6-fluoro-L-tryptophan (Trp(6-F)); and X8is penicillamine (Pen).

[0037] In embodiments, the peptide of formula (III) is a cyclic peptide.

[0038] In embodiments, the cyclic peptide comprises a disulfide bridge or a lactam bridge.

[0039] In embodiments, the cyclic peptide consists of the amino acid sequence as set forth in formula (IV):formula (IV) wherein in formula (IV): X1 is D-norarginine (D-Nar); 4123828-02-5133-WO X2is cysteine (Cys); X3is 3-Aminooxetane-3-carboxylic acid (Aib(O-cyclic)); X4 is glutamine (Gln); X5is 4-fluoro-D-phenylalanine (D-Phe(4-F)); X6is arginine (Arg); X7 is 6-fluoro-L-tryptophan (Trp(6-F)); and X8is penicillamine (Pen), wherein represents a disulfide bridge, and the peptide is capped with N-terminal ac

[0040] In embodiments, the peptide is capped with N-terminal acetyl and / or C-terminal amide groups. Inembodiments, the peptide is capped with N-terminal acetyl.

[0041] In embodiments, the disclosed peptide (e.g., peptide of formula I and / or peptide of formula III)demonstrates increased selectivity for MC4R over MC1R when administered to a subject compared to a control.

[0042] In embodiments, the peptide demonstrates increased selectivity for MC4R over MC1R as measuredby an in vitro, ex vivo, or in vivo assay when compared to a control.

[0043] In embodiments, the peptide demonstrates increased selectivity for MC4R over MC1R by at least about10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0044] In embodiments, the peptide demonstrates increased selectivity for MC4R over MC1R by at least about1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0045] In embodiments, the peptide demonstrates an increased ratio of MC4R intracellular signaling to MC1Rintracellular signaling when administered to a subject compared to a control.

[0046] In embodiments, the peptide demonstrates increased selectivity for MC4R intracellular signaling toMC1R intracellular signaling as measured by an in vitro, ex vivo, or in vivo assay when compared to a control. 5123828-02-5133-WO

[0047] In embodiments, the peptide demonstrates an increased ratio of MC4R intracellular signaling to MC1Rintracellular signaling by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when administered to a subject compared to a control.

[0048] In embodiments, the peptide demonstrates an increased ratio of MC4R intracellular signaling to MC1Rintracellular signaling by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when administered to a subject compared to a control.

[0049] In embodiments, the peptide demonstrates enhanced melanocortin 4 receptor (MC4R) function in asubject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control.

[0050] In embodiments, the peptide demonstrates decreased melanocortin 1 receptor (MC1R) function in asubject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control.

[0051] In embodiments, the peptide demonstrates enhanced melanocortin 4 receptor (MC4R) function asmeasured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0052] In embodiments, the peptide demonstrates decreased melanocortin 1 receptor (MC1R) function asmeasured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0053] In embodiments, the peptide demonstrates enhanced MC4R function and / or decreased MC1R functionby at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non- treatment state.

[0054] In embodiments, the peptide demonstrates enhanced MC4R function and / or decreased MC1R functionby at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state. 6123828-02-5133-WO

[0055] In embodiments, the cyclic peptide demonstrates increased selectivity for MC4R over MC1R by at leastabout 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0056] In embodiments, the cyclic peptide demonstrates increased selectivity for MC4R over MC1R by at leastabout 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0057] In embodiments, the peptide comprises a half-life extending moiety, optionally wherein the half-lifeextending moiety comprises polyethylene glycol (PEG), recombinant PEG mimetics, glycosylation of carbohydrates, Fc-fusion proteins or conjugates, albumin fusion proteins or conjugates, albumin-binding fusion proteins or conjugates, polypropylene glycol (PPG), XTEN fusion protein or conjugates, or a combination thereof.

[0058] In embodiments, the peptide further comprises at least 1, at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or at least 100 amino acids at the amino and / or carboxy terminus.

[0059] In embodiments, the peptide further comprises a therapeutic, diagnostic, and / or imaging moiety,optionally wherein the therapeutic, diagnostic, and / or imaging moiety comprises a small molecule, a biological (e.g., a biopolymer, a protein, a nucleic acid, a polysaccharide), or a radionuclide.

[0060] In embodiments, the peptide of formula (I) or formula (III) is conjugated to or co-formulated with anadditional therapeutic agent or therapeutic moiety.

[0061] In embodiments, the peptide of formula (II) is conjugated to or co-formulated with an additionaltherapeutic agent or therapeutic moiety.

[0062] In embodiments, the additional therapeutic agent or therapeutic moiety comprises an incretin, anincretin analogue, or a modulator of an incretin receptor.

[0063] In embodiments, the modulator is an agonist. In embodiments, the agonist is an agonist of GLP-1, GIP,and / or glucagon receptor. In embodiments, the agonist is a GLP-1 analogue. In embodiments, the GLP-1 analogue comprises a non-canonical amino acid. In embodiments, the GLP-1 analogue comprises tirzepatide, tirzepatide analogue, liraglutide, retatrutide, exenatide, lixisenatide, semaglutide or a semaglutide derivative. 7123828-02-5133-WO

[0064] In embodiments, the agonist is an agonist of GIP receptor. In embodiments, the agonist is a dual GLP-1-GIP receptor co-agonist. In embodiments, the agonist is a triple hormone receptor agonist. In embodiments, the agonist comprises retatrutide.

[0065] In embodiments, there is provided a protein comprising the peptide of the present disclosure.

[0066] In embodiments, the protein has a size of at least about 10 amino acid residues, or at least about 15residues, or at least about 20 residues, or at least about 25 residues, or at least about 30 residues, or at least about 35 residues, or at least about 40 residues, or at least about 45 residues, or at least about 50 residues, or at least about 60 residues, or at least about 70 residues, or at least about 80 residues, or at least about 90 residues, or at least about 100 residues, or at least about 250 residues, or at least about 500 residues, at least about 750 residues, at least about 1,000 residues, at least about 1,250 residues, at least about 1,500 residues, at least about 1,750 residues, at least about 2,000 residues, at least about 3,000 residues, at least about 4,000 residues, or at least about 5,000 residues.

[0067] In embodiments, there is provided a nucleic acid encoding the peptide of the present disclosure, or theprotein of the present disclosure.

[0068] In embodiments, there is provided a solid synthesis device conjugated to the peptide of the presentdisclosure, the protein of the present disclosure, or the nucleic acid of the present disclosure.

[0069] In embodiments, there is provided a pharmaceutical composition comprising a peptide of the presentdisclosure, or the proteins of the present disclosure, or the nucleic acid of the present disclosure and a pharmaceutically acceptable excipient or carrier.

[0070] In embodiments, the pharmaceutical composition further comprises an additional therapeutic,diagnostic, and / or imaging moiety.

[0071] In embodiments, the pharmaceutical composition is conjugated to or co-formulated with an additionaltherapeutic agent or therapeutic moiety.

[0072] In embodiments, the pharmaceutical composition is administered orally, parenterally, by inhalationspray, topically, rectally, nasally, buccally, sub-lingually, vaginally or via an implanted reservoir.

[0073] In embodiments, the pharmaceutical composition is administered via intravenous injection,intramuscular injection, subcutaneous injection, or depot injection.

[0074] In embodiments, there is provided a method of selectively increasing the activity of MC4R over MC1Rcomprising administering a peptide of the present disclosure, or the pharmaceutical composition of the present disclosure to a subject in need thereof.

[0075] In embodiments, the method prevents, reduces, or eliminates hyperpigmentation in the subject whencompared to an untreated or pre-treatment subject, or subject treated with a control. 8123828-02-5133-WO

[0076] In embodiments, the hyperpigmentation is reduced by at least about 10%, or at least about 20%, or atleast about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0077] In embodiments, the hyperpigmentation is reduced by at least about 1 fold, or at least about 2 fold, orat least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0078] In embodiments, there is provided a method of treating a disease or disorder associated with MC4Rfunction comprising administering a peptide of the present disclosure, or the pharmaceutical composition of the present disclosure to a subject in need thereof.

[0079] In embodiments, the disease or disorder is selected from genetic obesity, obesity, abnormal orexcessive fat accumulation, hypothalamic obesity, surgically-acquired obesity, a metabolic disorder, an eating disorder, hypothyroidism, Cushing syndrome, obesity due to proopiomelanocortin (POMC) variance or deficiency, obesity due to proprotein convertase subtilisin / kexin type 1 (PCSK1) variance or deficiency, obesity due to leptin receptor (LEPR) variant or deficiency, Bardet-Biedl syndrome (BBS), MC4R allele variant or deficiency, and Prader-Willi syndrome.

[0080] In embodiments, the method further comprises co-administration of an additional therapeutic agent.

[0081] In embodiments, the additional therapeutic agent comprises incretin, an incretin analogue, or amodulator of an incretin receptor.

[0082] In embodiments, the modulator is an agonist.

[0083] In embodiments, the agonist is an agonist of GLP-1, GIP, and / or glucagon receptor.

[0084] In embodiments, the agonist is a GLP-1 analogue.

[0085] In embodiments, the GLP-1 analogue comprises a non-canonical amino acid.

[0086] In embodiments, the GLP-1 analogue comprises tirzepatide, tirzepatide analogue, liraglutide,retatrutide, exenatide, lixisenatide, semaglutide or semaglutide derivative.

[0087] In embodiments, the subject is receiving and / or previously received treatment comprising incretin, anincretin analogue, or a modulator of an incretin receptor.

[0088] In embodiments, the subject has not or is not receiving treatment comprising incretin, an incretinanalogue, or a modulator of an incretin receptor. 9123828-02-5133-WO

[0089] In embodiments, there is provided a method of treating obesity or abnormal or excessive fataccumulation comprising administering a peptide of the present disclosure, or the pharmaceutical composition of the present disclosure to a subject in need thereof.

[0090] In embodiments, there is provided a method of treating a disease or disorder associated with MC4Rfunction comprising administering a peptide of the present disclosure, or the pharmaceutical composition of the present disclosure to a subject receiving and / or previously received incretin.

[0091] In embodiments, there is provided a method of treating a disease or disorder associated with MC4Rfunction comprising administering a peptide of the present disclosure, or the pharmaceutical composition of the present disclosure to a subject not receiving incretin.

[0092] In embodiments, the peptide or pharmaceutical composition is administered from a prefilled dosageform device, such as syringe or autoinjector. BRIEF DESCRIPTION OF THE DRAWINGS

[0093] FIG.1 shows the results of a weight loss study in mice administered with various nonlipidated peptides.The graph represents a comparison of the percentage of weight loss over three days in diet induced obese (DIO) mice with treatment of exemplary peptides.

[0094] FIG. 2 is a bar graph of the amount of food intake in DIO mice after treatment with exemplary peptides.

[0095] FIG. 3 is a graph of the amount of weight loss in DIO mice after treatment with 10 mg / kg of a MC4Ragonist peptide (molecule 1158) of the disclosure dosed once daily.

[0096] FIG. 4 is a table listing various exemplary peptides and their related results when assessing theselectivity of MC4R versus MC1R as well as the bias of MC4R B-arrestin versus MC4R cAMP. When comparing the selectivity of MC4R v MC1R, larger values indicate selectivity towards MC4R. When comparing the bias ofMC4R B-arrestin v MC4R cAMP, larger values indicate bias towards B-arrestin. * denotes MC4R vs MC1R10.00, +++ denotes MC4R B-arrestin v MC4R cAMP bias having a value of > 10.00. Grey color denotes peptides with a lipidated state. N / A denotes peptides with no data collected. IA denotes an inactive state. DETAILED DESCRIPTION

[0097] In aspects, the disclosure provides novel peptides useful for modulating the melanocortin 4 receptor(MC4R) useful for treating MC4R related diseases and disorders, such as, but not limited to, genetic obesity and hypothalamic obesity. In embodiments, the peptides of the disclosure have enhanced selectivity for MC4R over 10123828-02-5133-WO MCR1, and therefore may reduce or eliminate skin hyperpigmentation observed in subjects treated with non- selective MC4R agonists (e.g. setmelanotide).

[0098] The G protein-coupled receptor (GPCR) superfamily is collectively the largest family of transmembranereceptors in humans, consisting of nearly 800 distinct genes and their corresponding gene products. The general structure of GPCRs has been largely conserved through evolution and manifests as glycoproteins possessing seven transmembrane spanning segments that organize themselves in the cell’s plasma membrane. As they possess both extracellular and intracellular elements, they serve as ideal transducers of stimuli across the cellular membrane. GPCRs can recognize a wide variety of extracellular stimuli, including small molecules, ions, photons, peptides, and proteins, and communicate the stimuli across an impermeable membrane barrier to the intracellular domain to effect changes in cell function. Signaling is transmitted through a cascade of protein interactions and activation events, thereby evoking changes in the levels of intracellular biochemical mediators of cell function (e.g., second messengers), resulting in the regulation of several physiological functions.

[0099] Of the GPCR superfamily, the melanocortin receptor (MCR) subfamily plays significant physiologicalroles. MCRs are derived from five distinct genes encoding receptors (MC1R–MC5R). MC1R governs the mammalian skin and hair color by regulating the production of melanin. MC2R is mainly located in the adrenal cortex and controls the glucocorticoids that are responsible for modulating the immune system, regulating blood sugar level, and helping trigger nerve cell signaling in the brain. MC3R has been shown to regulate accumulation of adipose tissue. MC4R is known to regulate adipose tissue formation and energy homeostasis and is believed to be a monogenic target for anti-obesity therapeutics. MC5R is involved in exocrine gland dysfunction, sebum regulation, and waxy skin fatty protection.

[0100] Treatment of genetic obesity or hypothalamic obesity due to malfunctions of signaling cascadesterminating in, or including, MC4R signaling typically involves administration of pan-melanocortin receptor activating peptides and small molecule agonists. While viable agonists have been characterized in vitro, undesirable side effects frequently appeared during clinical trials.

[0101] For example, setmelanotide has demonstrated the undesired ability to generate skin hyperpigmentationin human trials and also in real world use, which is due to the molecule’s activity on the MC1R receptor.

[0102] In embodiments, these undesirable hyperpigmentation side effects can be reduced or eliminated byidentifying a MC4R agonist (e.g., without limitation, a peptide agonist) that is selective for MC4R over MC1R, and which also demonstrates potent binding to, and in vivo effects on MC4R. In embodiments, the peptides of the present disclosure have demonstrated increased ratios of MC4R intracellular signaling to MC1R intracellular signaling as determined by cAMP production. In embodiments, the peptides of the present disclosure, which are shown to be selective for MC4R over MC1R, demonstrate that MC4R agonism is a viable route to weight loss for a genetic, hypothalamic, and / or general obese population while reducing or eliminating a major unwanted side- effect of known MC4R agonists (i.e., hyperpigmentation) that could otherwise cause patients to reject or avoid treatment with a melanocortin agonist.

[0103] In embodiments, MC4R variants can be weight-reducing as opposed to weight-inducing. Whileinsufficiency of MC4R activity leads to weight gain, MC4R gene sequence variants that promote signaling 11123828-02-5133-WO preferentially through the B-arrestin pathway during MC4R activation have been demonstrated to lead to a reduction in weight in humans. In embodiments, the peptide or pharmaceutical composition of the present disclosure preferentially signals through the B-arrestin pathway, as compared to the canonical cAMP pathway, and can induce weight loss in a general-obesity population.

[0104] In aspects and embodiments, the disclosure provides macrocyclic peptides containing non-canonicalamino acid residues, where such macrocyclic peptides are potent and selective agonists of the genetically- validated, obesity-driving, G protein-coupled MC4R receptor. In embodiments, the peptides of the present disclosure are functionally selective for MC4R as compared to the MC1R. Without being bound to a particular theory, selections of two adjacent amino acids in the sequence within the ring of the macrocycle in positions X3 and X4, were found to be important to a significant loss of MC1R functional activity. In embodiments, the peptides described herein comprise multiple pairs of X3and X4that result in increased MC4R selectivity. In embodiments, while at times selectivity within a molecular class is achieved at the expense of some efficacy on the main target, the peptides of the present disclosure retained robust MC4R functional activity (cAMP production, and B-arrestin signaling). In embodiments, the peptides of the present disclosure are efficacious as weight-reducing agents. Peptides

[0105] In embodiments, the disclosure provides selective melanocortin 4 receptor (MC4R) agonist peptides,and corresponding methods of making and using the same, e.g., without limitation, for the treating and / or prevention of diseases or disorders associated with upregulation of MC4R. In embodiments, the peptides described herein, demonstrate enhanced MC4R function. In embodiments, the peptides described herein are MC4R agonistic peptides that display superior selectivity towards MC4R as compared with the other melanocortin receptors (such as MC1R). In embodiments, the peptides described herein display varying activity on G-protein coupled pathways stemming from the MC4R, namely one or more of Gs-coupled (e.g, cAMP), Gq-coupled, and B-arrestin dependent signaling pathways. In embodiments, the peptides of the present disclosure have increased in vitro selectivity and potency, in vivo effectiveness, pharmacokinetic attributes, and / or stability when compared to other melanocortin receptor binding peptides.

[0106] In aspects and embodiments, there is provided a peptide comprising the amino acid sequence offormula (I): X1-X2-X3-X4-X5-X6-X7-X8 formula (I) wherein in formula (I): X3 is 3-aminooxetane-3-carboxylic acid (Aib(O-cyclic)); X4 is glutamine (Gln), homocitrulline (hCit), citrulline (Cit), 3-(3-pyridyl)-L-alanine (3-Pal), L- homoglutamine (hGln), histidine (His), or L-ornithine (Orn); and X1, X2, X5, X6, X7, and X8are each independently a canonical or non-canonical amino acid. 12123828-02-5133-WO

[0107] In aspects and embodiments, there is provided a peptide comprising the amino acid sequence offormula (I): X1-X2-X3-X4-X5-X6-X7-X8formula (I) wherein in formula (I): X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table 1.

[0108] In aspects and embodiments, there is provided a peptide comprising the amino acid sequence offormula (I): X1-X2-X3-X4-X5-X6-X7-X8 formula (I) wherein in formula (I): X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and Table A2A.

[0109] In embodiments, the peptide consists of the amino acid sequence as set forth in formula (I).

[0110] In embodiments, the peptides of Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and TableA2A are not limited to N-terminal functional group, C-terminal functional group, and / or status or type of cyclic function.

[0111] In embodiments, the peptide is a cyclic peptide.

[0112] In embodiments, the cyclic peptide comprises a disulfide bridge or a lactam bridge.

[0113] In embodiments, the cyclic peptide has the formula (II):ormua ( ).

[00114] In embodiments, the cyclic peptide of formula (II) is a cyclic peptide of any one of:123828-02-5133-WOwherein X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1 and Table 2.

[0115] In embodiments, the cyclic peptide of formula (II) is a cyclic peptide of any one of formula (IIa), formula(IIb), formula (IIc), formula (IId), formula (IIe), or formula (IIf), wherein X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, and Table 3.

[0116] In embodiments, the cyclic peptide of formula (II) is a cyclic peptide of any one of formula (IIa), formula(IIb), formula (IIc), formula (IId), formula (IIe), or formula (IIf), wherein X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, and Table 3 or a linker.

[0117] In embodiments, the peptide consists of the amino acid sequence as set forth in formula (II). Inembodiments, the peptide consists of the amino acid sequence as set forth in formula (IIa). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (IIb). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (IIc). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (IId). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (IIe). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (IIf).

[0118] In embodiments, the cyclic peptide has a formula selected from formula (BII), formula (CII), formula(DII), formula (EII), and formula (FII).

[0119] In embodiments, the cyclic peptide of formula (II) is a cyclic peptide of any one of formula (IIa), formula(IIb), formula (IIc), formula (IId), formula (IIe), or formula (IIf). 14123828-02-5133-WO

[0120] In embodiments, the cyclic peptide of formula (BII) is a cyclic peptide of any one of formula (BIIa),formula (BIIb), formula (BIIc), formula (BIId), formula (BIIe), or formula (BIIf).

[0121] In embodiments, the cyclic peptide of formula (CII) is a cyclic peptide of any one of formula (CIIa),formula (CIIb), formula (CIIc), formula (CIId), formula (CIIe), or formula (CIIf).

[0122] In embodiments, the cyclic peptide of formula (DII) is a cyclic peptide of any one of formula (DIIa),formula (DIIb), formula (DIIc), formula (DIId), formula (IIe), or formula (DIIf).

[0123] In embodiments, the cyclic peptide of formula (EII) is a cyclic peptide of any one of formula (EIIa),formula (EIIb), formula (EIIc), formula (EIId), formula (EIIe), or formula (EIIf).

[0124] In embodiments, the cyclic peptide of formula (FII) is a cyclic peptide of any one of formula (FIIa),formula (FIIb), formula (FIIc), formula (FIId), formula (FIIe), or formula (IFIf).

[0125] In embodiments, the peptide consists of the amino acid sequence as set forth in formula (BII). Inembodiments, the peptide consists of the amino acid sequence as set forth in formula (BIIa). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (BIIb). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (BIIc). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (BIId). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (BIIe). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (BIIf).

[0126] In embodiments, the peptide consists of the amino acid sequence as set forth in formula (CII). Inembodiments, the peptide consists of the amino acid sequence as set forth in formula (CIIa). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (CIIb). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (CIIc). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (CIId). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (CIIe). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (CIIf).

[0127] In embodiments, the peptide consists of the amino acid sequence as set forth in formula (DII). Inembodiments, the peptide consists of the amino acid sequence as set forth in formula (DIIa). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (DIIb). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (DIIc). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (DIId). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (DIIe). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (DIIf).

[0128] In embodiments, the peptide consists of the amino acid sequence as set forth in formula (EII). Inembodiments, the peptide consists of the amino acid sequence as set forth in formula (EIIa). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (EIIb). In embodiments, the peptide 15123828-02-5133-WO consists of the amino acid sequence as set forth in formula (EIIc). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (EIId). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (EIIe). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (EIIf).

[00129] In embodiments, the peptide consists of the amino acid sequence as set forth in formula (FII). Inembodiments, the peptide consists of the amino acid sequence as set forth in formula (FIIa). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (FIIb). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (FIIc). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (FIId). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (FIIe). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (FIIf).

[0130] In embodiments, in formula (BIIa), formula (BIIb), formula (BIIc), formula (BIId), formula (BIIe), or formula(BIIf), X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, and Table 3 or a linker.

[0131] In embodiments, in formula (CIIa), formula (CIIb), formula (CIIc), formula (CIId), formula (CIIe), or formula(CIIf), X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10are each independently an amino acid selected ula(DIIf), X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, and Table 3 or a linker.

[0133] In embodiments, in formula (EIIa), formula (EIIb), formula (EIIc), formula (EIId), formula (EIIe), or formula(EIIf), X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10are each independently an amino acid selected from Table 1, Table 2, and Table 3 or a linker.

[0134] In embodiments, in formula (FIIa), formula (FIIb), formula (FIIc), formula (FIId), formula (FIIe), or formula(FIIf), X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, and Table 3 or a linker.

[0135] In embodiments, the peptide of formula (II) is selected from Table 2, Table A2 and Table A2A.

[0136] In embodiments, the peptide of formula (I) or formula (II) is selected from Table 1, Table 2, Table A1,Table A1A, Table A2, and Table A2A.

[0137] In embodiments, the peptides of formula (I) or formula (II) comprise a N-terminal functional group, a C-terminal functional group, and / or a cyclic function.

[0138] In embodiments, the peptide of formula (I) or formula (II) is selected from Table 1, Table 2, Table A1,Table A1A, Table A2, and Table A2A, wherein the N-terminal, C-terminal and / or cyclic structure are optional features.

[0139] In embodiments, the peptide is a cyclic peptide (e.g., Table 1). In embodiments, the cyclic peptidecomprises a disulfide bridge or a lactam bridge. 16123828-02-5133-WO

[0140] In embodiments, the peptide of formula (I) or formula (II) is lipidated (e.g., Table 2).

[0141] In embodiments, the peptide of formula (I) is selected from Table A1, Table A1A, Table A2 and TableA2A.

[0142] In embodiments, the peptides of Table 1, Table 2, Table A1, Table A1A, Table A2 and Table A2A are notlimited to N-terminal functional group, C-terminal functional group, and / or status or type of cyclic function. Table A1: Exemplary peptides.Molecule NameX1 X2 X3 X4 X5 X6 X7 X8 1093-1 D-Nar Cys Aib(O- Gln D-Phe(4-F) Arg Trp(6-F) Cys

[0143] In embodiments, the peptide of formula (I) is selected from Table B1, Table B1A, Table B2 and TableB2A.

[0144] In embodiments, the peptides of Table B1, Table B1A, Table B2 and Table B2A are not limited to N-terminal functional group, C-terminal functional group, and / or status or type of cyclic function.Table B1: Exemplary peptide.Molecule NameX1 X2 X3 X4 X5 X6 X7 X817123828-02-5133-WO 1119-1 D-Nar Cys Phg 3-Pal D-Phe(4-F) Arg Trp(6-F) Cys

[0146] In embodiments, the peptide of formula (I) is selected from Table B1A, wherein the N-terminal, C-terminal and / or cyclic structure are optional feature.Table B1A: Exemplary peptide with N-terminal, C-terminal and / or cyclic structure as optional feature.Molecule X1X2X3X4X5X6X7X8N-term C-term CyclicName 1119 D-Nar Cys Phg 3-Pal D-Phe(4-F) Arg Trp(6-F) Cys Ac NH2 Disulfid

[0007] n em o ments, t e pept e o ormua ( ) s seecte rom a e .Table B2: Exemplary lipidated peptides. Molecule NameX-4 X-3 X-2 X-1 X1 X2 X3 X4 X5 X6 X7 X8 ys ys ys ys

[0008] In embodments, t e peptde o ormua (II) s seected rom Tabe B .

[0149] In embodiments, the peptide of formula (II) is selected from Table B2A, wherein the N-terminal, C-terminal and / or cyclic structure are optional feature. Table B2A: Exemplary lipidated peptides. Molec N- C- Cyclic ule X X-3X-2X-1X1X X X4X5X6X7X8term term eee18123828-02-5133-WO 1147 LyD- PE D- Beta- C P 3- D-Arg Trp(6 Cys Ac NH2 Disulfides* Arg G1 Arg homoAr ys hg Pa Phe( -F) g l 4-F), , , C2A.

[0151] In embodiments, the peptides of Table C1, Table C1A, Table C2 and Table C2A are not limited to N- terminal functional group, C-terminal functional group, and / or status or type of cyclic function. Table C1: Exemplary peptide.Molecule X1 X2 X3 X4 X5 X6 X7 X8 Name 1094-1 D-Nar C s D- Gln D-Phe Ar Tr (6-F) C s

[0153] In embodiments, the peptide of formula (I) is selected from Table C1A, wherein the N-terminal, C-terminal and / or cyclic structure are optional feature. Table C1A: Exemplary peptides. Molecule X1 X2 X3 X4 X5 X6 X7 X8 N- C- Cycli Name term term c sulf

[0005] n emo ments, te pept e o ormua ()s seecte rom a e . Table C2: Exemplary lipidated peptides Molecule NameX-4 X-3 X-2 X-1 X1 X2 X3 X4 X5 X6 X7 X8 ys ys ys ys

[0055] In embodments, te peptde o ormua (II)s seectedrom Tabe C .

[0156] In embodiments, the peptide of formula (II) is selected from Table C2A, wherein the N-terminal, C- terminal and / or cyclic structure are optional feature. 19123828-02-5133-WO Table C2A: Exemplary lipidated peptides Molecul N- C- Cyclic eNameX- X- X-2 X-1 X1 X2 X3 X X5 X X ter ter 3 4 6 X7 4 8 m m lfid lfid lfid lfid

[0057] In embodments, t e peptdes o Tabe D , Tabe D , Tabe D and Tabe D are not mted to N-terminal functional group, C-terminal functional group, and / or status or type of cyclic function.

[00158] In embodiments, the peptide of formula (I) is selected from Table D1.Table D1: Exemplary peptides. Molecule X1 X2 X3 X4 X5 X6 X7 X8 Name20123828-02-5133-WO 1042-1 D-Nar Cys L-aMeAsp His D-Phe Arg Trp(6-F) Cys1024-1 Beta- Cys L-aMeGlu His D-Phe Arg Trp(6-Me) Cysh A

[00160] In embodiments, the peptide of formula (I) is selected from Table D1A, wherein the N-terminal, C-terminal and / or cyclic structure are optional feature. Table D1A: Exemplary peptides Molecul X1 X2 X3 X4 X5 X6 X7 X8 N- C- Cyc e Name ter ter lic sule sule sule sule sule sule sule sule21123828-02-5133-WO 1091 D-Nar Cys hGlu Gln D-Phe Arg Trp(6-F) Cys Ac NH2 Disulfide 1096 D-Nar Cys D- Gln D-Phe Arg Trp(6-F) Cys Ac NH2 DisulM S fide sule sule sule sule sule sule ctsule sule sule sule sule sule sule sule sule sule sule sul e sule sule sule sul e sule sule sule

[00161] In embodiments, the peptide of formula (II) is selected from Table D2.Table D2: Exemplary lapidated peptides. Molecul eNameX- X- X X X X X X X X X X X X X22123828-02-5133-WO 1129-2 Ly Gly D-D-Cys L-Hi D- A Trp( C s* Arg Nar aMe s Phe rg 6- ys Glu Me)23123828-02-5133-WO 1156-2 LyD-Gly D-D-Cys D-3- D- A Trp( C s* Ar Arg Nar aMe P Phe rg 6-F) ys g Orn al

[00163] In embodiments, the peptide of formula (II) is selected from Table D2A, wherein the N-terminal, C-terminal and / or cyclic structure are an optional feature. Table D2A: Exemplary lipidated peptides. Molecul N- C- Cyclic eNameX- X- X-2 X-1 X1 X X X ter ter 3 X2 X3 4 X5 6 X7 4 8 m m lfid lfid lfid lfid lfid lfid lfid lfid lfid lfid lfid lfid lfid24123828-02-5133-WO 1142 Ly Gly D-D-Cys Aib(Gl D- A Trp( CAc NHDisulfid s* Arg Nar O- n Phe( rg 6-F) ys 2 e cyclic 4-F) ) lfid lfid lfid lfid lfid

[00164] In embodiments, the peptides of Table E1, Table E1A, Table E2 and Table E2A are not limited to N-terminal functional group, C-terminal functional group, and / or status or type of cyclic function.

[00165] In embodiments, the peptide of formula (I) is selected from Table E1.

[0166] Table E1: Exemplary peptides.Molecule X1 X2 X3 X4 X5 X6 X7 X825123828-02-5133-WO D-Arg Cys Cyclo-Leu His D-Phe Arg Trp(6- Cys 1009-1 Me)26123828-02-5133-WO Beta- Cys L-aMeGlu His D-Phe Arg Trp(6-Cl) Cys 1032-1 homoArg27123828-02-5133-WO L-hArg Cys L-aMeGlu His D-Phe(4-F) Arg Trp(6-F) Cys 1054-1 D-Arg Cys D-aMeOrn His D-Phe Arg Trp(6- Cys28123828-02-5133-WO D-Nar Cys L-aMeGlu His D-Phe Arg Trp(6- Cys 1075-1 CF3)29123828-02-5133-WO D-Nar Cys D-aMeOrn hGln D-Phe Arg Trp(6-F) Cys 1100-1 D-Nar Cys D-aMeOrn hGln D-Phe(4-F) Arg Trp(6-F) Cys30123828-02-5133-WO 1124-1 D-Nar Cys D-aMeOrn 3-Pal D-Phe(4-F) Arg Trp(6-F) Cys 1125-1 D-Nar Cys D-aMeOrn Orn D-Phe(4-F) Arg Trp(6-F) Cys

[00168] In embodiments, the peptide of formula (I) is selected from Table E1A, wherein the N-terminal, C-terminal and / or cyclic structure are an optional feature. Table E1A: Exemplary peptides. Molecule X1 X2 X3 X4 X5 X6 X7 X8 N- C- Cyclic Name term term31123828-02-5133-WO Arg Cys Ala(2- Gln D-Phe Arg Trp Cys Ac NH2 Disulfide 1013 Me)32123828-02-5133-WO Beta- Cys bhGlu His D-Phe Arg Trp Cys Ac NH2 Disulfide 1033 homoArg33123828-02-5133-WO Beta- Cys Cyclo- His D-Phe Arg Trp(6- Cys Ac NH2 Disulfide 1052 homoArg Leu F)34123828-02-5133-WO D-Nar Cys L- His D-Phe(4- Arg Trp(6- Cys Ac NH2 Disulfide 1072 aMeGlu CF3) F)35123828-02-5133-WO D-Nar Cys L- Gln D-Phe Arg Trp(6- Cys Ac NH2 Disulfide 1090 aMeGlu F)36123828-02-5133-WO D-Nar Cys Phg His D-Phe Arg Trp(6- Cys Ac NH2 Disulfide 1110 F)

[00169] In embodiments, the peptide of formula (II) is selected from Table E2.37123828-02-5133-WO Table E2: Exemplary peptides. Molecul X- X- X X X1 X1 X-2 X-1 X1 X2 X3 X5 e NameX7 X8X94 3 4 6 0 138123828-02-5133-WO L- Ly D- Hi D- Ar Trp(6 Cy 1140-2 D-Nar Cys aMeGl s* Arg Glu s Phe g -F) s u39123828-02-5133-WO D- D- 3- D- Ly D- Ar Trp(6 Cy 1154-2 Ar Gly D-Nar Cys aMeO P Phe( s* Arg g -F) s g rn al 4-F) Ly s* Ly s*

[00170] In embodiments, the peptide of formula (II) is selected from Table E2A.

[0171] In embodiments, the peptide of formula (II) is selected from Table E2A, wherein the N-terminal, C-terminal and / or cyclic structure are optional feature. Table E2A: Exemplary lipidated molecules. N Molecul X - C- - X- X X X-2 X-1 X1 X2 X3 X5 X7 X8 ter ter Cyclic lfi lfi lfi lfi lfi40123828-02-5133-WO 5- triF) lfi lfi lfi lfi lfi lfi lfi lfi lfi lfi lfi lfi lfi41123828-02-5133-WO D- 3- D- Ly D- Ar Trp(6 Cy NH Disulfi 1146 Ar Gly D-Nar Cys Phg P Phe( Ac s* Arg g -F) s 2 de g al 4-F) lfi lfi lfi lfi lfi lfi lfi lfi lfi lfi lfi42123828-02-5133-WO eA sp, .

[0173] In embodiments, the peptides of Table F1 and Table F2 are not limited to N-terminal functional group,C-terminal functional group, and / or status or type of cyclic function.

[00174] In embodiments, the peptide of formula (I) is selected from Table F1.Table F1: Exemplary peptide. Molecule X1 X2 X3 X4 X5 X6 X7 X8 Name

[0175] In embodiments, the peptide of formula (I) is selected from Table F2.

[0176] In embodiments, the peptide of formula (I) is selected from Table F2, wherein the N-terminal, C-terminaland / or cyclic structure are optional feature. Table F2: Exemplary peptide.Molecule X1 X2 X3 X4 X5 X6 X7 X8 N- C- Cycl Name term term ic sule43OW- icle33c dfyie ludfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfilCisuDisuDisuDisuDisuDisuDisuDisuDisuDisuDisuDisuDisuDisuDisuDisuDisuis15D D-20- - 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 282CmretH N H N H N H N H N H N H N H N H N H N H N H N H N H N H N H N H N H N8321dulcgrg gAr rniseX1oAmoAmom dtriarNaraoh-ar r r ohr r r ohr r r r r rta a a-ata a a-ata a a a a ap -N-N-N-N-N-N-N-N-N-N-N N N Ne D D DeB D D DeB D D DeB D D - D - D - D - D pcilcyC.X1- gg1g g g1g g g1 sreAr-DA- GrD E PAr r r r r-gDAr-gDAr-GgD E PAr-gDAr-gDAr-GgD E PA- DA-A-A-Ar- -gArA-idD D D D D D tpep2- 1G 1G 1G 1G 1G 1 y XlyGlyG E P E PlyGlyG E P E PlyGlyG G E P E PlyGlyGlyGlyGlylyraG G lpmexX3-grgA *s*s rgArgA *s*s rgr*s*sgrgrgrgrgrgrgrE - DyLyL -D - DyLyLA- DA- DyLyLA- DA- DA- DA- DA- DA- DA- D : 1 leb X4-*s*ys*ys*ys*ys*ys*ys*s*s*s*s*saL L L L L LyLyLyLyLyLyLT] 7lee7uc10elmoaN649135147148149147136130152144141 2 3 4 5 6 715151515 5 5 50[M1 1 1 1 1 1 1 1 1 1 1 1 1 111111111OW- icledfie ldfie ldfie ldfie ldfie ldfie ldfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfi33cy ui ui ui ui ui uiluiluiluiluiluiluiluiluiluiluiluiluiluilui15-20-828321grgrgrgArX1oAmoAmoAmom rarNarararararararaoh--aoh- oh- oh- rararararararaDN- DN- DN- DN- DN- DN- DN- DN-tDe atBe atBe atBeBN- DN- DN- DN- DN- DN- DN- D X1- X2- X3- X4-leuc eelmoa2M N23124 5 6 71121121121121115262728292031323334353637383OW- icled3fiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfieded3cyluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluilu fiilu fiilui15-20-828321X1 rar r r r r r r r r r r r r rNaNaNaNaNa a a a a a a a a a-D - D - D - D - DN- DN- DN- DN- DN- DgrAgrAgrAgrAgrAN- DN- DN- DN- DN- D X1- X2- X3- X4-leuc eelmoaM N895311142434445464748494051525354555657585OW- icledfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfiedfiedfiedfiedfiedfiedfiedfi33cy ui ui ui ui ui ui ui ui ui ui ui uiluiluiluiluiluiluiluilui15-20-828321grgrgrgrgrg g g g1A Ar r r romoAmoAmoAmoAmoA A AmomomoX rarao- oh- raraohom hhr r ohohr r r ohohohr rN- DN- atat -DeBeBN- DN- at -ataDeBeBNa-- DN- at -ataDeBeBNa-DNa-- DN- at -at -ataDeBeBeBNa-DN- D X1- X2- X3- X4-leuc eelmoaM N9506162636465666768696071727374757677787OW- icledfie ldfie ldfie ldfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfi33cy ui ui uiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluilui15-20-828321grgrgrg1AroAmoAmoAmoXoh-aohte-aom h t-aoht-artarBeBeBeBNarDNarDNarDNarDNarDNarDNarararararararara- - - - - - -DN- DN- DN- DN- DN- DN- DN- DN- DN- D X1- X2- X3- X4-leuc eelmoaM N9708182838485868788898091929394959697989OW- icle33c dfyie ludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfiilui15-20-828321grg1ArgrgroAmoAoAoX raom m m h- oh- rararararaoh- oh- rar r r r r r r r rNatatBNDNDNDNDNatatD B BNaDNaDNaDNa a a a a a-DeBe - - - - - e e - - - -DN- DN- DN- DN- DN- DN- D X1-lyGly *s*sGlyGyL lyGlyGyL lyG X2- lyGly *s*sGyL lyGyL lyG X3- ly *s* *ys sGLyLyL* X4- syLleuc eelmoaN90010203040506070809001112 3 4 3 4 5 0 M9 1 1 1 1 1 1 1 1 1 1 1 111111121212131OW- icle33c dfyie ludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfiilui15-20-828321grAogrAgrgrAgrAgrAAoX1 mo o o oraraohm m m mm -rarara ohra ohra ohra ohr r ohN-N- at N-N NatB ANatD B ANatD B ANataD BNa- DNatD DeB D - DgrA - Degr - egr - egr - e - -DeB X1-ly *s* * * * * * * * * * *ylylysysysysysysysysys s s*sGLG GL L L L L L L LyLyLyLyLX2-*s*ys*sLyLyLX3- X4-leuc eelmoaN 1323738393041424344454647 8 9 0 1 2 3 4 M1 1 1 1 1 1 1 1 1 1 1 14141415151515151OW- icledfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfiedfiedfiedfiedfiedfiedfiedfiedfiedfi33cy ui ui ui ui ui ui ui uiluiluiluiluiluiluiluiluiluilui15-20-8283211omo o oXom -aom m hhohr r r ohr rt -at -ataNaNa-NataNarNarNarNarNar r r rNaNa a aeBeBeB - D - D - DeB - D - D - DgrA - D - D - D - DN- DN- DN- D X1- *s*s*y ysL LyLX2- X3- X4-leuc eelmoaN 5565758595061626364656667686960 1 2 M1 1 1 1 1 1 1 1 1 1 1 1 1 1 1717171OW- icledfie ldfie ldfie ldfie ldfie ldfie ldfiedfi33cy ui ui ui ui ui uiluilui15-20-828321C C C C C C C C X1 rarar r r r r rN NaNaNaNa a a-D - D - D - D - DN- DN- DN- D X1- X2- X3- X4-leuc eelmoaN 37475767778 9 0 M1 1 1 1 1717181OW- icledfie ldfie ldfie ldfie ldfiedfiedfiedfiedfi33cy ui ui ui uiluiluiluiluilui15-20-828321X1 rarararararar r rN- DN- DN- DN- DN- DNa-DNa-DNa-DN- D X1- X2- X3- X4-leuc eelmoaN 182838485868788 9 M1 1 1 1 1 1 18181OW- icledfie ldfie ldfie ldfiedfiedfiedfiedfiedfiedfiedfi33cy ui ui uiluiluiluiluiluiluiluilui15-20-828321X1 rararararararar r r rN N N N N N NaNaNa a-D - D - D - D - D - D - D - D - DN- DN- D X1- X2- X3- X4-leuc eelmoaN 0919293949596979899 0 M1 1 1 1 1 1 1 1 19102OW- icled3fiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfed3cyluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiilu fiilui15-20-828321X1bo oinm moa- h-4- NlyGgrAgrAgrAgrAgrAgrAgrAgrAgrAgrAgrAgrAgr atAeBgrAgrAgrAgrAgrA X1- X2- X3- X4-leuc eelmoaN 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6108 9 0 M0202020202020202021212121212121201121222OW- icledfie ldfie ldfie ldfie ldfie ldfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfi33cy ui ui ui ui uiluiluiluiluiluiluiluiluiluiluiluilui15-20-828321eavyubX1ognridonidgrAgrAgrAgrAgrAgrAgr-iAh-ADh ta-Llnie[adu idn-a] Gca [4u idGcagrAgrAgrAgrAgrAgrAgrA X1- X2- X3- X4-leuc eelmoaN 12223242200 6272829203300 24300 43536 7 M2 2 2 2 1 2 2 2 2 2 1 2 1 2 23232OW- icledfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfi33cyluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluilui15-20-828321o o oX1 mom m rgrgrgr h- grgroh- oh- grggAgrAgrAgrAA- DA- DgrAgrAA- atDeBA- DgrAA- atatDgrAgrAeBeBAr-DA- DnrO X1- X2- X3- X4-leuc eelmoa8 9 0 1 25M N304 5 6 7 8 9 0 1 2 3605707 232424242014242424242425252525201520152OW- icledfie ldfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfi33cy uiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluilui15-20-828321grg g gArArArX1omomoAmom raoh- ohohohN-g g g g g gat -at -at -atDrArArArArArAgrAgrAgrAgrAgrAgrAgrAeBgrAeBeBeB X1- X2- X3- X4-leuc eelmoaN 8595061626364656667686960717273747576 M2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 272OW- icle33c dfyie ludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfiilui15-20-8283211omomomomo o oXoao om m m h-tegrgh hohohohohBAr-grgr-at gr-at -at -at -at -atDA- DA- DgrAA- DeBgrAgrAA- DgrAgrAgrAgrAeBeBeBeBeBgrA ehPgX1- o rluGlulugGgGg lmyGorp ro- PIn yTh- aAtom DeBoh laAlaAlyGlaAorPlyG X2-grAluu GeL luGgru AeL lu eGhP X3- X4-leuc eelmoaN800 8799700 78889809192939495 6 7 8 9 0 1 5 M1 2 2 1 2 2 2 2 2 2 2 29292929292030343OW- icled3fiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfi3cyluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluilui15-20-828321X1 grsr rAgrAgrAgrAyL eSgrAgrAgrAgrAgrAgrAgrAgrAgrAaNgrAgrAgrAgrA X1-)eeh1 -rPyDT- rM(G DyTgrA E P X2-reS X3- X4-leuc eelmoa6 7 8 9 0 1 7 8 9 0 1 2 3 4 5 6 70M N419 0 343434353535353536363636363636363016373OW- icledfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfiedfiedfiedfiedfiedfiedfiedfiedfiedfi33cy ui ui ui ui ui ui ui ui ui uiluiluiluiluiluiluiluiluiluilui15-20-828321X1gr om ggrrg g g g g A-oh- AgrAgrAgrAAr r r r r-D- DA- DA- DgrAA- DgrAA- DA- De atMeBgrAgrAgrAgrAgrAgrA icm eX1- aaxhePogrba lu grGGg lyp GIn A-naDriTdcm A a aohh-bDaG X2- luG X3- X4-leuc eelmoaN 475767778797081828385868788809192 3 4 5 M3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 393939393OW- icledfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfiedfiedfiedfiedfi33cy ui ui ui ui ui ui ui ui ui ui ui ui ui ui uiluiluiluiluilui15-20-828321grg g g gArArAr r1omomoAmoAgr oXo-a r rohom m hg g o A-otegrA-eA-e-grgrgrg g g ga ht-ga ht-gat ggrA- Dh-e-atB A M M A A ArArArArAeBrAeBrAeBrA D MeB X1- abaGlyGlylu lGGagNr 2yT lyG X2- lns s GyLyLX3- X4-leuc eelmoaN 6979990011012010 73010 940011121314119511 2 M3 3 3 4 4 1 1 4 1 4 4 4 4 4 40114012424OW- icle33c dfyie ludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfiilui15-20-828321o o o o o o o o o o oX1 m rom m m m m m m m m m rg grgrgrrarara h-aoh-aoh-aoh-aoh-aoh- oh- oh- oh- oh- oh- grg AA- DA- DA- DA- DN- DN- DN-t t t t tatatatatatat ADeBeBeBeBeBeBeBeBeBeBeBh-LX1- 2GE PlyGlyGlyGlyG X2-*s*ysLyLX3- X4-leuc eelmoa6M N 42171819102122232425 6 7 8 94010108 124010101010102106 137 4329212 24013401440101OW- icle33c dfyie ludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfiilui15-20-828321grg g g g g g g g gArArArArAr r r r r1omomomomoAoAoAoAoAoX m m m m m m grohAh-aoh-aoh-aoh-aoh- oh- oh- oh- oh- oh- rarararararararara-Ltet t tatatatatatatBeBeBeBeBeBeBeBeBeBN- DN- DN- DN- DN- DN- DN- DN- DN- D X1- X2- X3- X4-leuc eelmoaN 404310320330340940515253504555653603738393043 M4 1 1 1 1 4 4 4 4 1 4 4 4 1010101010164OW- icledfie ldfie ldfie ldfie ldfie ldfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfi33cy ui ui ui ui uiluiluiluiluiluiluiluiluiluiluiluiluiluiluilui15-20-8283211oX m rar r r r r r r r r r r ohgrNa a a a a a a a a a ararara-- rDNa-gDN- DN- DN- DN- DN- DN- DN- DN- DN- DN- DN- DN- DN- at ADeBgrAh-LNr-DA- D X1- X2- X3- X4-leuc eelmoaN142043040 7684696450460470480490574005105205305405502 M51 1 1 4 4 4 1 1 1 1 1 4 1 1 1 1 1 18401OW- icle33c dfyie ludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfiilui15-20-828321grg1AroAogrgArgroAoAoX m rgaraom hr-aohgt -at gr rmA ragrrarararararomah- omta h- ota h-ta grAgrAN- DN- DeBeBA- Dh-LN- DA- DN- DN- DN- DN- DN- DN- DebebebA- D X1- gr1 1 `A- OlulyGE D R PGgG PlyG G E PlyG 1 1 X2- lyGluGlylyG GGE PlyG G E PlyG X3-*s*ys*s*s*s*s*s*sLyLyLyLyLyLyLyLX4-leuc eelmoa6M N57058 9 0 1 2 3 9 8 3 4 1 5 0 5105107 185409 186406106106102 2 3 693 6 343111111101941101110511OW- icledfie ldfie ldfie ldfie ldfie ldfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfi33cy ui ui ui ui uiluiluiluiluiluiluiluiluiluiluiluiluiluiluilui15-20-828321X1 rarararararararararar r r r r r r r rNDNDNa a a a a a a a a- - -DN- DgrAN- DN- DN- DN- DN- DN- DN- DN- DN- DN- DN- DN- DN- DN- DN- D X1- X2- X3- X4-leuc eelmoa6M N67068696071727374757677787970818283 4 5101010101010101010101010101010108108 810101OW- icledfie ldfie ldfie ldfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfiedfi33cy ui ui uiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluilui15-20-828321X1 rarararararararararararararararar r r rN N N N N N N N N N N N N N N NaNaNa a-D - D - D - D - D - D - D - D - D - D - D - D - D - D - D - D - D - DN- DN- D X1- X2- X3- X4-leuc eelmoa6M N870888982 3 4 5 6 7 8 9 009192939491010101353535353535353541 542 5450101010101OW- icle33c dfyie ludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfiilui15-20-828321X1 rarararararararararararararararararararNDNDNDNDNDNDNDNDNDN- DN- DN- DN- DNa- - - - - - - - - -DN- DN- DN- DN- DN- DN- D X1- 1G 1G 1grgrE G P E P E PorPorPA- DA- D X2- 1G 1 E G 1G P E P E PluGluGlyGlyG 3-gr1gAGl lr rrX - D E PuGuGeSeSA- D 4*s*s*s*s*s* *X-y y ys sL L LyLyLyLyLleuc eelmoaN697098099090 1 2 3 4 6 7 8 9 10010101010101010 01 2 3 446 7 M1 1 1 1 1 1 1 1 1 1 1111165656565116565OW- icle33c dfyie ludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfie iludfiilui15-20-828321X1grrararaA-rararararararar r r r r r rN- DN- DN- D- DeMN- DN- DN- DN- DN- DN- DNa-DN-r raDaNaNNa-DNa-DNa-DNa-DNa-DN- D X1- grA- DorPorP 2grX-reSlyGlyGlyGlyGluGluGA- DluG X3-grA- DluGly *s*Gys*Lys*Lys*LysLyL luG 4* * * *X- sys s sLyLyLyLleuc eelmoa3M N 869401112 56511 172 573 574 575 5751111113114115168 9 0 1 411111111111 2 2 3111111111OW- icled3fiedfiedfi3cyluiluilui15-20-828321XsysCysCyC )) )X7eMe e-6(M-Mpr6( -6(TprTprT X6grAgrAgrA ) FirtX5 -,5,43(ehe ePh h-DP- DP- D X4 isHisHisH 17X3 luGe luMaGluhG-Lb- hDb- D X2sys sCyCyC X1 rar rNaNa-D - DN- D X1- 1G 1 EorG P P E P 2- 1 1 X GE PluG G E P X3- luGluGluG ** *X4- sysysL LyLleuc eelmoa2M N31 9 0 18595123828-02-5133-WO

[00178] In embodiments, the peptide of formula (I) is selected from Table A1A.

[0179] In embodiments, the peptide of formula (I) is selected from Table A1A, wherein the N-terminal, C-terminal and / or cyclic structure are optional structure. Table A1A: Exemplary peptides. Molecule X1 X2 X3 X4 X5 X6 X7 X8 N- C- Cyclic Name term term dedededededededededede72123828-02-5133-WO 1158 D-Nar Cys Aib(O- Gln D-Phe(4- Arg Trp(6-F) Pen Ac NH2 Disulfidecyclic) F)Table A2: Exemplary peptides. Molecule Name X-4 X-3 X-2 X-1 X1 X2 X3 X4 X5 X6 X7 X8 ys ys ys ys ys ys

[00181] In embodiments, the peptide of formula (II) is selected from Table A2A.

[0182] In embodiments, the peptide of formula (II) is selected from Table A2A, wherein the N-terminal, C-terminal and / or cyclic structure are optional feature. Table A2A: Exemplary lipidated molecules. N- C- Cyclic Molecul X-4 X-3 X-2 X-1 X1 X2 X3 X4 X5 X X7 X8 ter ter lfid lfid lfid lfid73123828-02-5133-WO clic ) lfid lfid74O eW- icldfie3l dfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldfie ldefil dfie ldfie ldfie ldfie ldfie ldefil dfie ldfie ldfie ldfie ldfie ldefil dfie ldfie ldfie ldfie ldfie ldefil dfie ldfiedfiedfiedfi3 cy uCisuDisuDisuDisuDisuDisuDisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuisuilsuilsuilsuilsuis15D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D D-20-82 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 222 2 2 2 222 2 2 2 222 2 2 2 222 2 2 22m8321pcilX D D D B D D D B D D D B D D D D D D D D D D D D D D D D D D A D B A D B A D B A D cyC.segrgr1grgrgr1grgrgr1grgrgrgrgrgrgl A AGAG Gr*s*s*s*s*s*s*s*s*s*s*s*s*s*suX1- -D- DE P - DA- DA- DE PA- DA- DA- DE PA- DA- DA- DA- DA- DA- DA- DlyGlyGlyGyL lyGlyGyL lyGlyGyL lyGlyGyLyLyLyLyLyLyLyLyLyLyLcelomde1 t G1G 1G1G 1G 1G a*s*s*s*s*sidX2- lyGlyGE P E PlyGlyGE P E PlyGlyGE P E PlyGlyGlyGlyGlyGlyGlyGlyGyL lyGyL lyGyLyLyLpilyralpgrgm3-A-*s*s rgArgA *s*s rgArgA *s*s rg g g g g gArArArArAr r*s*s*sexX DyLyL -D- DyLyL -D- DyLyL -D- D- D- D- DA- DA- DlyGyLyLyLE:2*s* * * * * * * * * * * *leX4-ysys s s s s s s s s s sL LyLyLyLyLyLyLyLyLyLyLyLbaT] 3le8uc10 leeoma649 5 7 8 9 7 6 0 2 4 11314141414131315141415215315415515615715 12 3 4 3 450 1 2 8 901 2 3 4 567 8 9 0 0[M N1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1111111111121212131313131314141414141414141414151OWe-dedededededed edededededed edededededed edededededededededededededede3icl fififififififififififififififififififififififififififififififififi dfi3c luiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluiluilui15-20-828321sysyn n sysysysysysysysysysCysCysCys s s s s s s s s s s s s s s s s sX2 C CePeP C C C C C C C C CyCyCyCyCyCyCyCyCyCyCyCyCyCyCyCyCyCyC grgrAoA grogArAmomohar r ohmorr r r romogrrr r r r r r r r r A-rtaNaNgrA-ataNaNaNaNahN-ta h-ta grAaNaNaNaNaNa a a a aD- D D D D De ararararararararaX1eBgrA- D- D - DeB - D- D - D- D- Debeb -D- D- D- D - D- DN-N-N-N-N- MN- DN- DN- DN- DN- DN- DN- DN- DN- D *s*s*s*s l lgr111 1 1gAOlulyGE G GGGrgr lulululu gr lulu1G 1GgrX1-yLyLyLyLyGyG- DR PGgG PlyGE PlyGE P E P E PorPorPA- DA- DG-G-G-G-A- DorPG-G-orP E PorP E PA- D X2-*s*ysLyL lyGluGlyl1 y G1G GE PlyG 1 GE PlyG1G1G GE P E P E PluGluGlyGly rGeSlgyGlyGlyGlyGluGlur 1GA- DluG 1 G E PluG G E PlyG ** * * * * * * gr1grgr* * * * * grX3- sys s s s s s sLyLyLyLyLyLyLyLA- G DE PluGlu rGerSeSA- DA- DluGlysGys s s sLyLyLyLyL luGluGluGluGA- D X4-*s* * * * * * * * * * * * * *ys s s s s s s s s s s s s sLyLyLyLyLyLyLyLyLyLyLyLyLyLyLleucleeoma 1955 6 7 8 62823391303 4531 2 3 4146 7 8 9341 2 3 4 543239 064M N1616161243411111194111105116565656511656565651175757575751111859511123828-02-5133-WO

[0184] In embodiments, one or more amino acid residues and / or linkers are conjugated to X1 of any one ofthe peptides of formula (I) or formula (II). In embodiments, at least 1, or at least 2, or at least 3, or at least 4, or at least 5 amino acid residues are conjugated to X1of any one of the peptides of formula (I) or formula (II). In embodiments, at least 1, or at least 2, or at least 3, or at least 4, or at least 5 linkers are conjugated to X1of any one of the peptides of formula (I) or formula (II). In embodiments, the one or more amino acid residues and / or linkers and / or spacers conjugated to X1 have the sequential designation of X-1, X-2, X-3, X-4, X-5, and so forth. Non- limiting examples of linkers include lipids and PEG linkers (e.g. PEG-1). In embodiments, the one or more amino acid residues and / or linkers are selected from Table 2. In embodiments, the linker is a PEG linker or lipid selected from Table 2. In embodiments, one or more amino acid residues and / or linkers are conjugated to X8of any one of the peptides of formula (I) or formula (II). In embodiments, at least 1, or at least 2, or at least 3, or at least 4, or at least 5 amino acid residues are conjugated to X8 of any one of the peptides of formula (I) or formula (II). In embodiments, at least 1, or at least 2, or at least 3, or at least 4, or at least 5 linkers and / or spacers are conjugated to X1 of any one of the peptides of formula (I) or formula (II). In embodiments, the one or more amino acid residues and / or linkers conjugated to X8have the sequential designation of X9, X10, X11, X12, X13, X14and so forth. Non- limiting examples of linkers include lipids and PEG linkers (e.g. PEG-1). In embodiments, the one or more amino acid residues and / or linkers are selected from Table 2. In embodiments, the linker is a PEG linker or lipid selected from Table 2.

[0185] In embodiments, the one or more amino acid residues and / or linkers are selected from Table 3. Inembodiments, the linker is a PEG linker or lipid selected from Table 3.

[0186] In embodiments, a linker is an amino acid, including but not limited to modified amino acids. Non-limiting examples of modified amino acids include PEG groups (e.g., PEG-2), and lipids. In embodiments, the is Lys*.

[0187] In embodiments, the peptide further comprises one or more lipids conjugated to X1 and / or X8.

[0188] In embodiments, the peptide further comprises one or more PEG linkers conjugated to X1 and / or X8.

[0189] In embodiments, the peptide of formula (I) is a peptide of formula (Ia):X-4-X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (Ia) wherein in formula (Ia): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table 1 or a linker. In embodiments, the linker is a PEG linker (e.g. PEG-1).

[0190] In embodiments, the peptide of formula (I) is a peptide of formula (Ib):X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 77123828-02-5133-WO formula (Ib) wherein in formula (Ib): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table 1 or a linker. In embodiments, the linker is a PEG linker (e.g. PEG-1).

[0191] In embodiments, the peptide of formula (I) is a peptide of formula (Ic):X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8formula (Ic) wherein in formula (Ic): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table 1 or a linker. In embodiments, the linker is a PEG linker (e.g. PEG-1).

[0192] In embodiments, the peptide of formula (I) is a peptide of formula (Id):X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (Id) wherein in formula (Id): X-1, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table 1 or a linker. In embodiments, the linker is a PEG linker (e.g. PEG-1).

[0193] In embodiments, the peptide of formula (I) is a peptide of formula (Ie):X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10formula (Ie) wherein in formula (Ie): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10are each independently an amino acid selected from Table 1 or a linker. In embodiments, the linker is a PEG linker (e.g. PEG-1).

[0194] In embodiments, the peptide of formula (I) is a peptide of formula (If):X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 formula (If) wherein in formula (Ie): X-1, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1 or a linker. In embodiments, the linker is a PEG linker (e.g. PEG-1).

[0195] In embodiments, the cyclic peptide of formula (I) is a cyclic peptide of any one of formula (Ia), formula(Ib), formula (Ic), formula (Id), formula (Ie), or formula (If), wherein X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, and Table 3 or a linker.

[0196] In embodiments, the peptide consists of the amino acid sequence as set forth in formula (Ia). Inembodiments, the peptide consists of the amino acid sequence as set forth in formula (Ib). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (Ic). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (Id). In embodiments, the peptide consists of the amino acid 78123828-02-5133-WO sequence as set forth in formula (Ie). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (If).

[0197] In aspects and embodiments, there is provided a peptide comprising the amino acid sequence of formula(BI), formula (CI), formula (DI), formula (EI), or formula (FI).

[0198] In embodiments, in formula (BI), X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acidselected from Table 1, Table 2, Table 3, Table C1, Table C1A, Table C2, and Table C2A.

[0199] In embodiments, in formula (CI), X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acidselected from Table 1, Table 2, Table 3, Table C1, Table C1A, Table C2, and Table C2A.

[0200] In embodiments, in formula (DI), X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acidselected from Table 1, Table 2, Table 3, Table D1, Table D1A, Table D2, and Table D2A.

[0201] In embodiments, in formula (EI), X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acidselected from Table 1, Table 2, Table 3, Table E1, Table E1A, Table E2, and Table E2A.

[0202] In embodiments, in formula (FI), X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acidselected from Table 1, Table 2, Table 3, Table F1, Table F1A, Table F2, and Table F2A.

[0203] In embodiments, the peptide of formula (I) is a peptide of any one of formula (Ia), formula (Ib), formula(Ic), formula (Id), formula (Ie), or formula (If).

[0204] In embodiments, the peptide of formula (BI) is a peptide of any one of formula (BIa), formula (BIb), formula(BIc), formula (BId), formula (BIe), or formula (BIf).

[0205] In embodiments, in formula (BIa), formula (BIb), formula (BIc), formula (BId), formula (BIe), or formula(BIf), X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, and Table 3 or a linker.

[0206] In embodiments, the peptide of formula (CI) is a peptide of any one of formula (CIa), formula (CIb), formula(CIc), formula (CId), formula (CIe), or formula (CIf).

[0207] In embodiments, in formula (CIa), formula (CIb), formula (CIc), formula (CId), formula (CIe), or formula(CIf), X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, and Table 3 or a linker.

[0208] In embodiments, the peptide of formula (DI) is a peptide of any one of formula (DIa), formula (DIb), formula(DIc), formula (DId), formula (DIe), or formula (DIf).

[0209] In embodiments, in formula (DIa), formula (DIb), formula (DIc), formula (DId), formula (DIe), or formula(DIf), X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, and Table 3 or a linker.

[0210] In embodiments, the peptide of formula (EI) is a peptide of any one of formula (EIa), formula (EIb), formula(EIc), formula (EId), formula (EIe), or formula (EIf).

[0211] In embodiments, in formula (EIa), formula (EIb), formula (EIc), formula (EId), formula (EIe), or formula(EIf), X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, and Table 3 or a linker. 79123828-02-5133-WO

[0212] In embodiments, the peptide of formula (FI) is a peptide of any one of formula (FIa), formula (FIb), formula(FIc), formula (FId), formula (FIe), or formula (FIf).

[0213] In embodiments, in formula (FIa), formula (FIb), formula (FIc), formula (FId), formula (FIe), or formula(FIf), X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10are each independently an amino acid selected from Table 1, Table 2, and Table 3 or a linker.

[00214] In embodiments, the peptide further comprises at least 1, at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or at least 100 amino acids at the amino and / or carboxy terminus.

[0215] In embodiments, the peptide consists of the amino acid sequence as set forth in formula (BI). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (BIa). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (BIb). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (BIc). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (BId). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (BIe). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (BIf).

[00216] In embodiments, the peptide consists of the amino acid sequence as set forth in formula (CI). Inembodiments, the peptide consists of the amino acid sequence as set forth in formula (CIa). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (CIb). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (CIc). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (CId). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (CIe). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (CIf).

[00217] In embodiments, the peptide consists of the amino acid sequence as set forth in formula (DI). Inembodiments, the peptide consists of the amino acid sequence as set forth in formula (DIa). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (DIb). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (DIc). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (DId). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (DIe). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (DIf).

[00218] In embodiments, the peptide consists of the amino acid sequence as set forth in formula (EI). Inembodiments, the peptide consists of the amino acid sequence as set forth in formula (EIa). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (EIb). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (EIc). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (EId). In embodiments, the peptide consists of the amino acid sequence as set 80123828-02-5133-WO forth in formula (EIe). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (EIf).

[0219] In embodiments, the peptide consists of the amino acid sequence as set forth in formula (FI). Inembodiments, the peptide consists of the amino acid sequence as set forth in formula (FIa). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (FIb). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (FIc). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (FId). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (FIe). In embodiments, the peptide consists of the amino acid sequence as set forth in formula (FIf).

[0220] Amino acids described herein are construed as L-amino acids unless specified otherwise (e.g., D-amino acids, such as D-arginine (D-Arg)).

[0221] In embodiments, the peptide further comprises at least 1, at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or at least 100 linkers and / or spacers at the amino and / or carboxy terminus.

[0222] In embodiments, the peptides of formula (I) or formula (II) comprises an N-terminal and / or C-terminalmodification. In embodiments, the N-terminal modification comprises acetylation, propionylation, methylation, myristoylation, palmitoylation, or ubiquitylation. In embodiments, the N-terminal modification comprises acyl group. Non-limiting examples of acyl group include acetyl, propionyl, butyryl, formyl, propenyl, crotyl, butenyl, and benzyl. In embodiments, C-terminal modifications include neutralization of the negative charge that the carboxylic acid derivative displays at physiological pH. In embodiments, C-terminal modifications include NR1R2, wherein R1 and R2 are selected from H or alkyl.

[0223] In embodiments, the peptides of formula (I) or formula (II) comprises an N-terminal acetyl. In embodiments, the peptides of formula (I) or formula (II) comprises a C-terminal amide. In embodiments, the peptides of formula (I) or formula (II) comprises an N-terminal acetyl and C-terminal amide.

[0224] In embodiments, the peptide of formula (I) is selected from Table 1 and Table 2.

[0225] In embodiments, the peptide of formula (II) is selected from Table 1 and Table 2.

[0226] In embodiments, X4 is Gln. In embodiments, X4 is Cit. In embodiments, X4 is hCit. In embodiments, X4 is 3-Pal. In embodiments, X4is hGln. In embodiments, X4is His. In embodiments, X4is Orn.

[0227] In embodiments, X3-X4is selected from Aib(O-cyclic)-Gln, Aib(O-cyclic)-hCit, Aib(O-cyclic)-Cit, Aib(O- cyclic)-3-Pal, Aib(O-cyclic)-hGln, Aib(O-cyclic)-His, and Aib(O-cyclic)-Orn.

[0228] In embodiments, X5 is selected from 4-fluoro-D-phenylalanine (D-Phe(4-F)), D-phenylalanine (D-Phe), and 4-methyl-D-phenylalanine (D-Phe(4-Me)). 81123828-02-5133-WO

[0229] In embodiments, X5 is D-Phe(4-F).

[0230] In embodiments, X5 is D-Phe.

[0231] In embodiments, X5 is D-Phe(4-Me).

[0232] In embodiments, X6 is arginine (Arg).

[0233] In embodiments, X7 is 6-fluoro-L-tryptophan (Trp(6-F)).

[0234] In embodiments, X8 is cysteine (Cys).

[0235] In embodiments, X8 is penicillamine (Pen).

[0236] In embodiments, when X2 and X8 are Cys, X2 and X8 are linked by a disulfide bridge (-S-S-). Inembodiments, when one of X2and X8is Cys and the other of X2and X8is Pen, X2and X8are linked by a disulfide bridge. In embodiments, when X2 is Cys and X8 is Pen, X2 and X8 are linked by a disulfide bridge.

[0237] In embodiments, X1 is selected from D-norarginine (D-Nar) and beta-homo-L-arginine (Beta-homoArg).

[0238] In embodiments, X1 is D-Nar.

[0239] In embodiments, X1 is beta-homoArg.

[0240] In embodiments, X2 is Cys.

[0241] In embodiments, X3 is selected from X3 column in Table 9 and X4 is selected from X4 column in Table9. In embodiments, X3is selected from X3column in Table 1 and X4is selected from X4column in Table 1.

[0242] In embodiments, X3-X4 is selected from Phg-3-Pal, D-aMeOrn-Gln, Aib(O-cyclic)-Gln, Aib(O-cyclic)-hCit, Aib(O-cyclic)-Cit, Cyclo-Leu-3-Pal, L-aMeGlu-His, hGlu-Gln, D-aMeSer-Gln, Cyclo-Leu-Gln, hGlu-His, Ala(2-Me)-Gln, L-aMeAsp-His, Ala(2-Me)-His, D-bhGlu-His, D-aMeSer-His, bhGlu-His, D-aMeOrn-3-Pal, and Aib(O-cyclic)-3-Pal.

[0243] In embodiments, X3-X4 is selected from Phg-3-Pal, D-aMeOrn-Gln, Cyclo-Leu-3-Pal, and Aib(O-cyclic)-Gln.

[0244] In embodiments, X3-X4 is Phg-3-Pal.

[0245] In embodiments, X3-X4 is D-aMeOrn-Gln.

[0246] In embodiments, X3-X4 is Aib(O-cyclic)-Gln.

[0247] In embodiments, X3-X4 is Cyclo-Leu-3-Pal.Table 9. Exemplary combinations of X3 and X4 positions. X3X482123828-02-5133-WO Aib(O-cyclic) hCitAib(O-c clic) Cit

[0248] In embodiments, X5 is selected from 4-fluoro-D-phenylalanine (D-Phe(4-F)), D-phenylalanine (D-Phe),4-methyl-D-phenylalanine (D-Phe(4-Me)), 3-trifluoromethyl-D-phenylalanine (D-Phe(3-CF3)), 3-fluoro-D- phenylalanine (D-Phe(3-F)), 2,3-difluoro-D-phenylalanine (D-Phe(2,3-diF)), 2,4,5-trifluoro-D-phenylalanine (D- Phe(2,4,5-triF)), 2,4-dichloro-D-phenylalanine (D-Phe(2,4-diCl)), 2,4-difluoro-D-phenylalanine (D-Phe(2,4-diF)), 4-chloro-2-fluoro-D-phenylalanine (D-Phe(2-F,4-Cl)), 3,4,5-trifluoro-D-phenylalanine (D-Phe(3,4,5-triF)), 3,4- difluoro-D-phenylalanine (D-Phe(3,4-diF)), 3,4-dimethyl-D-phenylalanine (D-Phe(3,4-diMe)), 3-chloro-D- phenylalanine (D-Phe(3-Cl)), 4-methyl-3-fluoro-D-phenylalanine (D-Phe(3-F,4-Me)), 3-methyl-D-phenylalanine (D-Phe(3-Me)), 4-(trifluoromethyl)-D-phenylalanine (D-Phe(4-CF3)), and 4-chloro-D-phenylalanine (D-Phe(4-Cl)).

[0249] In embodiments, X5 is 4-fluoro-D-phenylalanine (D-Phe(4-F)) or D-phenylalanine (D-Phe). Inembodiments, X5is 4-Fluoro-D-phenylalanine (D-Phe(4-F)). In embodiments, X5is D-phenylalanine (D-Phe).

[0250] In embodiments, X6 is arginine (Arg).

[0251] In embodiments, X7 is selected from 4-fluoro-L-tryptophan (Trp(4-F)), 5-chloro-L-tryptophan (Trp(5-Cl)),5-fluoro-L-tryptophan (Trp(5-F)), 5-methyl-L-tryptophan (Trp(5-Me)), 6-bromo-L-tryptophan (Trp(6-Br)), 6- 83123828-02-5133-WO (trifluoromethyl)-L-tryptophan (Trp(6-CF3)), 6-chloro-L-tryptophan (Trp(6-Cl)), 6-fluoro-L-tryptophan (Trp(6-F)), 6- methyl-L-tryptophan (Trp(6-Me)), 7-fluoro-L-tryptophan (Trp(7-F)), and tryptophan (Trp).

[00252] In embodiments, X7 is 4-fluoro-L-tryptophan (Trp(4-F)). In embodiments, X7 is 6-fluoro-L-tryptophan(Trp(6-F)).

[00253] In embodiments, X8 is selected from Cysteine (Cys), 3-amino-L-alanine (Dap), and penicillamine (Pen).

[0254] In embodiments, X8 is cysteine (Cys). In embodiments, X8 is penicillamine (Pen).

[0255] In embodiments, X1 is selected from Arg, beta-homo-L-arginine (Beta-homoArg), D-arginine (D-Arg),D-norarginine (D-Nar), homo-L-arginine (L-hArg), and L-norarginine (Nar).

[00256] In embodiments, X1 is selected from D-arginine (D-Arg).

[0257] In embodiments, X2 is selected from aspartic acid (Asp), Cys, and L-glutamate (Glu).

[0258] In embodiments, X2 is Cysteine (Cys).

[0259] In embodiments, when X2 and X8 are Cys, the amino acids are linked by a disulfide bridge. Inembodiments, when one of X2 and X8 is Cys and the other of X2 and X8 is Pen, the amino acids are linked by a disulfide bridge. In embodiments, when X2 is Cys and X8 is Pen, the amino acids are linked by a disulfide bridge. In embodiments, when X2is Asp or Glu, and X8is Dap, the amino acids are linked by an amide bond.

[00260] In embodiments, X1 is selected from D-Nar, Arg, Beta-homoArg, D-Arg, X5 is selected from D-Phe(4-F), D-Phe, D-Phe(3-CF3), D-Phe(3-F), and X7 is selected from Trp(6-F), Trp(6-Me), Trp(5-Me) and Trp.

[00261] In embodiments, X1 is selected from X1 column of Table 10. In embodiments, X5 is selected from X5column of Table 10. In embodiments, X7is selected from X7column of Table 10. Table 10: Exemplary X1, X5, and X7 Residues X1 X5 X7 ) )

[00262] In embodiments, X1, X5, and X7 are D-Nar, D-Phe(4-F), and Trp(6-F), respectively. In embodiments, X1,X5, and X7 are D-Nar, D-Phe, and Trp(6-F), respectively. 84123828-02-5133-WO

[0263] In embodiments, X1, X5, and X7 are D-Nar, D-Phe(4-F), and Trp(6-F), respectively, and X8 ispenicillamine (Pen). In embodiments, X1, X5, and X7 are D-Nar, D-Phe, and Trp(6-F), respectively, and X8 is penicillamine (Pen).

[0264] In embodiments, the peptide is a peptide consisting of the amino acid sequence as set forth in formula(III): X1-X2-X3-X4-X5-X6-X7-X8formula (III) wherein in formula (III): X1is D-norarginine (D-Nar); X2 is cysteine (Cys); X3 is 3-Aminooxetane-3-carboxylic acid (Aib(O-cyclic)); X4is selected from glutamine (Gln), homocitrulline (hCit), and citrulline (Cit); X5is selected from 4-fluoro-D-phenylalanine (D-Phe(4-F)), D-phenylalanine (D-Phe), and 4-methyl-D- phenylalanine (D-Phe(4-Me)); X6is arginine (Arg); X7 is 6-fluoro-L-tryptophan (Trp(6-F)); and X8is penicillamine (Pen).

[0265] In embodiments of formula (III), X4 is glutamine (Gln). In embodiments of formula (III), X4 ishomocitrulline (hCit). In embodiments of formula (III), X4is citrulline (Cit). In embodiments of formula (III), X5is 4-fluoro-D-phenylalanine (D-Phe(4-F)). In embodiments of formula (III), X5is D-phenylalanine (D-Phe). In embodiments of formula (III), X5 is 4-methyl-D-phenylalanine (D-Phe(4-Me)). In embodiments, the peptide of formula (III) is capped with N-terminal acetyl.

[0266] In embodiments, the peptide is a peptide consisting of the amino acid sequence as set forth in formula(III): X1-X2-X3-X4-X5-X6-X7-X8 formula (III) wherein in formula (III): X1 is D-norarginine (D-Nar); X2is cysteine (Cys); X3 is 3-Aminooxetane-3-carboxylic acid (Aib(O-cyclic)); 85123828-02-5133-WO X4is glutamine (Gln); X5is 4-fluoro-D-phenylalanine (D-Phe(4-F)); X6 is arginine (Arg); X7is 6-fluoro-L-tryptophan (Trp(6-F)); and X8is penicillamine (Pen).

[0267] In embodiments, the peptide of formula (III) is capped with N-terminal acetyl.

[0268] In embodiments, the cyclic peptide is a peptide consisting of the amino acid sequence as set forth informula (IV):formula (IV) wherein in formula (IV): X1is D-norarginine (D-Nar); X2 is cysteine (Cys); X3 is 3-Aminooxetane-3-carboxylic acid (Aib(O-cyclic)); X4is selected from glutamine (Gln), homocitrulline (hCit), and citrulline (Cit); X5is selected from 4-fluoro-D-phenylalanine (D-Phe(4-F)), D-phenylalanine (D-Phe), and 4-methyl-D- phenylalanine (D-Phe(4-Me)); X6 is arginine (Arg); X7 is 6-fluoro-L-tryptophan (Trp(6-F)); and X8 is penicillamine (Pen), where represents a disulfide bridge, and the peptide is capped with N-terminal ace.

[0269] In embodiments of formula (IV), X4 is glutamine (Gln). In embodiments of formula (IV), X4 ishomocitrulline (hCit). In embodiments of formula (IV), X4 is citrulline (Cit). In embodiments of formula (IV), X5 is 4-fluoro-D-phenylalanine (D-Phe(4-F)). In embodiments of formula (IV), X5is D-phenylalanine (D-Phe). In embodiments of formula (IV), X5is 4-methyl-D-phenylalanine (D-Phe(4-Me)). In embodiments, the peptide of formula (IV) is capped with N-terminal acetyl. 86123828-02-5133-WO

[0270] In embodiments, the cyclic peptide is a peptide consisting of the amino acid sequence as set forth informula (IV):wherein in formula (IV): X1is D-norarginine (D-Nar); X2 is cysteine (Cys); X3 is 3-Aminooxetane-3-carboxylic acid (Aib(O-cyclic)); X4is glutamine (Gln); X5 is 4-fluoro-D-phenylalanine (D-Phe(4-F)); X6 is arginine (Arg); X7is 6-fluoro-L-tryptophan (Trp(6-F)); and X8 is penicillamine (Pen), wherei represents a disulfide bridge, and the peptide is capped with N-terminal acCyclic Peptides

[0271] In embodiments, the peptide of the present disclosure is a cyclic peptide. In the embodiments, cyclicpeptides include polypeptide chains taking cyclic ring structure. In embodiments, the ring structure is formed by linking one end of the peptide to its other end with an amide bond, or other chemically stable bonds such as lactam, ether, thioether, disulfide or via a stapled linkage. In embodiments, N-to-C (or head-to-tail) cyclization is amide bond formation between amino and carboxyl termini. In embodiments, the cyclic peptide comprises a bridge between amino acid at position X2 and amino acid at position X8 (e.g. as exemplified in formula II or formula IV).

[0272] In embodiments, the cyclic peptide comprises a disulfide bridge or a lactam bridge. In embodiments,the cyclic peptide comprises a disulfide bridge. In embodiments, the cyclic peptide comprises a lactam bridge (- NH-C(=O)-). In embodiments, the cyclic peptide comprises a bridge comprising one or more selected from amide, ether, disulfide, lactam, head-tail amidation, and Asp-Lys.

[0273] In embodiments, cyclic peptide comprises a bridge.87123828-02-5133-WO

[0274] As used herein, the notation represents the linkage between twoamino acids to form a cyclic peptide. In e bridge (e.g. a disulfide bridge -S-S-).

[0275] In embodiments, the cyclic peptide has the formula (II):

[0276] In embodiments, the peptide of formula (I) is a cyclic peptide of formula (II). In embodiments, thepeptide of formula (I) is a peptide of formula (II) comprising a disulfide bridge. In embodiments, the peptide of formula (I) is a peptide of formula (II) comprising a lactam bridge. In embodiments, the peptide of molecules 1150, 1142, 1144, 1151, or 1158 is a cyclic peptide comprising a disulfide bridge. In embodiments, the peptide of molecules 1150, 1142, 1144, 1151, or 1158 is a cyclic peptide comprising a lactam bridge.

[0277] In embodiments, the peptide further comprises one or more lipids conjugated to X1 and / or X8. Inembodiments, the peptide further comprises one or more amino acids conjugated to X1and / or X8.

[0278] In embodiments, the one or more lipids are directly conjugated to X1 and / or X8. In embodiments, theone or more lipids are directly conjugated to the one or more amino acids, and the one or more amino acids are directly conjugated to X1and / or X8.

[0279] In embodiments, the peptide further comprises one or more PEG linkers conjugated to X1 and / or X8.

[0280] In embodiments, the one or more PEG linkers are directly conjugated to X1 and / or X8. In embodiments,the one or more PEG linkers are directly conjugated to the one or more amino acids, and the one or more amino acids are directly conjugated to X1 and / or X8.

[0281] In embodiments, one or more amino acid residues and / or linkers are conjugated to X1 of any one ofthe peptides of formula (I) or formula (II). In embodiments, at least 1, or at least 2, or at least 3, or at least 4, or at least 5 amino acid residues are conjugated to X1 of any one of the peptides of formula (I) or formula (II). In embodiments, at least 1, or at least 2, or at least 3, or at least 4, or at least 5 linkers are conjugated to X1 of any one of the peptides of formula (I) or formula (II). In embodiments, the one or more amino acid residues and / or linkers and / or spacers conjugated to X1have the sequential designation of X-1, X-2, X-3, X-4, X-5, and so forth. Non- limiting examples of linkers include lipids and PEG linkers (e.g. PEG-1). In embodiments, the one or more amino acid residues and / or linkers are selected from Table 2. In embodiments, the linker is a PEG linker or lipid selected from Table 2.

[0282] In embodiments, one or more amino acid residues and / or linkers are conjugated to X8 of any one ofthe peptides of formula (I) or formula (II). In embodiments, at least 1, or at least 2, or at least 3, or at least 4, or at least 5 amino acid residues are conjugated to X8 of any one of the peptides of formula (I) or formula (II). In 88123828-02-5133-WO embodiments, at least 1, or at least 2, or at least 3, or at least 4, or at least 5 linkers are conjugated to X1of any one of the peptides of formula (I) or formula (II). In embodiments, the one or more amino acid residues and / or linkers and / or spacers conjugated to X8 have the sequential designation of X9, X10, X11, X12, X13, X14 and so forth. Non-limiting examples of linkers include lipids and PEG linkers (e.g. PEG-1). In embodiments, the one or more amino acid residues and / or linkers are selected from Table 2. In embodiments, the linker is a PEG linker or lipid selected from Table 2.

[0283] In embodiments, the peptide further comprises at least 1, at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or at least 100 amino acids at the amino and / or carboxy terminus.

[0284] In embodiments, the peptide further comprises at least 1, at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or at least 100 linkers and / or spacers at the amino and / or carboxy terminus.

[0285] In embodiments, the cyclic peptide of formula (II) is a cyclic peptide of formula (IIa):wherein in formula (IIa): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table 1 or a linker. In embodiments, the linker is a PEG linker (e.g. PEG-1).

[0286] In embodiments, the cyclic peptide of formula (II) is a cyclic peptide of formula (IIb):formula (IIb) wherein in formula (IIb): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table 1 or a linker. In embodiments, the linker is a PEG linker (e.g. PEG-1).

[0287] In embodiments, the cyclic peptide of formula (II) is a cyclic peptide of formula (IIc):123828-02-5133-WO wherein in formula (IIc): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table 1 or a linker. In embodiments, the linker is a PEG linker (e.g. PEG-1).

[0288] In embodiments, the cyclic peptide of formula (II) is a cyclic peptide of formula (IId):formula (IId) wherein in formula (IId): X-1, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table 1 or a linker. In embodiments, the linker is a PEG linker (e.g. PEG-1).

[0289] In embodiments, the cyclic peptide of formula (II) is a cyclic peptide of formula (IIe):wherein in formula (IIe): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1 or a linker. In embodiments, the linker is a PEG linker (e.g. PEG-1).

[0290] In embodiments, the cyclic peptide of formula (II) is a cyclic peptide of formula (IIf):wherein in formula (IIf): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1 or a linker. In embodiments, the linker is a PEG linker (e.g. PEG-1).

[0291] In embodiments, the cyclic peptide of formula (II) is a cyclic peptide of any one of formula (IIa), formula(IIb), formula (IIc), formula (IId), formula (IIe), or formula (IIf), wherein X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, and Table 3 or a linker.

[0292] In embodiments, the peptides of formula (I) or formula (II) comprises an N-terminal acetyl (-C(=O)CH3).In embodiments, the peptides of formula (I) or formula (II) comprises a C-terminal amide. In embodiments, the peptides of formula (I) or formula (II) comprises an N-terminal acetyl and C-terminal amide.

[0293] In embodiments, the peptide is capped with N-terminal acetyl and / or C-terminal amide groups.

[0294] In embodiments, the peptides of formula (I) or formula (II) comprises an N-terminal and / or C-terminalmodification. In embodiments, the N-terminal modification comprises acetylation, propionylation, methylation, myristoylation, palmitoylation or ubiquitylation. In embodiments, the N-terminal modification comprises acyl group. Non-limiting examples of acyl group include acetyl, propionyl, butyryl, formyl, propenyl, crotyl, butenyl, and benzyl. 90123828-02-5133-WO In embodiments, C-terminal modifications include neutralization of the negative charge that the carboxylic acid derivative displays at physiological pH. In embodiments, C-terminal modifications include NR1R2, wherein R1 and R2 are selected from H or alkyl.

[00295] In embodiments, the peptide of formula (I) or formula (II) is selected from Table 1 and Table 2.

[0296] In embodiments, the peptide of the disclosure is a peptide described in FIG. 1.

[0297] In embodiments, the peptide of the disclosure is a peptide described in FIG. 2.

[0298] In embodiments, the peptide of the disclosure is a peptide described in FIG. 3.

[0299] In embodiments, the peptide of the disclosure is a peptide described in FIG. 4.

[0300] In embodiments, the peptide of the disclosure is molecule 1092:N- C- Molecule X1 X2 X3 X4 X5 X6 X7 X8 term term Cyclic de

[0301] In embodiments, the peptide of the disclosure is molecule 1093:N- C- Molecule X1 X2 X3 X4 X5 X6 X7 X8 term term Cyclic de

[00302] In embodiments, the peptide of the disclosure is molecule 1094:N- C- Molecule X1 X2 X3 X4 X5 X6 X7 X8 term term Cyclic de

[00303] In embodiments, the peptide of the disclosure is molecule 1106:N- C- Molecule X1 X2 X3 X4 X5 X6 X7 X8 term term Cyclic de

[00304] In embodiments, the peptide of the disclosure is molecule 1107:N- C- Molecule X1 X2 X3 X4 X5 X6 X7 X8termterm C clicde

[00305] In embodiments, the peptide of the disclosure is molecule 1119:N- C- ic91123828-02-5133-WO 1119 D-Nar Cys Phg 3Pal D-Phe(4-F) Arg Trp(6-F) Cys Ac NH2 DisulfideN- C- Molecule X1 X2 X3 X4 X5 X6 X7 X8 term term Cyclic dep

[00307] In aspects, a method for achieving half-life extension is through chemical modification of molecules toextend their residence time in the serum. In embodiments, the peptides of the present disclosure are modified, for example, to achieve half-life extension. In embodiments, the peptides of the present disclosure comprise a lipid-containing moiety grafted with linker fragments onto a peptide (e.g., without limitation the peptides of Table 1 and Table 2). In embodiments, the half-life of the peptides of the present disclosure can be extended without substantially affecting the selectivity and efficacy parameters. In embodiments, the peptides of the present disclosure are highly selective, B-arrestin biased MC4R agonists that can be modified for extended half-life in vivo.

[00308] In embodiments, the peptides of the disclosure are lipidated. In a non-limiting example, a lipidatedpeptide further comprises one or more lipids conjugated to an amino acid of the peptide. In embodiments, the peptide of formula (I) comprises one or more lipids conjugated to one or more of X1-X8. In embodiments, the peptide of formula (I) comprises one or more lipids conjugated to X1 and / or X8. In embodiments, the one or more lipids comprise cysteine prenylation, N-terminal glycine myristylation, cysteine palmitoylation, and serine and / or lysine fatty acylation.

[00309] In embodiments, the peptide further comprises one or more amino acids conjugated to X1 and / or X8.In embodiments the one or more amino acids are selected from D-arginine (D-Arg), glycine (Gly), and L-selected from Table 1 and Table 2. In embodiments, the one or more amino acid is modified. Non-limiting examples of modified amino acids include PEG groups (e.g., PEG-2), and lipids. In embodiments, the modified

[00310] In embodiments, the peptide further comprises one or more lipids conjugated to X1 and / or X8. Inembodiments, the peptide further comprises one or more lipids conjugated to the one or more amino acids conjugated to X1 and / or X8.

[00311] In embodiments, the peptide further comprises one or more PEG linkers conjugated to X1 and / or X8.

[0312] In embodiments, the peptide further comprises one or more dicarboxylic acid, e.g., a C12 – C24dicarboxylic acid. 92123828-02-5133-WO

[0313] In embodiments, one or more amino acid residues are conjugated to X1 of any one of the peptides offormula (I) or formula (II). In embodiments, at least 1, or at least 2, or at least 3, or at least 4, or at least 5 amino acid residues are conjugated to X1 of any one of the peptides of formula (I) or formula (II). In embodiments, the one or more amino acid residues conjugated to X1have the sequential designation of X-1, X-2, X-3, X-4, X-5, and so forth.

[0314] In embodiments, one or more amino acid residues are conjugated to X8 of any one of the peptides offormula (I) or formula (II). In embodiments, at least 1, or at least 2, or at least 3, or at least 4, or at least 5 amino acid residues are conjugated to X8of any one of the peptides of formula (I) or formula (II). In embodiments, the one or more amino acid residues conjugated to X8have the sequential designation of X9, X10, X11, X12, X13, X14and so forth.

[0315] In embodiments, the peptides of formula (I) or formula (II) comprises an N-terminal acetyl. Inembodiments, the peptides of formula (I) or formula (II) comprises a C-terminal amide. In embodiments, the peptides of formula (I) or formula (II) comprises an N-terminal acetyl and C-terminal amide.

[0316] In embodiments, the peptide is capped with N-terminal acetyl and / or C-terminal amide groups.

[0317] In embodiments, the peptides of formula (I) or formula (II) comprises an N-terminal and / or C-terminalmodification. In embodiments, the N-terminal modification comprises acetylation, propionylation, methylation, myristoylation, palmitoylation or ubiquitylation. In embodiments, the N-terminal modification comprises acyl group. Non-limiting examples of acyl group include acetyl, propionyl, butyryl, formyl, propenyl, crotyl, butenyl, and benzyl. In embodiments, C-terminal modifications include neutralization of the negative charge that the carboxylic acid derivative displays at physiological pH. In embodiments, C-terminal modifications include NR1R2, wherein R1 and R2 are selected from H or alkyl.

[0318] In embodiments, the peptide of formula (I) or formula (II) is selected from Table 1 and Table 2.

[0319] In embodiments, one or more amino acid residues are conjugated to X8. In embodiments, the one ormore amino acid residues conjugated to X8have the sequential designation of X9, X10, X11, and X12as exemplified in Table 3. and / or cyclic structure.

[0320] In embodiments, the one or more amino acid residues conjugated to X8 comprise an N-terminal acetyland C-terminal amide and / or a cyclic structure as exemplified in Table 3. 93OW- le3i3cluec idefcliudefliudefliudefliudefliudefliudefliudflu1y leois5C m DisDisDisDisDisDisDisD-20.- 8828321ero- -4-4- - - - - - m D(eh )F - D(eh )F - D4(eh )F - D4(e)F - D4(e)F - D4(e)F - D4(e)F - D4(e)F r X5 P P PhPhPhPhPhP oenof4lnGlnGlnGlnGlnGlnlnlnoX G G G htiwse-) ) ) ) ) )iOd( ic- lcO( ic- lcO( ic- lcO( ic- lcO( ic- lcO( ic-)lcO( ic-)lO( icltip3bAyc ibAyc ibAyc ibAyc ibAyc ibAyc ibcAyc ibcyce X A pyralpsys s s s sCyCy y y ysysym 2 C C C C C C exX E:3rarle1Narararararara-DN- DN- DN-N-N-N-N- b X D D D D D aT] 1le2uc 5 6 7 8 9 0 1 230 leeoma11111111112121210[M NOW- leue3i idef idef idef idef idef idef idef idef idef idef idfma3cl cle lululululululululululutc15-20-828321- - - - -e e5 D4(eh )F - D4(eh )F - D4(eh )F - D4(eh )FhPheheheheheheh-DP-P-P-P-P-P-P- X P P P P D D D D D D D lal4Pal3Pal3PaPlnGlnGlnGlnGisHisHisHisH X3 3ghghghgh-nrDOe-nrnDOrnre- DOe- DOesysysyps3 P P P P C C C A XMaMaMaMasys eh2 CysCysCysCysCysCysCy5C4 lAyGP-grA X D rarararararararN-N-N N N N NaNgr1 D D - D - D - D- - -A X D D D leuc e 62728292334 5 6 1 2 3 4leom1 1 1 1 131313182828282MaNOW- leu m me3i idef idef idef idef idef idef idef idef idef idef idef idef idef ideideideid3cl cleatc atclululululululululululululu flu flu flu flu15-20-828321ehehe e e e e e e e e e e e e e e e e5Ph h h h h h h h h h h h h h h h h-DP- DP- DP- DP- DP- DP- DP- DP- DP- DP- DP- DP- DP- DP- DP-P-P-P- X D D D D isHisHisHisHisHisHisHisHisHisHisHisHisHisHisHisHisHisHisH X4 psps laAl-aAl-aAl-aAl-aAl-aAl-aAl-aAlaAlaAlaAlaAlaAlaAlaA sysy3 A A D D D D D D D - D - D - D - D - D - D - D - D C C X ly2 G54sAys s s sCyCyCyCysCysCysCysCysCysCysCysCysCysCyCorPlaA X grAgrAgrAgrAgrAgrAgrAgrAgrAgrAgrAgrAgrAgrAgrAgrAgrAgrA X1 leuc e 5868203040506070809 0 1 2 3 4 5 6 7 8leom2 2 3 3 3 3 3 3 303131313131313131313MaNOW- lee3i3cluc ildeefliudefliudefliudefliudefliudflumatcmatcmatcmatcmatcmatcmatcmeaticdefliudefliudflumatcmatcmatc15-20-828321ehehehehehehehehehehehehehehe e e e e eP P P P P P P P P P P Ph h h h h h5 - D - D - D - D - D - D - D- - - - -P-P-P-P-P-P-P-P- X D D D D D D D D D D D D D 4isHisHisHisHisHisHisHisHisHisHisHisHisHisHisHisHisHisHisHisH X sysCysCysCysCysCyCpsApsApspspspspspssysysypspsps3 A A A A A A C C C A A A X laA-or)eP-or lylaGA- la orAP-or laM2l(aA- lylalaA-grgrgr lylyly2 D D P D P AlD G A D A A A G G G X DaA grAgrgrgrgrgrAA-A-A-A-grAgrAgrAgrAgrgrgrgrAA-A-A-grAgrAgrA X1 D D D D D D D leuc e 91021222324252627282920 1 2 3 4 5 6 7 8leom3 3 3 3 3 3 3 3 3 3 3333333333333333333MaNOW- leu m3i amamea idef idef idef idef idef idef idef idef idef idefm midef idf3cl cle tctctclulululululululululu atc atclulu15-20-828321ehehe e e e e e e e e e e e e e e5Ph h h h h h h h h h h h h h h-DP- DP- DP- DP- DP- DP- DP- DP- DP- DP- DP- DP-P-P-P-P- X D D D D D 4isHisHisHisHisHisHisHisHisHisHisHisHisHisHisHisHisH X pspspssysysy laAl-aAl-aAl-aAl-aAl-aA-sy sylaLpssyA- 3 A A A C C C D D D D D D C A C D X lyGlyGlaAlyGlyGlyGsysysysysysy ly grGlyGly A-sy2 C C C C C C G D C X grAgrAgrAgrgrgrgrgrgrgrgrgrgrgrgrgr1 A A A A A A A A A A A A A X leuc e 930414243444253545556 1 2 3 4 9 8leom3 3 3 3 3 3 3 3 3 353737373838393MaNOW- le3i3cluec ildeefliudefliudflumatcmatcmeaticdefliudefliudefliudefliudflu15-20-828321abaGslalu r-y e leCAbG-a sysysysysyM D S A C C C C C99X8 - prTprTprTprTprTprTpr6()- Tpr e6(pr)- e6(pr)- e6(pr)eX7 T M T M T M T M 6grAgrAgrAgrAgrAgrAgrAgrAgrAgrAgrX A ehehehe e e e e e e eP P PhPhPhPhPhPh h h5- - - - - - - -P-P-P- X D D D D D D D D D D D 4isHisHisHisHisHisHisHisHisHisHisH X sly la sCA- ypspsps la u p-spspsD C A A AA- DLGe-LAe-LAe-LAeX3MaMaMaMalyGsyors s sClyGlyGlaAP- yCyCysCysCyC X2 D ggrgrgrgrgrgrgrrarNa-r-N- ta AogrA- X1 A A A A A A A D DebmohD leuc 2 3 4 6 7 8 3 7l1ee 50om 0404041414142494 02105 021MaN123828-02-5133-WO

[0322] In aspects, the peptides of the disclosure (e.g., without limitation, peptides of formula (I)) or formula (II)comprise additional substituents and / or functional groups that further modify the properties and / or function of the peptides.

[0323] In embodiments, the peptide comprises a half-life extending moiety. Non-limiting examples of half-lifeextending moieties include polyethylene glycol (PEG), recombinant PEG mimetics, glycosylation of carbohydrates, Fc-fusion proteins or conjugates, albumin fusion proteins or conjugates (including fusions with albumin-binding proteins and peptides that, in turn, recruit albumin molecules), polypropylene glycol (PPG), XTEN fusion protein or conjugates, or a combination thereof.

[0324] In embodiments, the peptides of the present disclosure are pegylated. In some embodiments,attachment of the PEG moiety increases the half-life and / or reduces the immunogenicity of the peptide. In some embodiments, wherein the PEG-based moiety comprises one or more of poly(ethylene glycol) (PEG), an amine reactive PEG-based linker (e.g. Bis-PEG-acid, Bis-PEG-NHS, Boc-PEG, Fmoc-PEG, PEG Acid, PEG Aldehyde, PEG NHS ester, PEG Phosphonate, PEG PFP ester, PEG Tosylate), a biotinylated PEG-based linker (e.g. PEG- biotin), a branched PEG-based linker; a reactive carbonyl PEG-based linker (e.g. aminooxy-PEG), a carboxyl and / or active ester reactive PEG-based linker (e.g. amine PEG), a click-reagent PEG-based linker (e.g. alkyne PEG, azide-PEG); a copper-free click chemistry PEG-based linker (e.g. DBCO-PEG, BCN-PEG); a Cu-catalyzed click chemistry PEG-based linker (e.g. propargyl-PEG); a fluorescent PEG labeling and homobifunctional PEG- based linker (e.g. bis-PEG-acid, bis-PEG-NHS, bis-PEG-PFP, bis-propargyl-PEG, amine-PEG-amine, azido- PEG-azide, bromo-PEG-bromide), a lipid PEG, a metal surface binding and thiol reactive PEG-based linker (e.g. Thiol PEG, Bromo-PEG, Mal PEG), PEG-pAsp, PEG-pGlu, PEG-b-PMPMC, and PEG-PGLA.

[0325] In embodiments, the peptide further comprises at least 1, at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or at least 100 amino acids at the amino and / or carboxy terminus.

[0326] In embodiments, the peptide further comprises a therapeutic, diagnostic, and / or imaging moiety. Non-limiting examples of therapeutic, diagnostic, and / or imaging moiety include a small molecule, a biological (e.g., without limitation, a biopolymer, a protein, a nucleic acid, a polysaccharide), or a radionuclide.

[0327] In embodiments, the therapeutic, diagnostic, and / or imaging moiety is the functional and clinicallysignificant part of the active ingredient substance(s) present in a medicinal product. In embodiments, the medicinal product comprises orlistat, phentermine-topiramate, naltrexone-bupropion, liraglutide, retatrutide, tirzepatide, semaglutide, and setmelanotide. 100123828-02-5133-WO

[0328] In embodiments, the therapeutic, diagnostic, and / or imaging moiety comprises an antibody or antigen-binding fragment thereof, an aptamer, a peptide, a biological ligand (e.g., including a glycoconjugate), lipid, sterol, cholesterol or derivative thereof, integrin, RGD peptide, or cell-penetrating peptide (CPP). In embodiments, the moiety is selected from a single-domain antibody, a single chain antibody, a bi-specific antibody, a recombinant heavy-chain-only antibody (VHH), a single-chain antibody (scFv), a shark heavy-chain-only antibody (VNAR), a microprotein (cysteine knot protein, knottin), a DARPin, a tetranectin, an affibody, a transbody, an anticalin, an AdNectin, an affilin, a microbody, a phylomer, a stradobody, a maxibody, an evibody, a fynomer, an armadillo repeat protein, a Kunitz domain, an avimer, an atrimer, a probody, an immunobody, a triomab, a troybody, a Various non-limiting examples of ligand-binding platforms are described in US Patent Nos. or Patent Publication Nos. US 7,417,130, US 2004 / 132094, US 5,831 ,012, US 2004 / 023334, US 7,250,297, US 6,818,418, US 2004 / 209243, US 7,838,629, US 7,186,524, US 6,004,746, US 5,475,096, US 2004 / 146938, US 2004 / 157209, US 6,994,982, US 6,794,144, US 2010 / 239633, US 7,803,907, US 2010 / 119446, and / or US 7,166,697, the contents of which are hereby incorporated by reference in their entireties.

[0329] In embodiments, the disclosure provides conjugates comprising a peptide or pharmaceuticalcomposition of the present disclosure (e.g., without limitation, a peptide of formula (I) or formula (II)) conjugated to or co-formulated with a therapeutic agent or therapeutic moiety).

[0330] In embodiments, the therapeutic moiety or therapeutic agent comprises incretin, an incretin analogue,or a modulator of an incretin receptor.

[0331] In embodiments, the modulator is an agonist. In embodiments, the agonist is an agonist of GLP-1, GIP,and / or glucagon receptor. In embodiments, the agonist is a GLP-1 analogue. In embodiments, the GLP-1 analogue comprises a non-canonical amino acid. In embodiments, the GLP-1 analogue comprises tirzepatide, liraglutide, retatrutide, exenatide, lixisenatide, semaglutide or a semaglutide derivative.

[0332] In embodiments, the agonist is an agonist of GIP receptor. In embodiments, the agonist is a dual GLP-1-GIP receptor co-agonist. In embodiments, the agonist is a triple hormone receptor agonist. In embodiments, the agonist comprises retatrutide.

[0333] In embodiments, the agonist is an agonist of the amylin receptor. In embodiments, the agonist is anamylin analogue. In embodiments, the amylin analogue is cagrlintide. In embodiments, the agonist is selected from a PYY (3-36) analogue, an orexin analogue, and a leptin analog.

[0334] In embodiments, the therapeutic agent is a clinically significant part of the active ingredientsubstance(s) present in a medicinal product. In embodiments, the medicinal product comprises orlistat, phentermine-topiramate, naltrexone-bupropion, liraglutide, retatrutide, semaglutide, tirzepatide, and setmelanotide. 101123828-02-5133-WO

[0335] In embodiments, the peptide or pharmaceutical composition of the present disclosure is labeled with afluorescent compound. In a non-limiting example, when the fluorescently labeled peptide is exposed to light of the proper wavelength, its presence and / or amount can then be detected. In embodiments, fluorescent labeling compounds are selected from fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde and fluorescamine. In embodiments, the peptide can also be detectably labeled using fluorescence emitting metals such as 152Eu, or others of the lanthanide series. In embodiments, the metal is attached to the peptide using such metal chelating groups as diethylenetriaminepentacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA). In embodiments, the peptide is detectably labeled by coupling to a chemiluminescent compound. In a non-limiting example, the presence of the chemiluminescent-tagged antibody coupled to the peptide is determined by detecting luminescence that arises during the course of a chemical reaction. In embodiments, chemiluminescent labeling compounds are selected from luminol, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester. In embodiments, a bioluminescent compound may be used to label the peptide. In a non-limiting example, the presence of a bioluminescent protein is determined by detecting the presence of luminescence. In embodiments, bioluminescent compounds for purposes of labeling are luciferin, luciferase and aequorin.

[0336] In embodiments, the disclosure provides a protein comprising a peptide or pharmaceutical compositionof the present disclosure (e.g., without limitation, a peptide of formula (I) or a peptide of formula (II)).

[0337] In embodiments, the protein has a size of at least about 10 amino acid residues, or at least about 15resides, or at least about 20 residues, or at least about 25 residues, or at least about 30 residues, or at least about 35 residues, or at least about 40 residues, or at least about 45 residues, or at least about 50 residues, or at least about 60 residues, or at least about 70 residues, or at least about 80 residues, or at least about 90 residues, or at least about 100 residues, or at least about 250 residues, or at least about 500 residues, at least about 750 residues, at least about 1,000 residues, at least about 1,250 residues, at least about 1,500 residues, at least about 1,750 residues, at least about 2,000 residues, at least about 3,000 residues, at least about 4,000 residues, or at least about 5,000 residues.

[0338] In embodiments, the disclosure provides a nucleic acid encoding the peptide of the present disclosure,or the protein of the present disclosure. In embodiments, the disclosure provides a system for encoding one or more non-canonical amino acids. Site-specific incorporation of unnatural amino acids with orthogonal chemical reactivity into proteins enables the synthesis of structurally defined protein conjugates. Amino acids containing ketone, azide, alkyne, alkene, and tetrazine side chains can be genetically encoded in response to nonsense and frameshift codons. Kim, Chan Hyuk et al. “Protein conjugation with genetically encoded unnatural amino acids.” Current opinion in chemical biology vol.17,3 (2013): 412-9.

[0339] In embodiments, the disclosure provides a solid synthesis device conjugated to a peptide of thepresent disclosure (e.g., without limitation, a peptide of formula (I) or formula (II)), a protein of the present disclosure, a nucleic acid of the present disclosure, and / or an amino acid therein. 102123828-02-5133-WO

[0340] In embodiments, the solid synthesis device is conjugated to one or more amino acids, wherein the oneor more amino acids are intermediates in the synthesis of a peptide of the present disclosure (e.g., without limitation, a peptide of formula (I) or formula (II)), a protein of the present disclosure, and / or a nucleic acid of the present disclosure. In embodiments, a non-limiting example of a solid synthesis device comprises covalently binding the peptide of the present disclosure onto a solid support material and synthesized step-by-step in a single reaction vessel utilizing selective protecting group chemistry. In embodiments, the peptides of the present disclosure are synthesized from the carbonyl group side (C-terminus) to amino group side (N-terminus) of the amino acid chain in the solid-phase peptide synthesis method.

[0341] The peptides of the present disclosure are described from N-terminus to C-terminus unless statedotherwise.

[0342] In embodiments, the solid synthesis device is conjugated to about 1, about 2, about 3, about 4, about5, about 6, about 7, about 8, or about 9, about 10, or about 10 or more amino acids, wherein the one or more amino acids are intermediates in the synthesis of a peptide of the present disclosure (e.g., without limitation, a peptide of formula (I) or formula (II)), a protein of the present disclosure, and / or a nucleic acid of the present disclosure.

[0343] In embodiments, the solid synthesis device comprises a solid phase material or resin. In embodiments,the resin is selected from core resin, Merrifield resin, hydroxymethyl resin, and amino core resin. In embodiments, the core resin comprises material selected from polystyrene polyacrylate, polyacrylamide, and polyethylene glycol. In embodiments, the polystyrene resin is crosslinked, uncrosslinked, or linear.

[0344] In embodiments, the solid synthesis device comprises aminomethyl resin or 4-methylbenzhydryl amineresin.

[0345] In embodiments, the solid synthesis device comprises polystyrene beads.

[0346] In embodiments, the size of the bead is about or at least about 1 micron, or about 5 microns, or about10 microns, or about 20 microns, or about 30 microns, or about 40 microns, or about 50 microns, or about 75 microns, or about 100 microns, or about 200 microns, or about 300 microns, or about 400 microns, or about 500 microns, or about 600 microns, or about 700 microns, or about 800 microns in diameter.

[0347] In embodiments, the solid synthesis device comprises dosage forms such as pre-filled syringes,(including auto-injectors), patches, containers, solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, emulsions, aerosols, sprays, and suspensions. Peptide Selectivity

[0348] In embodiments, the peptides of the disclosure (e.g., a peptide of formula (I) or formula (II))demonstrates increased selectivity for MC4R over MC1R when administered to a subject compared to a control. 103123828-02-5133-WO

[0349] In embodiments, the peptide demonstrates increased selectivity for MC4R over MC1R as measuredby an in vitro, ex vivo, or in vivo assay when compared to a control.

[0350] In embodiments, the peptide demonstrates increased selectivity for MC4R over MC1R by at least about10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0351] In embodiments, the peptide demonstrates increased selectivity for MC4R over MC1R by at least about1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0352] In embodiments, the peptide demonstrates an increased ratio of MC4R intracellular signaling to MC1Rintracellular signaling in a subject when administered to a subject compared to a control.

[0353] In embodiments, the peptide demonstrates an increased ratio of MC4R intracellular signaling to MC1Rintracellular signaling as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0354] In embodiments, the peptide demonstrates an increased ratio of MC4R intracellular signaling to MC1Rintracellular signaling by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre- treatment or non-treatment state.

[0355] In embodiments, the peptide demonstrates an increased ratio of MC4R intracellular signaling to MC1Rintracellular signaling by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0356] In embodiments, the peptide demonstrates enhanced melanocortin 4 receptor (MC4R) function in asubject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control. 104123828-02-5133-WO

[0357] In embodiments, the peptide demonstrates decreased melanocortin 1 receptor (MC1R) function in asubject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control.

[0358] In embodiments, the peptide demonstrates enhanced melanocortin 4 receptor (MC4R) function asmeasured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0359] In embodiments, the peptide demonstrates decreased melanocortin 1 receptor (MC1R) function asmeasured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0360] In embodiments, the peptide demonstrates enhanced MC4R function and / or decreased MC1R functionby at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non- treatment state.

[0361] In embodiments, the peptide demonstrates enhanced MC4R function and / or decreased MC1R functionby at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0362] In embodiments, the cyclic peptide demonstrates increased selectivity for MC4R over MC1R by at leastabout 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0363] In embodiments, the cyclic peptide demonstrates increased selectivity for MC4R over MC1R by at leastabout 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0364] In embodiments, the control is selected from LY2112688, setmelanotide, ring peptide compound fromKR2002-0038400, NDP-aMSH, melanotan-II, a-MSH, and bremelanotide.

[0365] In embodiments, the control comprises a vehicle control such as saline or mineral oil.105123828-02-5133-WO

[0366] In embodiments, the control comprises a subject that has not been administered the peptide orpharmaceutical composition of the present disclosure. In embodiments, the control comprises a subject that has been administered LY2112688, setmelanotide, Ring Peptide Compound from KR2002-0038400, NDP-aMSH, Melanotan-II, a-MSH, and / or Bremelanotide. In embodiments, the control is a subject that is in a pre-treatment or non-treatment state.

[0367] In embodiments, the in vitro, ex vivo, or in vivo assay that demonstrates increased selectivity for MC4Rover MC1R is selected from, one or more of: cAMP assay, B-arrestin assay, ELISA, electro-chemiluminescence assays, radioimmunoassay (RIA), fluorescence immunoassay (FIA), thermal shift assay, LC-MS detection, surface plasmon resonance (SPR), and bio-layer interferometry (BLI), including combinations of the foregoing. In embodiments, other assays to test the functionality of the protein include chromatographic, electrophoretic and chemical techniques. In embodiments, exemplary assays and technique include, but are not limited to, luciferase assays, bimolecular fluorescence complementation, affinity electrophoresis, pull down assays, ELISA, western blots, immunoblotting, high-through screening of protein interaction, in vivo crosslinking of protein complexes, chemical cross linking, chemical cross linking followed by high mass MALDI mass spectrometry, quantitative immunoprecipitation combined with knock-down (QUICK), proximity ligation assay in situ, surface plasmon resonance (SPR), dual polarization interferometry (DPI), static light scattering (SLS), dynamic light scattering (DLS), flow-induced dispersion analysis (FIDA), fluorescence polarization / anisotropy, fluorescence resonanceenergy transfer (FRET), bio-layer interferometry (BLI), rotating cell based ligand binding assay using radioactivityor fluorescence, single color reflectometry (SCORE), and protein NMR, including combinations of the foregoing. Pharmaceutical Compositions and Formulations

[0368] In aspects, the disclosure provides a pharmaceutical composition comprising a peptide of the presentdisclosure, or a protein of the present disclosure, or a nucleic acid of the present disclosure, and a pharmaceutically acceptable excipient or carrier.

[0369] In embodiments, the pharmaceutical composition further comprises an additional therapeutic,diagnostic, and / or imaging moiety.

[0370] In one aspect, the composition is a pharmaceutical composition. In some embodiments, thepharmaceutical compositions of the present disclosure are formulated to provide a therapeutically effective amount of the peptides, as described herein, as the active ingredient. In embodiments, the pharmaceutical compositions further comprise one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[0371] Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal,vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. 106123828-02-5133-WO In some embodiments, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any agent disclosed herein is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any composition disclosed herein, if desired, can also formulated with wetting or emulsifying agents, or pH buffering agents. Other examples of suitable pharmaceutical excipients are described in Remington’s Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19thed. 1995), incorporated herein by reference.

[0372] In embodiments, the compositions, e.g., pharmaceutical compositions, disclosed herein are suspendedin a saline buffer (including, without limitation TBS, PBS, and the like).

[0373] In embodiments, the disclosure includes the disclosed compositions and / or peptides in variousformulations of pharmaceutical compositions. Any compositions and / or peptides disclosed herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.

[0374] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray,topically, rectally, nasally, buccally, sub-lingually, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Sterile injectable forms of the compositions of this disclosure are aqueous or oleaginous suspension. These suspensions are formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation is a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that are employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0375] In embodiments, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fattyacids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. 107123828-02-5133-WO

[0376] Pharmaceutically acceptable compositions of this disclosure may be orally administered in any orallyacceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0377] Pharmaceutically acceptable compositions of this disclosure may also be administered topically,especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0378] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (seeabove) or in a suitable enema formulation. In embodiments, the pharmaceutical composition of the present disclosure are topically-transdermal patches. In embodiments, the pharmaceutical composition of the present disclosure are smart pills designed for targeted drug delivery to the GI tract and systemic, needle-free delivery.

[0379] For topical applications, provided pharmaceutically acceptable compositions may be formulated in asuitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0380] In certain embodiments, pharmaceutically acceptable compositions of this disclosure are formulatedfor oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.

[0381] Pharmaceutically acceptable compositions of this disclosure can be administered to humans and otheranimals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the disease being treated. In certain embodiments, the compounds of the disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0382] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptableemulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl 108123828-02-5133-WO acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0383] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In embodiments, pharmaceutically acceptable compositions of the present disclosure further comprise preservatives. Non-limiting examples of preservatives include m-cresol, phenol, benzyl alcohol, tonicifiers, such as glycerin, mannitol, sucrose, and buffering agents such as phosphate, Tris, acetate, citrate.

[0384] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, orby incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0385] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Insuch solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. In embodiments, the capsules, tablets, and pills can be enterically coated.

[0386] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. 109123828-02-5133-WO Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0387] One or more peptides can also be in micro-encapsulated form with one or more excipients as notedabove. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0388] Dosage forms for topical or transdermal administration of a compound of this disclosure includeointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Methods of Treatment

[0389] In one aspect, the present disclosure includes methods for treating, preventing, or ameliorating adisease or disorder in a subject in need thereof, comprising administering a composition comprising an effective amount of the peptide or pharmaceutical composition of the present disclosure to the subject.

[0390] In embodiments, there is provided a method of selectively increasing the activity of MC4R over MC1Rcomprising administering a peptide or pharmaceutical composition of the present disclosure (e.g., without limitation, a peptide of formula (I) or a peptide of formula (II)) or a pharmaceutical composition of the present disclosure to a subject in need thereof.

[0391] In embodiments, the method prevents, reduces, or eliminates hyperpigmentation in the subject whencompared to an untreated or pre-treatment subject, or subject treated with a control.

[0392] In embodiments, the hyperpigmentation is reduced by at least about 10%, or at least about 20%, or atleast about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at 110123828-02-5133-WO least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0393] In embodiments, the hyperpigmentation is reduced by at least about 1 fold, or at least about 2 fold, orat least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0394] In embodiments, there is provided a method of treating a disease or disorder associated withinsufficiency of MC4R signaling comprising administering a peptide of the present disclosure or the pharmaceutical composition of the present disclosure to a subject in need thereof. In embodiments, there is provided a method of treating a disease or disorder associated with MC4R function comprising administering a peptide of the present disclosure or the pharmaceutical composition of the present disclosure to a subject in need thereof.

[0395] In embodiments, there is provided a method of treating a disease or disorder associated with MC4Rfunction comprising administering a peptide of the present disclosure or the pharmaceutical composition of the present disclosure to a subject receiving and / or previously received incretin.

[0396] In embodiments, there is provided a method of treating a disease or disorder associated with MC4Rfunction comprising administering a peptide of the present disclosure or the pharmaceutical composition of the present disclosure to a subject not receiving incretin.

[0397] In embodiments, the method of the present disclosure further comprises administration of an additionaltherapeutic agent. In embodiments, the additional therapeutic agent is administered sequentially or concurrently (whether as a fixed dose combination, individually, or conjugate). In embodiments, the therapeutic agent comprises an incretin, an incretin analogue, or a modulator of an incretin receptor.

[0398] In embodiments, the modulator of an incretin receptor is an agonist. In embodiments, the agonist is anagonist of GLP-1, GIP, and / or glucagon receptor. In embodiments, the agonist is a GLP-1 analogue. In embodiments, the GLP-1 analogue comprises a non-canonical amino acid. In embodiments, the GLP-1 analogue comprises a semaglutide, tirzepatide liragutide, exenatide, lixisenatide, or a semaglutide derivative.

[0399] In embodiments, the agonist is an agonist of GIP receptor. In embodiments, the agonist is a dual GLP-1-GIP receptor co-agonist. In embodiments, the agonist is a triple hormone receptor agonist. In embodiments, the agonist comprises retatrutide.

[0400] In embodiments, the therapeutic agent is a clinically significant part of the active ingredientsubstance(s) present in a medicinal product. In embodiments, the medicinal product comprises orlistat, phentermine-topiramate, naltrexone-bupropion, tirzepatide, exenatide, lixisenatide liraglutide, retatrutide, semaglutide, and setmelanotide. 111123828-02-5133-WO

[0401] In embodiments, the therapeutic agent is an agonist of the amylin receptor. In embodiments, theagonist is an amylin analogue. In embodiments, the amylin analogue is cagrlintide. In embodiments, the therapeutic agent is an agonist selected from one or more of a PYY (3-36) analogue, an orexin analogue, and a leptin analog.

[0402] In embodiments, the subject is receiving or previously received treatment comprising incretin, anincretin analogue, or a modulator of an incretin receptor. In embodiments, the subject is not receiving treatment comprising incretin, an incretin analogue, or a modulator of an incretin receptor.

[0403] For example, including, but not limited to, embodiments pertaining to obesity and / or weightreduction / loss, the additional therapeutic agents include one or more of orlistat (e.g. ALLI, XENICAL), loracaserin (e.g. BELVIQ), phentermine-topiramate (e.g. QSYMIA), sibutramine (e.g. REDUCTIL or MERIDIA), rimonabant (ACOMPLIA), exenatide (e.g. BYETTA), pramlintide (e.g. SYMLIN) phentermine, benzphetamine, diethylpropion, phendimetrazine, bupropion, and metformin.

[0404] In embodiments, the therapeutic agents comprise GLP-1, GIP, and / or glucagon agonists. Inembodiments, the therapeutic agent is selected from one or more of zepbound, wegovy, ozempic, rybelsus, maridebart cafraglutide (AMG133), retatrutude, bimagrumab, and amycretin.

[0405] In embodiments, the therapeutic agent comprises agents that interfere with the body’s ability to absorbspecific nutrients in food, e.g. orlistat (e.g. ALU, XENICAL), glucomannan, and guar gum. In embodiments, agents that suppress appetite are also among the therapeutic agents, e.g. catecholamines and their derivatives (such as phenteimine and other amphetamine-based drugs), various antidepressants and mood stabilizers (e.g. bupropion and topiramate), anorectics (e.g. dexedrine, digoxin). In embodiments, agents that increase the body’s metabolism are also among the therapeutic agents.

[0406] In some embodiments, additional agents are selected from among appetite suppressants,neurotransmitter reuptake inhibitors, dopaminergic agonists, serotonergic agonists, modulators of GABAergic signaling, anticonvulsants, antidepressants, monoamine oxidase inhibitors, substance P (NK1) receptor antagonists, melanocortin receptor agonists and antagonists, lipase inhibitors, inhibitors of fat absorption, regulators of energy intake or metabolism, cannabinoid receptor modulators, agents for treating addiction, agents for treating metabolic syndrome, peroxisome proliferator-activated receptor (PPAR) modulators; dipeptidyl peptidase 4 (DPP- 4) inhibitors, agents for treating cardiovascular disease, agents for treating elevated triglyceride levels, agents for treating low HDL, agents for treating hypercholesterolemia, and agents for treating hypertension. Some agents for cardiovascular disease include statins (e.g. lovastatin, atorvastatin, fluvastatin, rosuvastatin, simvastatin and pravastatin) and omega-3 agents (e.g. LOVAZA, EPANQVA, VASCEPA, esterified omega- 3's in general, fish oils, krill oils, algal oils). In some embodiments, additional agents are selected from among amphetamines, benzodiazepines, suifonyl ureas, meglitinides, thiazolidinediones, biguanides, beta-blockers, XCE inhibitors, diuretics, nitrates, calcium channel blockers, phentermine, sibutramine, iorcaserin, cetilistat, rimonabant, taranabant, topiramate, gabapentin, valproate, vigabatrin, bupropion, tiagabine, sertraline, fluoxetine, 112123828-02-5133-WO trazodone, zonisamide, methylphenidate, varenicline, naltrexone, diethylpropion, phendimetrazine, rapaglinide, nateglinide, glimepiride, metformin, pioglitazone, rosiglilazone, and sitagliptin.

[0407] In embodiments, the disease or disorder is selected from genetic obesity, obesity, abnormal orexcessive fat accumulation, hypothalamic obesity, surgically-acquired obesity, a metabolic disorder, an eatingdisorder, hypothyroidism, Cushing syndrome, obesity due to proopiomelanocortin (POMC) variance or deficiency,obesity due to proprotein convertase subtilisin / kexin type 1 (PCSK1) variance or deficiency, obesity due to leptin receptor (LEPR) variant or deficiency, Bardet-Biedl syndrome (BBS), MC4R allele variant or deficiency or downregulation, and Prader-Willi syndrome.

[0408] In embodiments, MC4R allele variant or deficiency or downregulation in a subject is exemplified by atleast about 5%, or at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% decrease in MC4R activity compared to a healthy subject.

[0409] In embodiments, there is provided a method of treating obesity or abnormal or excessive fataccumulation comprising administering a peptide of the present disclosure or the pharmaceutical composition of the present disclosure to a subject in need thereof.

[0410] In embodiments, the peptide or pharmaceutical composition of the present disclosure treats and / orprevents eating disorders such as overeating, metabolic disorders typified by positive energy imbalance, emotional or mental disorders, and dietary or syndromic obesity.

[0411] Diseases or disorders of particular interest are obesity, morbid obesity, morbid obesity prior to surgery,obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, hyperlipidemia, dyslipidemia, hypercholesterolemia, atherogenic dyslipidemia, fatty liver disease (FLD), insulin resistance, glucose intolerance, pre-diabetes, increased fasting glucose, diabetes mellitus, including type 2 diabetes mellitus, inflammation, including vascular inflammation, hypertension, endothelial dysfunction, dyslipidemia (e.g. high triglycerides, low HDL cholesterol and / or high LDL cholesterol), Prader-Willi Syndrome, insulin resistance, glucose intolerance, pre-diabetes, increased fasting glucose, diabetes mellitus, type 2 diabetes mellitus, inflammation, metabolic syndrome (insulin resistance, hypertension, hyperlipidemia), a metabolic disorder, excess body weight, and a combination of any two or more thereof.

[0412] In some embodiments, the metabolic disorder is excess body weight (e.g., excess body fat, such asvisceral fat, subcutaneous fat, intramuscular fat, and combinations of the foregoing. In embodiments the at least one peptide selected from Table 1 and Table 2, or a variant thereof, is used to promote weight loss, e.g., by reducing excess body fat, such as visceral fat, subcutaneous fat, intramuscular fat, and combinations of the foregoing). 113123828-02-5133-WO

[0413] In some embodiments, the metabolic disorder is selected from the group consisting of obesity,diabetes, hypercholesterolemia, metabolic dysfunction–associated steatohepatitis (MASH), which includes but is not limited to nonalcoholic steatohepatitis, hyperlipidemia, and fatty liver.

[0414] In some embodiments, the present disclosure relates to methods for treating obesity. Obesity is achronic disease that is highly prevalent in modem society and is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including diabetes mellitus, insulin resistance, hypertension, hypercholesterolemia, cholelithiasis, osteoarthritis, orthopedic injury, thromboembolic disease, cancer, and coronary heart disease. Rissanen et al, British Medical Journal, 301: 835-837 (1990). In some embodiments, Obesity can be calculated using the body mass index (BMI: body weight per height in meters squared). In some embodiments, obesity is defined as an otherwise healthy subject that has a BMI greater than or equal to 30 kg / m2, or a condition whereby a subject with at least one co-morbidity has a BMI greater than or equal to 27 kg / m2. In some embodiments of the method of the disclosure, the subject is obese and has a body mass index of greater than about 30. In some embodiments, the subject is overweight and has a body mass index of about 25-29.9. In some embodiments, the method induces weight loss. In some embodiments, the method prevents weight gain. In some embodiments, the method prevents the growth of adipose tissue and impair adipocyte differentiation.

[0415] In this aspect, the patient may not substantially change caloric intake. In some embodiments, thecaloric intake is high, relative to guidelines, such as the USDA tables. In some embodiments, the patient’s caloric intake is 2000-10000 calories / day, or greater than about 2000 calories / day, or about 2200 calories / day, or about 2400 calories / day, or about 2600 calories / day, or about 2800 calories / day, or about 3000 calories / day, or about 3200 calories / day, or about 3400 calories / day, or about 3600 calories / day, or about 3800 calories / day, or about 4000 calories / day, or about 5000 calories / day, or about 6000 calories / day. In some embodiments, the patient has a high caloric intake and does not gain weight or even loses weight. Therefore, the present disclosure provides for an effect without lifestyle changes that often reduce patient adherence (e.g., failed dieting). In some embodiments, the patient’s caloric intake is not restricted by more than about 20%, or not by more than about 10%, or not by more than about 5% of the patient’s caloric intake at the start of treatment. In some embodiments, a high proportion of the patient’s caloric intake is “empty calories,” i.e. calories from solid fats and / or added sugars. In some embodiments, greater than about 15%, or 20%, or 25%, or 30%, or 35%, or 50% of the patient’s caloric intake is empty calories. Even in these embodiments, a patient may not gain weight or even lose weight.

[0416] In some embodiments, the patient of the present disclosure is overweight or obese. In someembodiments, the patient of the present disclosure suffers from central obesity. In some embodiments, the obesity of one of simple obesity (alimentary obesity; usually resulting from consumption of more calories than the body can utilize), secondary obesity (usually resulting from an underlying medical condition, such as, for example, Cushing’s syndrome and polycystic ovary syndrome), and childhood obesity. In some embodiments, the obesity is classified as: Class I, which includes a BMI between 30 and 34.99; Class II, which includes BMIs of 35 to 39.99; and Class III, which includes a BMI of over 40. Further, the present disclosure provides for obesity of any of 114123828-02-5133-WO classes I, II, or III that is further classified as severe, morbid, and super obesity. In some embodiments, the patient is at risk of further weight gain, as assessed by, for example, daily caloric intake.

[0417] In some embodiments, simple circumferential measurement of the body may be used. In someembodiments, a patient of the present disclosure has a waist circumference exceeding about 35 inches, or about 36 inches, or about 37 inches, or about 38 inches, or about 39 inches, or about 40 inches, or about 41 inches, or about 42 inches, or about 43 inches, or about 44 inches, or about 45 inches, or about 46 inches, or about 47 inches, or about 48 inches, or about 50 inches, or about 55 inches, or about 60 inches. In some embodiments, the patient is male human with a waist circumference exceeding 40 inches. In some embodiments, the patient is a female human with a waist circumference exceeding 35 inches.

[0418] In embodiments, the methods of the disclosure may be used to treat humans having a body fatpercentage above the recommended body fat percentage, i.e., at least in the “overweight” range, or at least in the “obese” range. The body fat percentage will differ between women and men. Specifically, for women, the methods of the disclosure may be used to treat a female human having a body fat percentage of at least about 25%, above 25%, at least about 32%, or above 32%. For men, the methods of the disclosure may be used to treat a male human having a body fat percentage of at least about 14%, above 14%, at least about 18%, above 18%, at least about 25%, or above 25%. Body fat percentage may be estimated using any method accepted in the art, including, for example, near infrared interactance, dual energy X-ray absorptiometry, body density measurement, bioelectrical impedance analysis, and the like.

[0419] The methods of the disclosure may be used to treat a patient who is a man that is greater than 100pounds overweight and / or has waist circumference exceeding 40 inches. The methods of the disclosure may be used to treat a patient who is a woman that is greater than 80 pounds’ overweight and / or waist circumference exceeding 35 inches.

[0420] In some embodiments, the present disclosure relates to glucose tolerance. The term “glucosetolerance” refers to the ability and time required for the body to respond to the administration of glucose by clearing excess glucose from the circulation. A common test for measuring glucose tolerance is to perform a glucose tolerance test (GTT) on an individual, which typically involves orally administering 75 g of a glucose solution to a fasted individual and measuring blood glucose levels at intervals between 0 and 2 hours after administration. An individual who is “glucose intolerant”, as defined by the World Health Organization, has a 2-hour blood glucose level of between 140 to 199 mg per dL (7.8 to 11.0 mmol / l). An individual who has a 2-hour blood glucose level above 199 mg per dL is also glucose intolerant, but is additionally considered to have type II diabetes. Several different parameters of the GTT may be considered to evaluate the glucose tolerance of an individual, such as the 2-hour blood glucose level, fasting blood glucose level, GTT area under the curve, the max / peak blood glucose concentration obtained by an individual and mean blood glucose level. In some embodiments, improved glucose tolerance is an increase in the amount of glucose tolerance in an individual by at least about 0.5%, and preferably an increase of about 1% or more, e.g. by 5%, 10%, 30%, 50%, 70% or greater of the glucose tolerance of an individual prior to treatment with a compound of the disclosure, or a reduction in the rate that an individual develops glucose intolerance by at least about 1% or more, such as a reduction of glucose tolerance loss by 115123828-02-5133-WO about 5% or more, e.g. by 10%, 30%, 50%, 70%, 90% or greater than the rate of glucose tolerance loss of the individual prior to treatment. Lean mass, blood cholesterol level, blood triglyceride level and glucose tolerance are commonly measured in the fasted state in order to minimize the amount of nutrients which are newly entering circulation from the digestion of food and minimize the amount of nutrients which have yet to be been cleared from the blood following ingestion of food.

[0421] The term “impaired glucose tolerance” (IGT) or “pre-diabetes” refers to a condition in a person who,when given a glucose tolerance test, has a blood glucose level that falls between normal and hyperglycemic, i.e., has abnormal glucose tolerance, e.g., pathologically abnormal glucose tolerance. Such a person is at a higher risk of developing diabetes although not clinically characterized as having diabetes. In a non-limiting example, impaired glucose tolerance refers to a condition in which a patient has a fasting blood glucose concentration or fasting serum glucose concentration greater than 110 mg / dl and less than 126 mg / dl (7.00 mmol / L), or a 2 hour postprandial blood glucose or serum glucose concentration greater than 140 mg / dl (7.78 mmol / L) and less than 200 mg / dl (11.11 mmol / L). Prediabetes, also referred to as impaired glucose tolerance or impaired fasting glucose is a major risk factor for the development of type 2 diabetes mellitus, cardiovascular disease and mortality.

[0422] In some embodiments, the present disclosure provides for methods of treating impaired glucosetolerance in a patient in need thereof. In some embodiments, the present disclosure provides for methods of promoting improved glucose tolerance in a patient in need thereof. Subjects and / or Animals

[0423] In some embodiments, the subject and / or animal is a mammal, e.g., a human, mouse, rat, guinea pig,dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In other embodiments, the subject and / or animal is a non-mammal, such, for example, a zebrafish. In some embodiments, the subject and / or animal is a human. In some embodiments, the human is a pediatric human. In some embodiments, the human is an infant or child. In some embodiments, the human is an adult human. In some embodiments, the human is a geriatric human. In other embodiments, the human may be referred to as a patient.

[0424] In certain some embodiments, the human has an age in a range of from about 0 months to about 6months old, from about 6 to about 12 months old, from about 6 to about 18 months old, from about 18 to about 36 months old, from about 1 to about 5 years old, from about 5 to about 10 years old, from about 10 to about 15 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old. 116123828-02-5133-WO

[00425] In other embodiments, the subject is a non-human animal, and therefore the disclosure pertains toveterinary use. In a specific embodiment, the non-human animal is a household pet. In another specific embodiment, the non-human animal is a livestock animal.

[00426] In some embodiments, such a subject and / or animal is administered an agent of the disclosure or isnot administered an agent of the disclosure. Definitions

[00427] The following definitions are used in connection with the disclosure disclosed herein. Unless definedotherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of skill in the art to which this disclosure belongs.

[00428] An “effective amount” is an amount that is effective for treating, preventing, or ameliorating a diseaseor disorder such as those described herein.

[00429] An agent is “useful for the treatment of a disease or disorder” if the agent provides a measurabletreatment, prevention, or reduction in the rate of pathogenesis of a disease or disorder.

[00430] As used herein, “a,” “an,” or “the” can mean one or more than one.

[0431] As referred to herein, all compositional percentages are by weight of the total composition, unlessotherwise specified. As used herein, the word “include,” and its variants, is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the materials, compositions, devices, and methods of this technology. Similarly, the terms “can” and “may” and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features.

[00432] Although the open-ended term “comprising,” as a synonym of terms such as including, containing, orhaving, is used herein to describe and claim the disclosure, the present disclosure, or embodiments thereof, may alternatively be described using alternative terms such as “consisting of” or “consisting essentially of.”

[00433] Table 22 provides a list of residue shorthands and associated full residue name.

[0434] Table 22: Amino Acid ResiduesResidue Shorthand Full Residue Name117123828-02-5133-WO 3-aminoazetidine-3-carboxylic acid 3-aminoazetidine-3-carboxylic acid3-Pal 3-(3-Pyridyl)-L-alanine118123828-02-5133-WO bhDSER beta-homo-D-SerinebhGlu beta-L-homoglutamic acid119123828-02-5133-WO D-Lys D-LysineD-Nar D-Norarginine120123828-02-5133-WO Dap 3-Amino-L-Alaninedelta-Guanidinovaleric acid 5-guanidinopentanoic acid121123828-02-5133-WO N-4-aminobutyl-Gly N-(4-aminobutyl)-GlycineN-Me-His N-Methyl-L-Histidine122123828-02-5133-WO Trp(6-F) 6-Fluoro-L-TryptophanTrp(6-Me) 6-Methyl-L-TryptophanNUMBERED EMBODIMENTS

[00435] The disclosure will be further described in the following series of embodiments (i.e., series A, B, C,D, E, and F), which do not limit the scope of the disclosure described in the claims.

[00436] Embodiments - Series A

[0437] Embodiment 1A. A peptide comprising the amino acid sequence of formula (I):X1-X2-X3-X4-X5-X6-X7-X8formula (I) wherein in formula (I): X3is 3-Aminooxetane-3-carboxylic acid (Aib(O-cyclic)); X4 is glutamine (Gln), homocitrulline (hCit), citrulline (Cit), 3-(3-pyridyl)-L-alanine (3-Pal), L- homoglutamine (hGln), histidine (His), or L-ornithine (Orn); and X1, X2, X5, X6, X7, and X8 are each independently a canonical or non-canonical amino acid.

[00438] Embodiment 2A. The peptide of Embodiment 1A, wherein the peptide of formula (I) is a peptideof any one of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), or formula (If): X-4-X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (Ia) wherein in formula (Ia): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table A1; or Table A1 or a linker; X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (Ib) wherein in formula (Ib): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table A1; or Table A1 or a linker; X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (Ic) wherein in formula (Ic): 123123828-02-5133-WO X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table A1; or Table A1 or a linker; X-1-X1-X2-X3-X4-X5-X6-X7-X8formula (Id) wherein in formula (Id): X-1, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table A1; or Table A1 or a linker; X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 formula (Ie) wherein in formula (Ie): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10are each independently an amino acid selected from Table A1; or Table A1 or a linker; X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10formula (If) wherein in formula (If): X-1, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table A1; or Table A1 or a linker.

[0439] Embodiment 3A. The peptide of Embodiment 1A or 2A, wherein the peptide of formula (I) is apeptide of formula (Ia).

[0440] Embodiment 4A. The peptide of Embodiment 1A or 2A, wherein the peptide of formula (I) is apeptide of formula (Ib).

[0441] Embodiment 5A. The peptide of Embodiment 1A or 2A, the peptide of formula (I) is a peptide offormula (Ic).

[0442] Embodiment 6A. The peptide of Embodiment 1A or 2A, the peptide of formula (I) is a peptide offormula (Id).

[0443] Embodiment 7A. The peptide of Embodiment 1A or 2A, the peptide of formula (I) is a peptide offormula (Ie).

[0444] Embodiment 8A. The peptide of Embodiment 1A or 2A, the peptide of formula (I) is a peptide offormula (If).

[0445] Embodiment 9A. The peptide of any one of Embodiments 1A-8A, wherein X4 is Gln.

[0446] Embodiment 10A. The peptide of any one of Embodiments 1A-8A, wherein X4 is Cit.

[0447] Embodiment 11A. The peptide of any one of Embodiments 1A-8A, wherein X4 is hCit.

[0448] Embodiment 12A. The peptide of any one of Embodiments 1A-8A, wherein X4 is 3-Pal.124123828-02-5133-WO

[0449] Embodiment 13A. The peptide of any one of Embodiments 1A-8A, wherein X4 is hGln.

[0450] Embodiment 14A. The peptide of any one of Embodiments 1A-8A, wherein X4 is His.

[0451] Embodiment 15A. The peptide of any one of Embodiments 1A-8A, wherein X4 is Orn.

[0452] Embodiment 16A. The peptide of any one of Embodiments 1A-15A, wherein X5 is selected from4-fluoro-D-phenylalanine (D-Phe(4-F)), D-phenylalanine (D-Phe), and 4-methyl-D-phenylalanine (D-Phe(4-Me)).

[0453] Embodiment 17A. The peptide of Embodiment 16A, wherein X5 is D-Phe(4-F).

[0454] Embodiment 18A. The peptide of Embodiment 16A, wherein X5 is D-Phe.

[0455] Embodiment 19A. The peptide of Embodiment 16A, wherein X5 is D-Phe(4-Me).

[0456] Embodiment 20A. The peptide of any one of Embodiments 1A-19A, wherein X6 is arginine (Arg).

[0457] Embodiment 21A. The peptide of any one of Embodiments 1A-20A, wherein X7 is 6-fluoro-L-tryptophan (Trp(6-F)).

[0458] Embodiment 22A. The peptide of any one of Embodiments 1A-21A, wherein X8 is penicillamine(Pen) or cysteine (Cys).

[0459] Embodiment 23A. The peptide of any one of Embodiments 1A-22A, wherein X1 is selected fromD-norarginine (D-Nar) and beta-homo-L-arginine (Beta-homoArg).

[0460] Embodiment 24A. The peptide of any one of Embodiments 1A-23A, wherein X1 is D-Nar.

[0461] Embodiment 25A. The peptide of any one of Embodiments 1A-24A, wherein X2 is Cys.

[0462] Embodiment 26A. The peptide of any one of Embodiments 1A-25A, wherein the peptide offormula (I) is selected from Table A1, Table A1A, Table A2 and Table A2A.

[0463] Embodiment 27A. The peptide of any one of Embodiments 1A-26A, wherein the peptide is acyclic peptide.

[0464] Embodiment 28A. The peptide of Embodiment 27A, wherein the cyclic peptide comprises adisulfide bridge or a lactam bridge.

[0465] Embodiment 29A. The peptide of Embodiment 27A or 28A, wherein the cyclic peptide has theformula (II):formula (II).

[0466] Embodiment 30A. The peptide of any one of Embodiments 1A-29A, wherein the cyclic peptideof formula (II) is a cyclic peptide of any one of formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), or formula (IIf):123828-02-5133-WO wherein in formula (IIa): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table A1; or Table A1 or a linker; acidwherein in formula (IIc): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table A1; or Table A1or a linker;formula (IId) wherein in formula (IId): X-1, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table A1; or Table A1or a linker; acidformula (IIf) wherein in formula (IIf): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table A1; or Table A1or a linker.

[0467] Embodiment 31A. The peptide of Embodiments 29A or 30A, wherein the cyclic peptide of formula(II) is a cyclic peptide of formula (IIa).

[0468] Embodiment 32A. The peptide of Embodiments 29A or 30A, wherein the cyclic peptide of formula(II) is a cyclic peptide of formula (IIb). 126123828-02-5133-WO

[0469] Embodiment 33A. The peptide of Embodiments 29A or 30A, wherein the cyclic peptide of formula(II) is a cyclic peptide of formula (IIc).

[0470] Embodiment 34A. The peptide of Embodiments 29A or 30A, wherein the cyclic peptide of formula(II) is a cyclic peptide of formula (IId).

[0471] Embodiment 35A. The peptide of Embodiments 29A or 30A, wherein the cyclic peptide of formula(II) is a cyclic peptide of formula (IIe).

[0472] Embodiment 36A. The peptide of Embodiments 29A or 30A, wherein the cyclic peptide of formula(II) is a cyclic peptide of formula (IIf).

[0473] Embodiment 37A. The peptide of any one of Embodiments 1A-36A, wherein the peptide furthercomprises one or more amino acids conjugated to X1and / or X8, optionally wherein the one or more amino acids (Lys*).

[0474] Embodiment 38A. The peptide of any one of Embodiments 1A-37A, wherein the peptide furthercomprises one or more lipids conjugated to X1 and / or X8.

[0475] Embodiment 39A. The peptide of any one of Embodiments 1A-38A, wherein the peptide iscapped with N-terminal acetyl and / or C-terminal amide groups.

[0476] Embodiment 40A. The peptide of any one of Embodiments 1A-39A, wherein the peptide isselected from Table A1, Table A1A, Table A2 and Table A2A.

[0477] Embodiment 41A. A peptide consisting of the amino acid sequence as set forth in formula (III):X1-X2-X3-X4-X5-X6-X7-X8formula (III) wherein in formula (III): X1is D-norarginine (D-Nar); X2is cysteine (Cys); X3 is 3-Aminooxetane-3-carboxylic acid (Aib(O-cyclic)); X4 is glutamine (Gln); X5is 4-fluoro-D-phenylalanine (D-Phe(4-F)); X6is arginine (Arg); X7 is 6-fluoro-L-tryptophan (Trp(6-F)); and X8 is penicillamine (Pen).

[0478] Embodiment 42A. The peptide of Embodiment 41A, wherein the peptide is a cyclic peptide.

[0479] Embodiment 43A. The peptide of Embodiment 42A, wherein the cyclic peptide comprises adisulfide bridge or a lactam bridge.

[0480] Embodiment 44A. The peptide of Embodiment 42A or 43A, wherein the cyclic peptide is a peptideconsisting of the amino acid sequence as set forth in formula (IV): 127123828-02-5133-WOwherein in formula (IV): X1 is D-norarginine (D-Nar); X2is cysteine (Cys); X3is 3-Aminooxetane-3-carboxylic acid (Aib(O-cyclic)); X4 is selected from glutamine (Gln), homocitrulline (hCit), and citrulline (Cit); X5 is is selected from 4-fluoro-D-phenylalanine (D-Phe(4-F)), D-phenylalanine (D-Phe), and 4-methyl- D-phenylalanine (D-Phe(4-Me)); X6is arginine (Arg); X7is 6-fluoro-L-tryptophan (Trp(6-F)); and X8 is penicillamine (Pen).

[0481] Embodiment 45A. The peptide of any one of Embodiments 41A-44A, wherein the peptide iscapped with N-terminal acetyl and / or C-terminal amide groups.

[0482] Embodiment 46A. The peptide of any one of Embodiments 41A-45A, wherein the peptide iscapped with N-terminal acetyl.

[0483] Embodiment 47A. The peptide of any one of Embodiments 1A-46A, wherein the peptidedemonstrates increased selectivity for MC4R over MC1R when administered to a subject compared to a control.

[0484] Embodiment 48A. The peptide of any one of Embodiments 1A-47A, wherein the peptidedemonstrates increased selectivity for MC4R over MC1R as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0485] Embodiment 49A. The peptide of Embodiment 47A or 48A, wherein the peptide demonstratesincreased selectivity for MC4R over MC1R by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0486] Embodiment 50A. The peptide of Embodiment 47A or 48A, wherein the peptide demonstratesincreased selectivity for MC4R over MC1R by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state. 128123828-02-5133-WO

[0487] Embodiment 51A. The peptide of any one of Embodiments 1A-46A, wherein the peptidedemonstrates an increased ratio of MC4R intracellular signaling to MC1R intracellular signaling when administered to a subject compared to a control.

[0488] Embodiment 52A. The peptide of any one of Embodiments 1A-47A, wherein the peptidedemonstrates increased selectivity for MC4R intracellular signaling to MC1R intracellular signaling as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0489] Embodiment 53A. The peptide of Embodiment 51A or 52A, wherein the peptide demonstratesan increased ratio of MC4R intracellular signaling to MC1R intracellular signaling by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when administered to a subject compared to a control.

[0490] Embodiment 54A. The peptide of Embodiment 51A or 52A, wherein the peptide demonstratesan increased ratio of MC4R intracellular signaling to MC1R intracellular signaling by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when administered to a subject compared to a control.

[0491] Embodiment 55A. The peptide of any one of Embodiments 1A-54A, wherein the peptidedemonstrates enhanced melanocortin 4 receptor (MC4R) function in a subject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control.

[0492] Embodiment 56A. The peptide of any one of Embodiments 1A-55A, wherein the peptidedemonstrates decreased melanocortin 1 receptor (MC1R) function in a subject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control.

[0493] Embodiment 57A. The peptide of any one of Embodiments 1A-56A, wherein the peptidedemonstrates enhanced melanocortin 4 receptor (MC4R) function as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0494] Embodiment 58A. The peptide of any one of Embodiments 1A-57A, wherein the peptidedemonstrates decreased melanocortin 1 receptor (MC1R) function as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0495] Embodiment 59A. The peptide of any one of Embodiments 55A-58A, wherein the peptidedemonstrates enhanced MC4R function and / or decreased MC1R function by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state. 129123828-02-5133-WO

[0496] Embodiment 60A. The peptide of any one of Embodiments 55A-58A, wherein the peptidedemonstrates enhanced MC4R function and / or decreased MC1R function by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0497] Embodiment 61A. The peptide of any one of Embodiments 33A-60A, wherein the cyclic peptidedemonstrates increased selectivity for MC4R over MC1R by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0498] Embodiment 62A. The peptide of any one of Embodiments 33A-60A, wherein the cyclic peptidedemonstrates increased selectivity for MC4R over MC1R by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0499] Embodiment 63A. The peptide of any one of Embodiments 1A-62A, wherein the peptidecomprises a half-life extending moiety, optionally wherein the half-life extending moiety comprises polyethylene glycol (PEG), recombinant PEG mimetics, glycosylation of carbohydrates, Fc-fusion proteins or conjugates, albumin fusion proteins or conjugates, albumin-binding fusion proteins or conjugates, polypropylene glycol (PPG), XTEN fusion protein or conjugates, or a combination thereof.

[0500] Embodiment 64A. The peptide of any one of Embodiments 1A-63A, wherein the peptide furthercomprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or at least 100 amino acids at the amino and / or carboxy terminus.

[0501] Embodiment 65A. The peptide of any one of Embodiments 1A-64A, wherein the peptide furthercomprises a therapeutic, diagnostic, and / or imaging moiety, optionally wherein the therapeutic, diagnostic, and / or imaging moiety comprises a small molecule, a biological (e.g., a biopolymer, a protein, a nucleic acid, a polysaccharide), or a radionuclide.

[0502] Embodiment 66A. The peptide of any one of Embodiments 1A-65A, wherein the peptide offormula (I) or formula (III) is conjugated to or co-formulated with an additional therapeutic agent or therapeutic moiety. 130123828-02-5133-WO

[0503] Embodiment 67A. The peptide of Embodiments 65A or 66A, wherein the additional therapeuticagent or therapeutic moiety comprises incretin, an incretin analogue, or a modulator of an incretin receptor.

[0504] Embodiment 68A. The peptide of Embodiment 67A, wherein the modulator is an agonist.

[0505] Embodiment 69A. The peptide of Embodiment 68A, wherein the agonist is an agonist of GLP-1,GIP, and / or glucagon receptor.

[0506] Embodiment 70A. The peptide of Embodiment 68A, wherein the agonist is a GLP-1 analogue.

[0507] Embodiment 71A. The peptide of Embodiment 70A, wherein the GLP-1 analogue comprises anon-canonical amino acid.

[0508] Embodiment 72A. The peptide of Embodiment 70A, wherein the GLP-1 analogue comprisestirzepatide, tirzepatide analogue, liraglutide, retatrutide, exenatide, lixisenatide, semaglutide or semaglutide derivative.

[0509] Embodiment 73A. A protein comprising the peptide of any one of Embodiments 1A to 72A.

[0510] Embodiment 74A. The protein of Embodiment 73A, wherein the protein has a size of at leastabout 10 amino acid residues, or at least about 15 resides, or at least about 20 residues, or at least about 25 residues, or at least about 30 residues, or at least about 35 residues, or at least about 40 residues, or at least about 45 residues, or at least about 50 residues, or at least about 60 residues, or at least about 70 residues, or at least about 80 residues, or at least about 90 residues, or at least about 100 residues, or at least about 250 residues, or at least about 500 residues, at least about 750 residues, at least about 1,000 residues, at least about 1,250 residues, at least about 1,500 residues, at least about 1,750 residues, at least about 2,000 residues, at least about 3,000 residues, at least about 4,000 residues, or at least about 5,000 residues.

[0511] Embodiment 75A. A nucleic acid encoding the peptide of any one of Embodiments 1A to 72A, orthe protein of Embodiment 73A or 74A.

[0512] Embodiment 76A. A solid synthesis device conjugated to the peptide of any one of Embodiments1A to 72A, or the protein of Embodiment 73 or 74, or the nucleic acid of Embodiment 75A.

[0513] Embodiment 77A. A pharmaceutical composition comprising a peptide of any one ofEmbodiments 1A to 72A, or the protein of Embodiment 73A or 74A, or the nucleic acid of Embodiment 75A, and a pharmaceutically acceptable excipient or carrier.

[0514] Embodiment 78A. The pharmaceutical composition of Embodiment 77A, wherein thepharmaceutical composition further comprises an additional therapeutic, diagnostic, and / or imaging moiety.

[0515] Embodiment 79A. The pharmaceutical composition of Embodiment 77A or 78A, wherein thepharmaceutical composition is conjugated to or co-formulated with an additional therapeutic agent or therapeutic moiety.

[0516] Embodiment 80. The pharmaceutical composition of any one of Embodiments 77A or 78A,wherein the pharmaceutical composition is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, sub-lingually, vaginally or via an implanted reservoir. 131123828-02-5133-WO

[0517] Embodiment 81. The pharmaceutical composition of any one of Embodiments 77A or 78A,wherein the pharmaceutical composition is administered via intravenous injection, intramuscular injection, subcutaneous injection, or depot injection.

[0518] Embodiment 82A. A method of selectively increasing the activity of MC4R over MC1R comprisingadministering a peptide of any one of Embodiments 1A to 72A or the pharmaceutical composition of Embodiments 77A to 81A to a subject in need thereof.

[0519] Embodiment 83. The method of Embodiment 82A, wherein the method prevents, reduces, oreliminates hyperpigmentation in the subject when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0520] Embodiment 84A. The method of Embodiment 83A, wherein the hyperpigmentation is reducedby at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% when compared to an untreated or pre- treatment subject, or subject treated with a control.

[0521] Embodiment 85A. The method of Embodiment 83A, wherein the hyperpigmentation is reducedby at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0522] Embodiment 86A. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1A to 72A or the pharmaceutical composition of Embodiments 77A to 81A to a subject in need thereof.

[0523] Embodiment 87A. The method of Embodiment 86A, wherein the disease or disorder is selectedfrom genetic obesity, obesity, abnormal or excessive fat accumulation, hypothalamic obesity, surgically-acquired obesity, a metabolic disorder, an eating disorder, hypothyroidism, Cushing syndrome, obesity due to proopiomelanocortin (POMC) variance or deficiency, obesity due to proprotein convertase subtilisin / kexin type 1 (PCSK1) variance or deficiency, obesity due to leptin receptor (LEPR) variant or deficiency, Bardet-Biedl syndrome (BBS), MC4R allele variant or deficiency, and Prader-Willi syndrome.

[0524] Embodiment 88A. The method of Embodiment 86A or 87A, wherein the method furthercomprises co-administration of an additional therapeutic agent.

[0525] Embodiment 89A. The method of any one of Embodiments 86A-88A, wherein the additionaltherapeutic agent comprises incretin, an incretin analogue, or a modulator of an incretin receptor.

[0526] Embodiment 90A. The method of Embodiment 89A, wherein the modulator is an agonist.

[0527] Embodiment 91A. The method of Embodiment 90A, wherein the agonist is an agonist of GLP-1,GIP, and / or glucagon receptor.

[0528] Embodiment 92A. The method of Embodiment 90A, wherein the agonist is a GLP-1 analogue.132123828-02-5133-WO

[00529] Embodiment 93. The method of Embodiment 92A, wherein the GLP-1 analogue comprises anon-canonical amino acid.

[00530] Embodiment 94. The method of Embodiment 92A, wherein the GLP-1 analogue comprisestirzepatide, tirzepatide analogue, liraglutide, retatrutide, exenatide, lixisenatide, semaglutide or semaglutide derivative.

[00531] Embodiment 95A. The method of Embodiment 89A, wherein the subject is receiving and / orpreviously received treatment comprising incretin, an incretin analogue, or a modulator of an incretin receptor.

[00532] Embodiment 96A. The method of Embodiment 89A, wherein the subject has not or is notreceiving treatment comprising incretin, an incretin analogue, or a modulator of an incretin receptor.

[00533] Embodiment 97A. A method of treating obesity or abnormal or excessive fat accumulationcomprising administering a peptide of any one of Embodiments 1A to 72A or the pharmaceutical composition of Embodiments 77A to 81A to a subject in need thereof.

[00534] Embodiment 98A. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1A to 72A or the pharmaceutical composition of Embodiments 77A to 81A to a subject receiving and / or previously received incretin.

[00535] Embodiment 99A. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1A to 72A or the pharmaceutical composition of Embodiments 77A to 81A to a subject not receiving incretin.

[00536] Embodiment 100A. The method of any one of Embodiments 82A to 99A, wherein the peptide orpharmaceutical composition is administered from a prefilled dosage form device, such as syringe or autoinjector.

[00537] Embodiment 101A. A peptide consisting of the amino acid sequence as set forth in formula (IV):wherein in formula (IV): X1is D-norarginine (D-Nar); X2 is cysteine (Cys); X3 is 3-Aminooxetane-3-carboxylic acid (Aib(O-cyclic)); X4 is glutamine (Gln); X5is 4-fluoro-D-phenylalanine (D-Phe(4-F)); X6is arginine (Arg); X7is 6-fluoro-L-tryptophan (Trp(6-F)); and X8 is penicillamine (Pen), wherein represents a disulfide bridge, and the peptide is capped witha N-terminal acetyl. 133123828-02-5133-WO

[0538] Embodiments - Series B

[0539] Embodiment 1B. A peptide comprising the amino acid sequence of formula (BI):X1-X2-X3-X4-X5-X6-X7-X8formula (BI) wherein in formula (BI): X3 is L-Phenylglycine (Phg); X4 is 3-(3-Pyridyl)-L-alanine (3-Pal); and X1, X2, X5, X6, X7, and X8are each independently a canonical or non-canonical amino acid.

[0540] Embodiment 2B. The peptide of Embodiment 1B, wherein the peptide of formula (BI) is apeptide of any one of formula (BIa), formula (BIb), formula (BIc), formula (BId), formula (BIe), or formula (BIf).

[0541] Embodiment 3B. The peptide of Embodiment 1B or 2B, wherein the peptide of formula (BI) is apeptide of formula (BIa): X-4-X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (BIa) wherein in formula (BIa): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table B1; or Table B1 or a linker.

[0542] Embodiment 4B. The peptide of Embodiment 1B or 2B, wherein the peptide of formula (BI) is apeptide of formula (BIb): X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8formula (BIb) wherein in formula (Ib): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table B1; or Table B1 or a linker.

[0543] Embodiment 5B. The peptide of Embodiment 1B or 2B, the peptide of formula (BI) is a peptideof formula (BIc): X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (BIc) wherein in formula (Ic): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table B1; or Table B1 or a linker.

[0544] Embodiment 6B. The peptide of Embodiment 1B or 2B, the peptide of formula (BI) is a peptideof formula (BId): X-1-X1-X2-X3-X4-X5-X6-X7-X8 134123828-02-5133-WO formula (BId) wherein in formula (Id): X-1, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table B1; or Table B1 or a linker.

[0545] Embodiment 7B. The peptide of Embodiment 1B or 2B, the peptide of formula (BI) is a peptideof formula (BIe): X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10formula (BIe) wherein in formula (Ie): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10are each independently an amino acid tideof formula (BIf): X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 formula (BIf) wherein in formula (BIf): X-1, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10are each independently an amino acid selected from Table B1; or Table B1 or a linker.

[0547] Embodiment 9B. The peptide of any one of Embodiments 1B-8B, wherein X5 is selected from4-Fluoro-D-phenylalanine (D-Phe(4-F)).

[0548] Embodiment 10B. The peptide of any one of Embodiments 1B-9B, wherein X6 is Arginine (Arg).

[0549] Embodiment 11B. The peptide of any one of Embodiments 1B-10B, wherein X7 is 6-Fluoro-L-Tryptophan (Trp(6-F)).

[0550] Embodiment 12B. The peptide of any one of Embodiments 1B-11B, wherein X8 is Cysteine (Cys).

[0551] Embodiment 13B. The peptide of any one of Embodiments 1B-12B, wherein X1 is selected fromD-Norarginine (D-Nar) and beta-homo-L-arginine (Beta-homoArg).

[0552] Embodiment 14B. The peptide of any one of Embodiments 1B-13B, wherein X1 is Beta-homoArg.

[0553] Embodiment 15B. The peptide of any one of Embodiments 1B-14B, wherein X2 is Cys.

[0554] Embodiment 16B. The peptide of any one of Embodiments 1B-15B, wherein the peptide offormula (I) is selected from Table B1, Table B1A, Table B2, and Table B2A.

[0555] Embodiment 17B. The peptide of any one of Embodiments 1B-16B, wherein the peptide is acyclic peptide.

[0556] Embodiment 18B. The peptide of Embodiment 17B, wherein the cyclic peptide comprises adisulfide bridge or a lactam bridge.

[0557] Embodiment 19B. The peptide of Embodiment 17B or 18B, wherein the cyclic peptide has theformula (II):123828-02-5133-WO

[0558] Embodiment 20B. The peptide of any one of Embodiments 1B-19B, wherein the cyclic peptideof formula (BII) is a cyclic peptide of any one of formula (BIIa), formula (BIIb), formula (BIIc), formula (BIId), ulawherein in formula (BIIa): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table B1; or Table B1 or a linker.

[0560] Embodiment 22B. The peptide of Embodiments 19B or 20B, wherein the cyclic peptide of formula(BII) is a cyclic peptide of formula (BIIb): acid ulawherein in formula (BIIc): X-1, X-2,X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table B1; or Table B1 or a linker.

[0562] Embodiment 24B. The peptide of Embodiments 19B or 20B, wherein the cyclic peptide of formula(II) is a cyclic peptide of formula (BIId):formula (BIId) wherein in formula (IId): X-1, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table B1; or Table B1 or a linker.

[0563] Embodiment 25B. The peptide of Embodiments 19B or 20B, wherein the cyclic peptide of formula(II) is a cyclic peptide of formula (BIIe): 136123828-02-5133-WOwherein in formula (IIe): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10are each independently an amino acid selected from Table B1; or Table B1 or a linker.

[0564] Embodiment 26B. The peptide of Embodiments 19B or 20B, wherein the cyclic peptide of formula(II) is a cyclic peptide of formula (BIIf):wherein in formula (IIf): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table B1; or Table B1 or a linker.

[0565] Embodiment 27B. The peptide of any one of Embodiments 1B-26B, wherein the peptide furthercomprises one or more amino acids conjugated to X1and / or X8, optionally wherein the one or more amino acids (Lys*).

[0566] Embodiment 28B. The peptide of any one of Embodiments 1B-27B, wherein the peptide furthercomprises one or more lipids conjugated to X1and / or X8.

[0567] Embodiment 29B. The peptide of any one of Embodiments 1B-28B, wherein the peptide iscapped with N-terminal acetyl and / or C-terminal amide groups.

[0568] Embodiment 30B. The peptide of any one of Embodiments 1B-29B, wherein the peptide isselected from Table B1, Table B1A, Table B2, and Table B2A.

[0569] Embodiment 31B. The peptide of any one of Embodiments 1B-30B, wherein the peptidedemonstrates increased selectivity for MC4R over MC1R when administered to a subject compared to a control.

[0570] Embodiment 32B. The peptide of any one of Embodiments 1B-31B, wherein the peptidedemonstrates increased selectivity for MC4R over MC1R as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0571] Embodiment 33B. The peptide of Embodiment 31B or 32B, wherein the peptide demonstratesincreased selectivity for MC4R over MC1R by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0572] Embodiment 34B. The peptide of Embodiment 31B or 32B, wherein the peptide demonstratesincreased selectivity for MC4R over MC1R by at least about 1 fold, or at least about 2 fold, or at least about 3 137123828-02-5133-WO fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0573] Embodiment 35B. The peptide of any one of Embodiments 1B-30B, wherein the peptidedemonstrates an increased ratio of MC4R intracellular signaling to MC1R intracellular signaling when administered to a subject compared to a control.

[0574] Embodiment 36B. The peptide of any one of Embodiments 1B-31B, wherein the peptidedemonstrates increased selectivity for MC4R intracellular signaling to MC1R intracellular signaling as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0575] Embodiment 37B. The peptide of Embodiment 35B or 36B, wherein the peptide demonstratesan increased ratio of MC4R intracellular signaling to MC1R intracellular signaling by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when administered to a subject compared to a control.

[0576] Embodiment 38B. The peptide of Embodiment 35B or 36B, wherein the peptide demonstratesan increased ratio of MC4R intracellular signaling to MC1R intracellular signaling by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when administered to a subject compared to a control.

[0577] Embodiment 39B. The peptide of any one of Embodiments 1B-38B, wherein the peptidedemonstrates enhanced melanocortin 4 receptor (MC4R) function in a subject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control.

[0578] Embodiment 40B. The peptide of any one of Embodiments 1B-39B, wherein the peptidedemonstrates decreased melanocortin 1 receptor (MC1R) function in a subject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control.

[0579] Embodiment 41B. The peptide of any one of Embodiments 1B-40B, wherein the peptidedemonstrates enhanced melanocortin 4 receptor (MC4R) function as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0580] Embodiment 42B. The peptide of any one of Embodiments 1B-41B, wherein the peptidedemonstrates decreased melanocortin 1 receptor (MC1R) function as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0581] Embodiment 43B. The peptide of any one of Embodiments 39B-42B, wherein the peptidedemonstrates enhanced MC4R function and / or decreased MC1R function by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 138123828-02-5133-WO 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0582] Embodiment 44B. The peptide of any one of Embodiments 39B-42B, wherein the peptidedemonstrates enhanced MC4R function and / or decreased MC1R function by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0583] Embodiment 45B. The peptide of any one of Embodiments 17B-44B, wherein the cyclic peptidedemonstrates increased selectivity for MC4R over MC1R by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0584] Embodiment 46B. The peptide of any one of Embodiments 17B-44B, wherein the cyclic peptidedemonstrates increased selectivity for MC4R over MC1R by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0585] Embodiment 47B. The peptide of any one of Embodiments 1B-46B, wherein the peptidecomprises a half-life extending moiety, optionally wherein the half-life extending moiety comprises polyethylene glycol (PEG), recombinant PEG mimetics, glycosylation of carbohydrates, Fc-fusion proteins or conjugates, albumin fusion proteins or conjugates, albumin-binding fusion proteins or conjugates, polypropylene glycol (PPG), XTEN fusion protein or conjugates, or a combination thereof.

[0586] Embodiment 48B. The peptide of any one of Embodiments 1B-47B, wherein the peptide furthercomprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or at least 100 amino acids at the amino and / or carboxy terminus.

[0587] Embodiment 49B. The peptide of any one of Embodiments 1B-48B, wherein the peptide furthercomprises a therapeutic, diagnostic, and / or imaging moiety, optionally wherein the therapeutic, diagnostic, and / or imaging moiety comprises a small molecule, a biological (e.g., a biopolymer, a protein, a nucleic acid, a polysaccharide), or a radionuclide. 139123828-02-5133-WO

[0588] Embodiment 50B. The peptide of any one of Embodiments 1B-49B, wherein the peptide offormula (BI) is conjugated to or co-formulated with an additional therapeutic agent or therapeutic moiety.

[0589] Embodiment 51B. The peptide of Embodiments 49B or 50B, wherein the additional therapeuticagent or therapeutic moiety comprises incretin, an incretin analogue, or a modulator of an incretin receptor.

[0590] Embodiment 52B. The peptide of Embodiment 51B, wherein the modulator is an agonist.

[0591] Embodiment 53B. The peptide of Embodiment 52B, wherein the agonist is an agonist of GLP-1,GIP, and / or glucagon receptor.

[0592] Embodiment 54B. The peptide of Embodiment 52B, wherein the agonist is a GLP-1 analogue.

[0593] Embodiment 55B. The peptide of Embodiment 54B, wherein the GLP-1 analogue comprises anon-canonical amino acid.

[0594] Embodiment 56B. The peptide of Embodiment 54B, wherein the GLP-1 analogue comprisestirzepatide, tirzepatide analogue, liraglutide, retatrutide, exenatide, lixisenatide, semaglutide or semaglutide derivative.

[0595] Embodiment 57B. A protein comprising the peptide of any one of Embodiments 1B to 56B.

[0596] Embodiment 58B. The protein of Embodiment 57B, wherein the protein has a size of at leastabout 10 amino acid residues, or at least about 15 resides, or at least about 20 residues, or at least about 25 residues, or at least about 30 residues, or at least about 35 residues, or at least about 40 residues, or at least about 45 residues, or at least about 50 residues, or at least about 60 residues, or at least about 70 residues, or at least about 80 residues, or at least about 90 residues, or at least about 100 residues, or at least about 250 residues, or at least about 500 residues, at least about 750 residues, at least about 1,000 residues, at least about 1,250 residues, at least about 1,500 residues, at least about 1,750 residues, at least about 2,000 residues, at least about 3,000 residues, at least about 4,000 residues, or at least about 5,000 residues.

[0597] Embodiment 59B. A nucleic acid encoding the peptide of any one of Embodiments 1B to 56B, orthe protein of Embodiment 57B or 58B.

[0598] Embodiment 60B. A solid synthesis device conjugated to the peptide of any one of Embodiments1B to 56B, the protein of Embodiment 57B or 58B, or the nucleic acid of Embodiment 59B.

[0599] Embodiment 61B. A pharmaceutical composition comprising a peptide of any one ofEmbodiments 1B to 56B, or the protein of Embodiment 57B or 58B, or the nucleic acid of Embodiment 59B, and a pharmaceutically acceptable excipient or carrier.

[0600] Embodiment 62B. The pharmaceutical composition of Embodiment 61B, wherein thepharmaceutical composition further comprises an additional therapeutic, diagnostic, and / or imaging moiety.

[0601] Embodiment 63B. The pharmaceutical composition of Embodiment 61B or 62B, wherein thepharmaceutical composition is conjugated to or co-formulated with an additional therapeutic agent or therapeutic moiety.

[0602] Embodiment 64B. The pharmaceutical composition of any one of Embodiments 61B or 62B,wherein the pharmaceutical composition is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, sub-lingually, vaginally or via an implanted reservoir. 140123828-02-5133-WO

[0603] Embodiment 65B. The pharmaceutical composition of any one of Embodiments 61B or 62B,wherein the pharmaceutical composition is administered via intravenous injection, intramuscular injection, subcutaneous injection, or depot injection.

[0604] Embodiment 66B. A method of selectively increasing the activity of MC4R over MC1R comprisingadministering a peptide of any one of Embodiments 1B to 56B or the pharmaceutical composition of Embodiments 61B to 65B to a subject in need thereof.

[0605] Embodiment 67B. The method of Embodiment 66B, wherein the method prevents, reduces, oreliminates hyperpigmentation in the subject when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0606] Embodiment 68B. The method of Embodiment 67B, wherein the hyperpigmentation is reducedby at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% when compared to an untreated or pre- treatment subject, or subject treated with a control.

[0607] Embodiment 69B. The method of Embodiment 67B, wherein the hyperpigmentation is reducedby at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0608] Embodiment 70B. A method of treating a disease or disorder associated with MC4R, functioncomprising administering a peptide of any one of Embodiments 1B to 56B or the pharmaceutical composition of Embodiments 61B to 6B5 to a subject in need thereof.

[0609] Embodiment 71B. The method of Embodiment 70B, wherein the disease or disorder is selectedfrom genetic obesity, obesity, abnormal or excessive fat accumulation, hypothalamic obesity, surgically-acquired obesity, a metabolic disorder, an eating disorder, hypothyroidism, Cushing syndrome, obesity due to proopiomelanocortin (POMC) variance or deficiency, obesity due to proprotein convertase subtilisin / kexin type 1 (PCSK1) variance or deficiency, obesity due to leptin receptor (LEPR) variant or deficiency, Bardet-Biedl syndrome (BBS), MC4R allele variant or deficiency, and Prader-Willi syndrome.

[0610] Embodiment 72B. The method of Embodiment 70B or 71B, wherein the method furthercomprises co-administration of an additional therapeutic agent.

[0611] Embodiment 73B. The method of any one of Embodiments 70B to 72B, wherein the additionaltherapeutic agent comprises incretin, an incretin analogue, or a modulator of an incretin receptor.

[0612] Embodiment 74B. The method of Embodiment 73B, wherein the modulator is an agonist.

[0613] Embodiment 75B. The method of Embodiment 74B, wherein the agonist is an agonist of GLP-1,GIP, and / or glucagon receptor.

[0614] Embodiment 76B. The method of Embodiment 74B, wherein the agonist is a GLP-1 analogue.141123828-02-5133-WO

[0615] Embodiment 77B. The method of Embodiment 76B, wherein the GLP-1 analogue comprises anon-canonical amino acid.

[0616] Embodiment 78B. The method of Embodiment 76B, wherein the GLP-1 analogue comprisestirzepatide, tirzepatide analogue, liraglutide, retatrutide, exenatide, lixisenatide, semaglutide or semaglutide derivative.

[0617] Embodiment 79B. The method of Embodiment 73B, wherein the subject is receiving and / orpreviously received treatment comprising incretin, an incretin analogue, or a modulator of an incretin receptor.

[0618] Embodiment 80B. The method of Embodiment 73B, wherein the subject has not or is notreceiving treatment comprising incretin, an incretin analogue, or a modulator of an incretin receptor.

[0619] Embodiment 81B. A method of treating obesity or abnormal or excessive fat accumulationcomprising administering a peptide of any one of Embodiments 1B to 56B or the pharmaceutical composition of Embodiments 61B to 65B to a subject in need thereof.

[0620] Embodiment 82B. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1B to 56B or the pharmaceutical composition of Embodiments 61B to 65B to a subject receiving and / or previously received incretin.

[0621] Embodiment 83B. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1B to 56B or the pharmaceutical composition of Embodiments 61B to 65B to a subject not receiving incretin.

[0622] Embodiment 84B. The method of any one of Embodiments 65B to 83B, wherein the peptide orpharmaceutical composition is administered from a prefilled dosage form device, such as syringe or autoinjector.

[0623] Embodiments - Series C

[0624] Embodiment 1C. A peptide comprising the amino acid sequence of formula (I):X1-X2-X3-X4-X5-X6-X7-X8formula (CI) wherein in formula (CI): X3 is alpha-Methyl-D-Ornithine (D-aMeOrn); X4is Glutamine (Gln); and X1, X2, X5, X6, X7, and X8 are each independently a canonical or non-canonical amino acid.

[0625] Embodiment 2C. The peptide of Embodiment 1C, wherein the peptide of formula (CI) is apeptide of any one of formula (CIa), formula (CIb), formula (CIc), formula (CId), formula (CIe), or formula (CIf).

[0626] Embodiment 3C. The peptide of Embodiment 1C or 2C, wherein the peptide of formula (CI) is apeptide of formula (CIa): X-4-X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8formula (CIa) 142123828-02-5133-WO wherein in formula (CIa): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table C1; or Table C1 or a linker.

[0627] Embodiment 4C. The peptide of Embodiment 1C or 2C, wherein the peptide of formula (I) is apeptide of formula (Ib): X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8formula (Ib) wherein in formula (Ib): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table C1; or Table C1 or a linker.

[0628] Embodiment 5C. The peptide of Embodiment 1C or 2C, the peptide of formula (CI) is a peptideof formula (CIc): X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (CIc) wherein in formula (Ic): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table C1; or Table C1 or a linker.

[0629] Embodiment 6C. The peptide of Embodiment 1C or 2C, the peptide of formula (CI) is a peptideof formula (Id): X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (CId) wherein in formula (Id): X-1, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table C1; or Table C1 or a linker.

[0630] Embodiment 7C. The peptide of Embodiment 1C or 2C, the peptide of formula (CI) is a peptideof formula (CIe): X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10formula (CIe) wherein in formula (Ie): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table C1; or Table C1 or a linker.

[0631] Embodiment 8C. The peptide of Embodiment 1C or 2C, the peptide of formula (CI) is a peptideof formula (CIf): X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 formula (CIf) wherein in formula (If): X-1, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10are each independently an amino acid selected from Table C1; or Table C1 or a linker.

[0632] Embodiment 9C. The peptide of any one of Embodiments 1C-8C, wherein X5 is D-Phenylalanine(D-Phe). 143123828-02-5133-WO

[0633] Embodiment 10C. The peptide of any one of Embodiments 1C-9C, wherein X6 is Arginine (Arg).

[0634] Embodiment 11C. The peptide of any one of Embodiments 1C-10C, wherein X7 is 6-Fluoro-L-Tryptophan (Trp(6-F)).

[0635] Embodiment 12C. The peptide of any one of Embodiments 1C-11C, wherein X8 is Cysteine(Cys).

[0636] Embodiment 13C. The peptide of any one of Embodiments 1C-12C, wherein X1 is selected fromD-Norarginine (D-Nar) and beta-homo-L-arginine (Beta-homoArg).

[0637] Embodiment 14C. The peptide of any one of Embodiments 1C-13C, wherein X1 is D-Nar.

[0638] Embodiment 15C. The peptide of any one of Embodiments 1C-14C, wherein X2 is Cys.

[0639] Embodiment 16C. The peptide of any one of Embodiments 1C-15C, wherein the peptide offormula (I) is selected from Table C1, Table C1A, Table C2, and Table C2A.

[0640] Embodiment 17C. The peptide of any one of Embodiments 1C-16C, wherein the peptide is acyclic peptide.

[0641] Embodiment 18C. The peptide of Embodiment 17C, wherein the cyclic peptide comprises adisulfide bridge or a lactam bridge.

[0642] Embodiment 19C. The peptide of Embodiment 17C or 18C, wherein the cyclic peptide has theformula (CII):.

[0643] Embodiment 20C. The peptide of any one of Embodiments 1C-19C, wherein the cyclic peptideof formula (CII) is a cyclic peptide of any one of formula (CIIa), formula (CIIb), formula (CIIc), formula (CIId), formula (CIIe), or formula (CIIf).

[0644] Embodiment 21C. The peptide of Embodiments 19C or 20C, wherein the cyclic peptide offormula (CII) is a cyclic peptide of formula (CIIa):formula (IIa) wherein in formula (IIa): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table C1; or Table C1 or a linker.

[0645] Embodiment 22C. The peptide of Embodiments 19C or 20C, wherein the cyclic peptide offormula (CII) is a cyclic peptide of formula (CIIb):123828-02-5133-WO formula (CIIb) wherein in formula (IIb): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table C1; or Table C1 or a linker. ofwherein in formula (IIc): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table C1; or Table C1 or a linker.

[0647] Embodiment 24C. The peptide of Embodiments 19C or 20C, wherein the cyclic peptide offormula (CII) is a cyclic peptide of formula (CIId):formula (CIId) wherein in formula (IId): X-1, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table C1; or Table C1 or a linker.

[0648] Embodiment 25C. The peptide of Embodiments 19C or 20C, wherein the cyclic peptide offormula (CII) is a c clic e tide of formula (CIIe):wherein in formula (IIe): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table C1; or Table C1 or a linker.

[0649] Embodiment 26C. The peptide of Embodiments 19C or 20C, wherein the cyclic peptide offormula (CIIf) wherein in formula (IIf): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table C1; or Table C1 or a linker.

[0650] Embodiment 27C. The peptide of any one of Embodiments 1C-26C, wherein the peptide furthercomprises one or more amino acids conjugated to X1 and / or X8, optionally wherein the one or more amino acids 145123828-02-5133-WO (Lys*).

[0651] Embodiment 28C. The peptide of any one of Embodiments 1C-27C, wherein the peptide furthercomprises one or more lipids conjugated to X1and / or X8C.

[0652] Embodiment 29C. The peptide of any one of Embodiments 1C-28C, wherein the peptide iscapped with N-terminal acetyl and / or C-terminal amide groups.

[0653] Embodiment 30C. The peptide of any one of Embodiments 1C-29C, wherein the peptide isselected from Table C1, Table C1A, Table C2, and Table C2A.

[0654] Embodiment 31C. The peptide of any one of Embodiments 1C-30C, wherein the peptidedemonstrates increased selectivity for MC4R over MC1R when administered to a subject compared to a control.

[0655] Embodiment 32C. The peptide of any one of Embodiments 1C-31C, wherein the peptidedemonstrates increased selectivity for MC4R over MC1R as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0656] Embodiment 33C. The peptide of Embodiment 31C or 32C, wherein the peptide demonstratesincreased selectivity for MC4R over MC1R by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0657] Embodiment 34C. The peptide of Embodiment 31C or 32C, wherein the peptide demonstratesincreased selectivity for MC4R over MC1R by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0658] Embodiment 35C. The peptide of any one of Embodiments 1C-30C, wherein the peptidedemonstrates an increased ratio of MC4R intracellular signaling to MC1R intracellular signaling when administered to a subject compared to a control.

[0659] Embodiment 36C. The peptide of any one of Embodiments 1C-31C, wherein the peptidedemonstrates increased selectivity for MC4R intracellular signaling to MC1R intracellular signaling as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0660] Embodiment 37C. The peptide of Embodiment 35C or 36C, wherein the peptide demonstratesan increased ratio of MC4R intracellular signaling to MC1R intracellular signaling by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when administered to a subject compared to a control. 146123828-02-5133-WO

[0661] Embodiment 38C. The peptide of Embodiment 35C or 36C, wherein the peptide demonstratesan increased ratio of MC4R intracellular signaling to MC1R intracellular signaling by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when administered to a subject compared to a control.

[0662] Embodiment 39C. The peptide of any one of Embodiments 1C-38C, wherein the peptidedemonstrates enhanced melanocortin 4 receptor (MC4R) function in a subject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control.

[0663] Embodiment 40C. The peptide of any one of Embodiments 1C-39C, wherein the peptidedemonstrates decreased melanocortin 1 receptor (MC1R) function in a subject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control.

[0664] Embodiment 41C. The peptide of any one of Embodiments 1C-40C, wherein the peptidedemonstrates enhanced melanocortin 4 receptor (MC4R) function as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0665] Embodiment 42C. The peptide of any one of Embodiments 1C-41C, wherein the peptidedemonstrates decreased melanocortin 1 receptor (MC1R) function as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0666] Embodiment 43C. The peptide of any one of Embodiments 39C-42C, wherein the peptidedemonstrates enhanced MC4R function and / or decreased MC1R function by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0667] Embodiment 44C. The peptide of any one of Embodiments 39C-42C, wherein the peptidedemonstrates enhanced MC4R function and / or decreased MC1R function by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0668] Embodiment 45C. The peptide of any one of Embodiments 17C-44C, wherein the cyclic peptidedemonstrates increased selectivity for MC4R over MC1R by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state. 147123828-02-5133-WO

[0669] Embodiment 46C. The peptide of any one of Embodiments 17C-44C, wherein the cyclic peptidedemonstrates increased selectivity for MC4R over MC1R by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0670] Embodiment 47C. The peptide of any one of Embodiments 1C-46C, wherein the peptidecomprises a half-life extending moiety, optionally wherein the half-life extending moiety comprises polyethylene glycol (PEG), recombinant PEG mimetics, glycosylation of carbohydrates, Fc-fusion proteins or conjugates, albumin fusion proteins or conjugates, albumin-binding fusion proteins or conjugates, polypropylene glycol (PPG), XTEN fusion protein or conjugates, or a combination thereof.

[0671] Embodiment 48C. The peptide of any one of Embodiments 1C-47C, wherein the peptide furthercomprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or at least 100 amino acids at the amino and / or carboxy terminus.

[0672] Embodiment 49C. The peptide of any one of Embodiments 1C-48C, wherein the peptide furthercomprises a therapeutic, diagnostic, and / or imaging moiety, optionally wherein the therapeutic, diagnostic, and / or imaging moiety comprises a small molecule, a biological (e.g., a biopolymer, a protein, a nucleic acid, a polysaccharide), or a radionuclide.

[0673] Embodiment 50C. The peptide of any one of Embodiments 1C-49C, wherein the peptide offormula (I) is conjugated to or co-formulated with an additional therapeutic agent or therapeutic moiety.

[0674] Embodiment 51C. The peptide of Embodiments 49C or 50C, wherein the additional therapeuticagent or therapeutic moiety comprises incretin, an incretin analogue, or a modulator of an incretin receptor.

[0675] Embodiment 52C. The peptide of Embodiment 51C, wherein the modulator is an agonist.

[0676] Embodiment 53C. The peptide of Embodiment 52C, wherein the agonist is an agonist of GLP-1,GIP, and / or glucagon receptor.

[0677] Embodiment 54C. The peptide of Embodiment 52C, wherein the agonist is a GLP-1 analogue.

[0678] Embodiment 55C. The peptide of Embodiment 54C, wherein the GLP-1 analogue comprises anon-canonical amino acid.

[0679] Embodiment 56C. The peptide of Embodiment 54C, wherein the GLP-1 analogue comprisestirzepatide, tirzepatide analogue, liraglutide, retatrutide, exenatide, lixisenatide, semaglutide or semaglutide derivative.

[0680] Embodiment 57C. A protein comprising the peptide of any one of Embodiments 1C to 56C.

[0681] Embodiment 58C. The protein of Embodiment 57C, wherein the protein has a size of at leastabout 10 amino acid residues, or at least about 15 resides, or at least about 20 residues, or at least about 25 148123828-02-5133-WO residues, or at least about 30 residues, or at least about 35 residues, or at least about 40 residues, or at least about 45 residues, or at least about 50 residues, or at least about 60 residues, or at least about 70 residues, or at least about 80 residues, or at least about 90 residues, or at least about 100 residues, or at least about 250 residues, or at least about 500 residues, at least about 750 residues, at least about 1,000 residues, at least about 1,250 residues, at least about 1,500 residues, at least about 1,750 residues, at least about 2,000 residues, at least about 3,000 residues, at least about 4,000 residues, or at least about 5,000 residues.

[0682] Embodiment 59C. A nucleic acid encoding the peptide of any one of Embodiments 1C to 56C, orthe protein of Embodiment 57C or 58C.

[0683] Embodiment 60C. A solid synthesis device conjugated to the peptide of any one of Embodiments1C to 56C, the protein of Embodiment 57C or 58C, or the nucleic acid of Embodiment 59C.

[0684] Embodiment 61C. A pharmaceutical composition comprising a peptide of any one ofEmbodiments 1C to 56C, or the protein of Embodiment 57C or 58C, or the nucleic acid of Embodiment 59C, and a pharmaceutically acceptable excipient or carrier.

[0685] Embodiment 62C. The pharmaceutical composition of Embodiment 61C, wherein thepharmaceutical composition further comprises an additional therapeutic, diagnostic, and / or imaging moiety.

[0686] Embodiment 63C. The pharmaceutical composition of Embodiment 61C or 62C, wherein thepharmaceutical composition is conjugated to or co-formulated with an additional therapeutic agent or therapeutic moiety.

[0687] Embodiment 64C. The pharmaceutical composition of any one of Embodiments 61C or 62C,wherein the pharmaceutical composition is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, sub-lingually, vaginally or via an implanted reservoir.

[0688] Embodiment 65C. The pharmaceutical composition of any one of Embodiments 61C or 62C,wherein the pharmaceutical composition is administered via intravenous injection, intramuscular injection, subcutaneous injection, or depot injection.

[0689] Embodiment 66C. A method of selectively increasing the activity of MC4R over MC1R comprisingadministering a peptide of any one of Embodiments 1C to 56C or the pharmaceutical composition of Embodiments 61C to 65C to a subject in need thereof.

[0690] Embodiment 67C. The method of Embodiment 66C, wherein the method prevents, reduces, oreliminates hyperpigmentation in the subject when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0691] Embodiment 68C. The method of Embodiment 67C, wherein the hyperpigmentation is reducedby at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% when compared to an untreated or pre- treatment subject, or subject treated with a control.

[0692] Embodiment 69C. The method of Embodiment 67C, wherein the hyperpigmentation is reducedby at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 149123828-02-5133-WO 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0693] Embodiment 70C. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1C to 56C or the pharmaceutical composition of Embodiments 61C to 65 to a subject in need thereof.

[0694] Embodiment 71C. The method of Embodiment 70C, wherein the disease or disorder is selectedfrom genetic obesity, obesity, abnormal or excessive fat accumulation, hypothalamic obesity, surgically-acquired obesity, a metabolic disorder, an eating disorder, hypothyroidism, Cushing syndrome, obesity due to proopiomelanocortin (POMC) variance or deficiency, obesity due to proprotein convertase subtilisin / kexin type 1 (PCSK1) variance or deficiency, obesity due to leptin receptor (LEPR) variant or deficiency, Bardet-Biedl syndrome (BBS), MC4R allele variant or deficiency, and Prader-Willi syndrome.

[0695] Embodiment 72C. The method of Embodiment 70C or 71C, wherein the method furthercomprises co-administration of an additional therapeutic agent.

[0696] Embodiment 73C. The method of any one of Embodiments 70C to 72C, wherein the additionaltherapeutic agent comprises incretin, an incretin analogue, or a modulator of an incretin receptor.

[0697] Embodiment 74C. The method of Embodiment 73C, wherein the modulator is an agonist.

[0698] Embodiment 75C. The method of Embodiment 74C, wherein the agonist is an agonist of GLP-1,GIP, and / or glucagon receptor.

[0699] Embodiment 76C. The method of Embodiment 74C, wherein the agonist is a GLP-1 analogue.

[0700] Embodiment 77C. The method of Embodiment 76C, wherein the GLP-1 analogue comprises anon-canonical amino acid.

[0701] Embodiment 78C. The method of Embodiment 76C, wherein the GLP-1 analogue comprisestirzepatide, tirzepatide analogue, liraglutide, retatrutide, exenatide, lixisenatide, semaglutide or semaglutide derivative.

[0702] Embodiment 79C. The method of Embodiment 73C, wherein the subject is receiving and / orpreviously received treatment comprising incretin, an incretin analogue, or a modulator of an incretin receptor.

[0703] Embodiment 80C. The method of Embodiment 73C, wherein the subject has not or is notreceiving treatment comprising incretin, an incretin analogue, or a modulator of an incretin receptor.

[0704] Embodiment 81C. A method of treating obesity or abnormal or excessive fat accumulationcomprising administering a peptide of any one of Embodiments 1C to 56C or the pharmaceutical composition of Embodiments 61C to 65 to a subject in need thereof.

[0705] Embodiment 82C. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1C to 56C or the pharmaceutical composition of Embodiments 61C to 65 to a subject receiving and / or previously received incretin. 150123828-02-5133-WO

[0706] Embodiment 83C. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1C to 56C or the pharmaceutical composition of Embodiments 61C to 65 to a subject not receiving incretin.

[0707] Embodiment 84C. The method of any one of Embodiments 65C to 83C, wherein the peptide orpharmaceutical composition is administered from a prefilled dosage form device, such as syringe or autoinjector.

[0708] Embodiments - Series D

[0709] Embodiment 1D. A peptide comprising the amino acid sequence of formula (DI):X1-X2-X3-X4-X5-X6-X7-X8formula (DI) wherein in formula (DI): X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table D1.

[0710] Embodiment 2D. The peptide of Embodiment 1D, wherein the peptide of formula (DI) is apeptide of any one of formula (DIa), formula (DIb), formula (DIc), formula (DId), formula (DIe), or formula (DIf).

[0711] Embodiment 3D. The peptide of Embodiment 1D or 2D, wherein the peptide of formula (DI) is apeptide of formula (DIa): X-4-X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8formula (DIa) wherein in formula (DIa): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table D1; or Table D1 or a linker.

[0712] Embodiment 4D. The peptide of Embodiment 1D or 2D, wherein the peptide of formula (DI) is apeptide of formula (DIb): X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (DIb) wherein in formula (Ib): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table D1; or Table D1 or a linker.

[0713] Embodiment 5D. The peptide of Embodiment 1D or 2D, the peptide of formula (DI) is a peptideof formula (DIc): X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (DIc) wherein in formula (Ic): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table D1; or Table D1 or a linker. 151123828-02-5133-WO

[0714] Embodiment 6D. The peptide of Embodiment 1D or 2D, the peptide of formula (DI) is a peptideof formula (DId): X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (DId) wherein in formula (Id): X-1, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table D1; or Table D1 or a linker.

[0715] Embodiment 7D. The peptide of Embodiment 1D or 2D, the peptide of formula (DI) is a peptideof formula (DIe): X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 formula (DIe) wherein in formula (Ie): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table D1; or Table D1 or a linker.

[0716] Embodiment 8D. The peptide of Embodiment 1D or 2D, the peptide of formula (DI) is a peptideof formula (DIf): X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 formula (DIf) wherein in formula (DIf): X-1, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table D1; or Table D1 or a linker.

[0717] Embodiment 9D. The peptide of any one of Embodiments 1D-8D, wherein X3 is selected from2-methyl-alanine (Ala(2-Me)), 3-aminooxetane-3-carboxylic acid (Aib(O-cyclic)), alpha-methyl-D-aspartic acid (L- aMeAsp), alpha-methyl-D-ornithine (D-aMeOrn), alpha-methyl-D-serine (D-aMeSer), alpha-methyl-L-glutamic acid (L-aMeGlu), cycloleucine (Cyclo-Leu), beta-D-homoglutamic acid (D-bhGlu), beta-L-homoglutamic acid (bhGlu), L-homoglutamic acid (hGlu), and L-phenylglycine (Phg).

[0718] Embodiment 10D. The peptide of any one of Embodiments 1D-9D, wherein X4 is selected from3-(3-pyridyl)-L-alanine (3-Pal), glutamine (Gln), homocitrulline (hCit), citrulline (Cit), histidine (His), and L-ornithine (Orn).

[0719] Embodiment 11D. The peptide of any one of Embodiments 1D-10D, wherein X3 is selected fromX3 column in Table D1 and Table D1A and X4 is selected from X4 column in Table D1 and Table D1A.

[0720] Embodiment 12D. The peptide of any one of Embodiments 1D-10D, wherein X3-X4 is selectedfrom Phg-3-Pal, D-aMeOrn-Gln, Aib(O-cyclic)-Gln, Aib(O-cyclic)-hCit, Aib(O-cyclic)-Cit, hGlu-Gln, D-aMeSer-Gln, Cyclo-Leu-Gln, hGlu-His, Ala(2-Me)-Gln, L-aMeGlu-His, L-aMeAsp-His, and Ala(2-Me)-His, Phg-His, Cyclo-Leu- 3-Pal, D-bhGlu-His, D-aMeSer-His, bhGlu-His, D-aMeOrn-3-Pal, and Aib(O-cyclic)-3-Pal.

[0721] Embodiment 13D. The peptide of any one of Embodiments 1D-12D, wherein X5 is selected from4-fluoro-D-phenylalanine (D-Phe(4-F)), D-phenylalanine (D-Phe), 4-methyl-D-phenylalanine (D-Phe(4-Me)), 3- trifluoromethyl-D-phenylalanine (D-Phe(3-CF3)), and 3-fluoro-D-phenylalanine (D-Phe(3-F)). 152123828-02-5133-WO

[0722] Embodiment 14D. The peptide of any one of Embodiments 1D-13D, wherein X6 is arginine (Arg).

[0723] Embodiment 15D. The peptide of any one of Embodiments 1D-14D, wherein X7 is selected from6-fluoro-L-tryptophan (Trp(6-F)), 6-methyl-L-tryptophan (Trp(6-Me)), tryptophan (Trp), and 5-methyl-L-tryptophan (Trp(5-Me)).

[0724] Embodiment 16D. The peptide of any one of Embodiments 1D-15D, wherein X8 is cysteine (Cys)or penicillamine (Pen).

[0725] Embodiment 17D. The peptide of any one of Embodiments 1D-16D, wherein X1 is selected fromD-norarginine (D-Nar), Arg, and beta-homo-L-arginine (Beta-homoArg).

[0726] Embodiment 18D. The peptide of any one of Embodiments 1D-17D, wherein X2 is Cys.

[0727] Embodiment 19D. The peptide of any one of Embodiments 1D-18D, wherein the peptide offormula (I) is selected from Table D1, Table D1A , Table D2, and Table D2A.

[0728] Embodiment 20D. The peptide of any one of Embodiments 1D-19D, wherein the peptide is acyclic peptide.

[0729] Embodiment 21D. The peptide of Embodiment 20D, wherein the cyclic peptide comprises adisulfide bridge or a lactam bridge.

[0730] Embodiment 22D. The peptide of Embodiment 20D or 21D, wherein the cyclic peptide has theformula (DII): tideIId), offormula (DIIa) wherein in formula (DIIa): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table D1; or Table D1 or a linker.

[0733] Embodiment 25D. The peptide of Embodiments 22D or 23D, wherein the cyclic peptide of123828-02-5133-WO formula (DIIb) wherein in formula (DIIb): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table D1; or Table D1 or a linker.

[0734] Embodiment 26D. The peptide of Embodiments 22D or 23D, wherein the cyclic peptide offormula (DII) is a cyclic peptide of formula (DIIc):wherein in formula (DIIc): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table D1; or Table D1 or a linker.

[0735] Embodiment 27D. The peptide of Embodiments 22D or 23D, wherein the cyclic peptide offormula (II) is a cyclic peptide of formula (DIId):formula (DIId) wherein in formula (DIId): X-1, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table D1; or Table D1 or a linker.

[0736] Embodiment 28D. The peptide of Embodiments 22D or 23D, wherein the cyclic peptide offormula (II) is a c clic e tide of formula (IIe):ormua ( e) wherein in formula (DIIe): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table D1; or Table D1 or a linker.

[0737] Embodiment 29D. The peptide of Embodiments 22D or 23D, wherein the cyclic peptide offormula (DIIf) wherein in formula (DIIf): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table D1; or Table D1 or a linker. 154123828-02-5133-WO

[0738] Embodiment 30D. The peptide of any one of Embodiments 1D-29D, wherein the peptide furthercomprises one or more amino acids conjugated to X1 and / or X8, optionally wherein the one or more amino acids (Lys*).

[0739] Embodiment 31. The peptide of any one of Embodiments 1D-30D, wherein the peptide furthercomprises one or more lipids conjugated to X1and / or X8.

[0740] Embodiment 32D. The peptide of any one of Embodiments 1D-31D, wherein the peptide iscapped with N-terminal acetyl and / or C-terminal amide groups.

[0741] Embodiment 33D. The peptide of any one of Embodiments 1D-32D, wherein the peptide isselected from Table D1, Table D1A , Table D2, and Table 2.

[0742] Embodiment 34D. The peptide of any one of Embodiments 1D-33D, wherein the peptidedemonstrates increased selectivity for MC4R over MC1R when administered to a subject compared to a control.

[0743] Embodiment 35D. The peptide of any one of Embodiments 1D-34D, wherein the peptidedemonstrates increased selectivity for MC4R over MC1R as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0744] Embodiment 36D. The peptide of Embodiment 34D or 35D, wherein the peptide demonstratesincreased selectivity for MC4R over MC1R by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0745] Embodiment 37D. The peptide of Embodiment 34D or 35D, wherein the peptide demonstratesincreased selectivity for MC4R over MC1R by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0746] Embodiment 38D. The peptide of any one of Embodiments 1D-33D, wherein the peptidedemonstrates an increased ratio of MC4R intracellular signaling to MC1R intracellular signaling when administered to a subject compared to a control.

[0747] Embodiment 39D. The peptide of any one of Embodiments 1D-34D, wherein the peptidedemonstrates increased selectivity for MC4R intracellular signaling to MC1R intracellular signaling as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0748] Embodiment 40D. The peptide of Embodiment 38D or 39D, wherein the peptide demonstratesan increased ratio of MC4R intracellular signaling to MC1R intracellular signaling by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at 155123828-02-5133-WO least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when administered to a subject compared to a control.

[0749] Embodiment 41D. The peptide of Embodiment 38D or 39D, wherein the peptide demonstratesan increased ratio of MC4R intracellular signaling to MC1R intracellular signaling by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when administered to a subject compared to a control.

[0750] Embodiment 42D. The peptide of any one of Embodiments 1D-41D, wherein the peptidedemonstrates enhanced melanocortin 4 receptor (MC4R) function in a subject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control.

[0751] Embodiment 43D. The peptide of any one of Embodiments 1D-42D, wherein the peptidedemonstrates decreased melanocortin 1 receptor (MC1R) function in a subject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control.

[0752] Embodiment 44D. The peptide of any one of Embodiments 1D-43D, wherein the peptidedemonstrates enhanced melanocortin 4 receptor (MC4R) function as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0753] Embodiment 45D. The peptide of any one of Embodiments 1D-44D, wherein the peptidedemonstrates decreased melanocortin 1 receptor (MC1R) function as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0754] Embodiment 46D. The peptide of any one of Embodiments 42D-45D, wherein the peptidedemonstrates enhanced MC4R function and / or decreased MC1R function by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0755] Embodiment 47D. The peptide of any one of Embodiments 42D-45D, wherein the peptidedemonstrates enhanced MC4R function and / or decreased MC1R function by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0756] Embodiment 48D. The peptide of any one of Embodiments 20D-47D, wherein the cyclic peptidedemonstrates increased selectivity for MC4R over MC1R by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least 156123828-02-5133-WO about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0757] Embodiment 49D. The peptide of any one of Embodiments 20D-47D, wherein the cyclic peptidedemonstrates increased selectivity for MC4R over MC1R by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0758] Embodiment 50D. The peptide of any one of Embodiments 1D-49D, wherein the peptidecomprises a half-life extending moiety, optionally wherein the half-life extending moiety comprises polyethylene glycol (PEG), recombinant PEG mimetics, glycosylation of carbohydrates, Fc-fusion proteins or conjugates, albumin fusion proteins or conjugates, albumin-binding fusion proteins or conjugates, polypropylene glycol (PPG), XTEN fusion protein or conjugates, or a combination thereof.

[0759] Embodiment 51D. The peptide of any one of Embodiments 1D-50D, wherein the peptide furthercomprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or at least 100 amino acids at the amino and / or carboxy terminus.

[0760] Embodiment 52D. The peptide of any one of Embodiments 1D-51D, wherein the peptide furthercomprises a therapeutic, diagnostic, and / or imaging moiety, optionally wherein the therapeutic, diagnostic, and / or imaging moiety comprises a small molecule, a biological (e.g., a biopolymer, a protein, a nucleic acid, a polysaccharide), or a radionuclide.

[0761] Embodiment 53D. The peptide of any one of Embodiments 1D-52D, wherein the peptide offormula (I) is conjugated to or co-formulated with an additional therapeutic agent or therapeutic moiety.

[0762] Embodiment 54D. The peptide of Embodiments 52D or 53D, wherein the additional therapeuticagent or therapeutic moiety comprises incretin, an incretin analogue, or a modulator of an incretin receptor.

[0763] Embodiment 55D. The peptide of Embodiment 54D, wherein the modulator is an agonist.

[0764] Embodiment 56D. The peptide of Embodiment 55D, wherein the agonist is an agonist of GLP-1,GIP, and / or glucagon receptor.

[0765] Embodiment 57D. The peptide of Embodiment 55D, wherein the agonist is a GLP-1 analogue.

[0766] Embodiment 58D. The peptide of Embodiment 57D, wherein the GLP-1 analogue comprises anon-canonical amino acid.

[0767] Embodiment 59D. The peptide of Embodiment 57D, wherein the GLP-1 analogue comprisestirzepatide, tirzepatide analogue, liraglutide, retatrutide, exenatide, lixisenatide, semaglutide or semaglutide derivative.

[0768] Embodiment 60D. A protein comprising the peptide of any one of Embodiments 1D to 59D.157123828-02-5133-WO

[0769] Embodiment 61D. The protein of Embodiment 60D, wherein the protein has a size of at leastabout 10 amino acid residues, or at least about 15 resides, or at least about 20 residues, or at least about 25 residues, or at least about 30 residues, or at least about 35 residues, or at least about 40 residues, or at least about 45 residues, or at least about 50 residues, or at least about 60 residues, or at least about 70 residues, or at least about 80 residues, or at least about 90 residues, or at least about 100 residues, or at least about 250 residues, or at least about 500 residues, at least about 750 residues, at least about 1,000 residues, at least about 1,250 residues, at least about 1,500 residues, at least about 1,750 residues, at least about 2,000 residues, at least about 3,000 residues, at least about 4,000 residues, or at least about 5,000 residues.

[0770] Embodiment 62D. A nucleic acid encoding the peptide of any one of Embodiments 1D to 59D, orthe protein of Embodiment 60D or 61D.

[0771] Embodiment 63D. A solid synthesis device conjugated to the peptide of any one of Embodiments1D to 59D, the protein of Embodiment 60D or 61D, or the nucleic acid of Embodiment 62D.

[0772] Embodiment 64D. A pharmaceutical composition comprising a peptide of any one ofEmbodiments 1D to 59D, or the protein of Embodiment 60D or 61D, or the nucleic acid of Embodiment 62D, and a pharmaceutically acceptable excipient or carrier.

[0773] Embodiment 65D. The pharmaceutical composition of Embodiment 64D, wherein thepharmaceutical composition further comprises an additional therapeutic, diagnostic, and / or imaging moiety.

[0774] Embodiment 66D. The pharmaceutical composition of Embodiment 64D or 65D, wherein thepharmaceutical composition is conjugated to or co-formulated with an additional therapeutic agent or therapeutic moiety.

[0775] Embodiment 67D. The pharmaceutical composition of any one of Embodiments 64D or 65D,wherein the pharmaceutical composition is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, sub-lingually, vaginally or via an implanted reservoir.

[0776] Embodiment 68D. The pharmaceutical composition of any one of Embodiments 64D or 65D,wherein the pharmaceutical composition is administered via intravenous injection, intramuscular injection, subcutaneous injection, or depot injection.

[0777] Embodiment 69D. A method of selectively increasing the activity of MC4R over MC1R comprisingadministering a peptide of any one of Embodiments 1D to 59D or the pharmaceutical composition of Embodiments 64D to 68D to a subject in need thereof.

[0778] Embodiment 70D. The method of Embodiment 69D, wherein the method prevents, reduces, oreliminates hyperpigmentation in the subject when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0779] Embodiment 71. The method of Embodiment 70D, wherein the hyperpigmentation is reducedby at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% when compared to an untreated or pre- treatment subject, or subject treated with a control. 158123828-02-5133-WO

[0780] Embodiment 72D. The method of Embodiment 70D, wherein the hyperpigmentation is reducedby at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0781] Embodiment 73D. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1D to 59D or the pharmaceutical composition of Embodiments 64D to 68D to a subject in need thereof.

[0782] Embodiment 74D. The method of Embodiment 73D, wherein the disease or disorder is selectedfrom genetic obesity, obesity, abnormal or excessive fat accumulation, hypothalamic obesity, surgically-acquired obesity, a metabolic disorder, an eating disorder, hypothyroidism, Cushing syndrome, obesity due to proopiomelanocortin (POMC) variance or deficiency, obesity due to proprotein convertase subtilisin / kexin type 1 (PCSK1) variance or deficiency, obesity due to leptin receptor (LEPR) variant or deficiency, Bardet-Biedl syndrome (BBS), MC4R allele variant or deficiency, and Prader-Willi syndrome.

[0783] Embodiment 75D. The method of Embodiment 73D or 74D, wherein the method furthercomprises co-administration of an additional therapeutic agent.

[0784] Embodiment 76D. The method of any one of Embodiments 73D-75D, wherein the additionaltherapeutic agent comprises incretin, an incretin analogue, or a modulator of an incretin receptor.

[0785] Embodiment 77D. The method of Embodiment 76D, wherein the modulator is an agonist.

[0786] Embodiment 78D. The method of Embodiment 77D, wherein the agonist is an agonist of GLP-1,GIP, and / or glucagon receptor.

[0787] Embodiment 79D. The method of Embodiment 77D, wherein the agonist is a GLP-1 analogue.

[0788] Embodiment 80D. The method of Embodiment 79D, wherein the GLP-1 analogue comprises anon-canonical amino acid.

[0789] Embodiment 81D. The method of Embodiment 79D, wherein the GLP-1 analogue comprisestirzepatide, tirzepatide analogue, liraglutide, retatrutide, exenatide, lixisenatide, semaglutide or semaglutide derivative.

[0790] Embodiment 82D. The method of Embodiment 76D, wherein the subject is receiving and / orpreviously received treatment comprising incretin, an incretin analogue, or a modulator of an incretin receptor.

[0791] Embodiment 83D. The method of Embodiment 76D, wherein the subject has not or is notreceiving treatment comprising incretin, an incretin analogue, or a modulator of an incretin receptor.

[0792] Embodiment 84D. A method of treating obesity or abnormal or excessive fat accumulationcomprising administering a peptide of any one of Embodiments 1D to 59D or the pharmaceutical composition of Embodiments 64D to 68D to a subject in need thereof.

[0793] Embodiment 85D. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1D to 59D or the pharmaceutical composition of Embodiments 64D to 68D to a subject receiving and / or previously received incretin. 159123828-02-5133-WO

[0794] Embodiment 86D. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1D to 59D or the pharmaceutical composition of Embodiments 64D to 68D to a subject not receiving incretin.

[0795] Embodiment 87D. The method of any one of Embodiments 69D to 86D, wherein the peptide orpharmaceutical composition is administered from a prefilled dosage form device, such as syringe or autoinjector.

[0796] Embodiments - Series E

[0797] Embodiment 1E. A peptide comprising the amino acid sequence of formula (EI):X1-X2-X3-X4-X5-X6-X7-X8formula (EI) wherein in formula (EI): X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table E1.

[0798] Embodiment 2E. The peptide of Embodiment 1E, wherein the peptide of formula (EI) is apeptide of any one of formula (EIa), formula (EIb), formula (EIc), formula (EId), formula (EIe), or formula (EIf).

[0799] Embodiment 3E. The peptide of Embodiment 1E or 2E, wherein the peptide of formula (EI) is apeptide of formula (EIa): X-4-X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8formula (EIa) wherein in formula (EIa): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table E1; or Table E1 or a linker.

[0800] Embodiment 4E. The peptide of Embodiment 1E or 2E, wherein the peptide of formula (EI) is apeptide of formula (EIb): X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (EIb) wherein in formula (Ib): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table E1; or Table E1 or a linker.

[0801] Embodiment 5E. The peptide of Embodiment 1E or 2E, the peptide of formula (EI) is a peptideof formula (EIc): X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (EIc) wherein in formula (Ic): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table E1; or Table E1 or a linker. 160123828-02-5133-WO

[0802] Embodiment 6E. The peptide of Embodiment 1E or 2E, the peptide of formula (EI) is a peptideof formula (EId): X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (EId) wherein in formula (Id): X-1, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table E1; or Table E1 or a linker.

[0803] Embodiment 7E. The peptide of Embodiment 1E or 2E, the peptide of formula (EI) is a peptideof formula (Ie): X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 formula (EIe) wherein in formula (Ie): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table E1; or Table E1 or a linker.

[0804] Embodiment 8E. The peptide of Embodiment 1E or 2E, the peptide of formula (EI) is a peptideof formula (If): X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 formula (EIf) wherein in formula (EIf): X-1, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table E1; or Table E1 or a linker.

[0805] Embodiment 9E. The peptide of any one of Embodiments 1E-8E, wherein X3 is selected from2-methyl-alanine (Ala(2-Me)), 3-aminooxetane-3-carboxylic acid (Aib(O-cyclic)), alpha-methyl-D-aspartic acid (L- aMeAsp), alpha-methyl-D-ornithine (D-aMeOrn), alpha-methyl-D-serine (D-aMeSer), alpha-methyl-L-glutamic acid (L-aMeGlu), cycloleucine (Cyclo-Leu), L-homoglutamic acid (hGlu), L-phenylglycine (Phg), beta-L- homoglutamic acid (bhGlu), D-alanine (D-ala), D-2,4-diaminobutyric acid (D-Dab), and L-homoglutamic acid (hGlu).

[0806] Embodiment 10E. The peptide of any one of Embodiments 1E-9E, wherein X4 is selected from3-(3-Pyridyl)-L-alanine (3-Pal), 3-(4-pyridyl)-L-alanine (4-Pal), glutamine (Gln), homocitrulline (hCit), citrulline (Cit), histidine (His), L-homoglutamine (hGln) and L-ornithine (Orn).

[0807] Embodiment 11E. The peptide of any one of Embodiments 1E-10E, wherein X3 is selected fromX3column in Table E1, and Table E1A and X4is selected from X4column in Table E1, and Table E1A.

[0808] Embodiment 12E. The peptide of any one of Embodiments 1E-11E, wherein X5 is selected from4-fluoro-D-phenylalanine (D-Phe(4-F)), D-phenylalanine (D-Phe), 4-methyl-D-phenylalanine (D-Phe(4-Me)), 3- trifluoromethyl-D-phenylalanine (D-Phe(3-CF3)), 3-fluoro-D-phenylalanine (D-Phe(3-F)), 2,3-difluoro-D- phenylalanine (D-Phe(2,3-diF)), 2,4,5-trifluoro-D-phenylalanine (D-Phe(2,4,5-triF)), 2,4-dichloro-D-phenylalanine (D-Phe(2,4-diCl)), 2,4-difluoro-D-phenylalanine (D-Phe(2,4-diF)), 4-Chloro-2-fluoro-D-phenylalanine (D-Phe(2- F,4-Cl)), 3,4,5-trifluoro-D-phenylalanine (D-Phe(3,4,5-triF)), 3,4-difluoro-D-phenylalanine (D-Phe(3,4-diF)), 3,4- 161123828-02-5133-WO dimethyl-D-phenylalanine (D-Phe(3,4-diMe)), 3-chloro-D-phenylalanine (D-Phe(3-Cl)), 4-methyl-3-fluoro-D- phenylalanine (D-Phe(3-F,4-Me)), 3-methyl-D-phenylalanine (D-Phe(3-Me)), 4-(trifluoromethyl)-D-phenylalanine (D-Phe(4-CF3)), and 4-chloro-D-phenylalanine (D-Phe(4-Cl)).

[0809] Embodiment 13E. The peptide of any one of Embodiments 1E-12E, wherein X6 is Arginine (Arg).

[0810] Embodiment 14E. The peptide of any one of Embodiments 1E-13E, wherein X7 is selected from4-fluoro-L-tryptophan (Trp(4-F)), 5-chloro-L-tryptophan (Trp(5-Cl)), 5-fluoro-L-tryptophan (Trp(5-F)), 5-methyl-L- tryptophan (Trp(5-Me)), 6-bromo-L-tryptophan (Trp(6-Br)), 6-(trifluoromethyl)-L-tryptophan (Trp(6-CF3)), 6- chloro-L-tryptophan (Trp(6-Cl)), 6-fluoro-L-tryptophan (Trp(6-F)), 6-methyl-L-tryptophan (Trp(6-Me)), 7-fluoro-L- tryptophan (Trp(7-F)), and tryptophan (Trp).

[0811] Embodiment 15E. The peptide of any one of Embodiments 1E-14E, wherein X8 is selected fromcysteine (Cys), 3-amino-L-alanine (Dap), and penicillamine (Pen).

[0812] Embodiment 16E. The peptide of any one of Embodiments 1E-15E, wherein X1 is selected fromArg, beta-homo-L-arginine (Beta-homoArg), D-arginine (D-Arg), D-norarginine (D-Nar), homo-L-arginine (L-hArg), and L-norarginine (Nar).

[0813] Embodiment 17E. The peptide of any one of Embodiments 1E-16E, wherein X2 is selected fromaspartic acid (Asp), Cys, and L-glutamate (Glu).

[0814] Embodiment 18E. The peptide of any one of Embodiments 1E-17E, wherein the peptide offormula (I) is selected from Table E1, Table E1A, Table E2 and Table E2A.

[0815] Embodiment 19E. The peptide of any one of Embodiments 1E-18E, wherein the peptide is acyclic peptide.

[0816] Embodiment 20E. The peptide of Embodiment 19E, wherein the cyclic peptide comprises adisulfide bridge or a lactam bridge.

[0817] Embodiment 21. The peptide of Embodiment 19E or 20E, wherein the cyclic peptide has theformula (EII):formula (EII).

[0818] Embodiment 22E. The peptide of any one of Embodiments 1E-21E, wherein the cyclic peptideof formula (EII) is a cyclic peptide of any one of formula (EIIa), formula (EIIb), formula (EIIc), formula (EIId), formula (EIIe), or formula (EIIf).

[0819] Embodiment 23E. The peptide of Embodiments 21E or 22E, wherein the cyclic peptide of formula(EII) is a cyclic peptide of formula (EIIa):123828-02-5133-WO wherein in formula (EIIa): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table E1; or Table E1 or a linker.

[0820] Embodiment 24E. The peptide of Embodiments 21E or 22E, wherein the cyclic peptide of formula(EII) is a cyclic peptide of formula (EIIb):wherein in formula (EIIb): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table E1; or Table E1 or a linker.

[0821] Embodiment 25E. The peptide of Embodiments 21E or 22E, wherein the cyclic peptide of formula(EII) is a cyclic peptide of formula (EIIc):wherein in formula (EIIc): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table E1; or Table E1 or a linker.

[0822] Embodiment 26E. The peptide of Embodiments 21E or 22E, wherein the cyclic peptide of formula(EII) is a cyclic peptide of formula (EIId):formula (EIId) wherein in formula (IId): X-1, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table E1; or Table E1 or a linker.

[0823] Embodiment 27E. The peptide of Embodiments 21E or 22E, wherein the cyclic peptide of formulaformula (EIIe) wherein in formula (EIIe): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table E1; or Table E1 or a linker. 163123828-02-5133-WO

[0824] Embodiment 28E. The peptide of Embodiments 21E or 22E, wherein the cyclic peptide of formula(EII) is a cyclic peptide of formula (EIIf):wherein in formula (EIIf): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table E1; or Table E1 or a linker.

[0825] Embodiment 29E. The peptide of any one of Embodiments 1E-28E, wherein the peptide furthercomprises one or more amino acids conjugated to X1 and / or X8, optionally wherein the one or more amino acids (Lys*).

[0826] Embodiment 30E. The peptide of any one of Embodiments 1E-29E, wherein the peptide furthercomprises one or more lipids conjugated to X1 and / or X8.

[0827] Embodiment 31E. The peptide of any one of Embodiments 1E-30E, wherein the peptide iscapped with N-terminal acetyl and / or C-terminal amide groups.

[0828] Embodiment 32E. The peptide of any one of Embodiments 1E-31E, wherein the peptide isselected from Table E1, Table E1A, Table E2 and Table E2A.

[0829] Embodiment 33E. The peptide of any one of Embodiments 1E-32E, wherein the peptidedemonstrates increased selectivity for MC4R over MC1R when administered to a subject compared to a control.

[0830] Embodiment 34E. The peptide of any one of Embodiments 1E-33E, wherein the peptidedemonstrates increased selectivity for MC4R over MC1R as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0831] Embodiment 35E. The peptide of Embodiment 33E or 34E, wherein the peptide demonstratesincreased selectivity for MC4R over MC1R by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0832] Embodiment 36E. The peptide of Embodiment 33E or 34E, wherein the peptide demonstratesincreased selectivity for MC4R over MC1R by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state. 164123828-02-5133-WO

[0833] Embodiment 37E. The peptide of any one of Embodiments 1E-32E, wherein the peptidedemonstrates an increased ratio of MC4R intracellular signaling to MC1R intracellular signaling when administered to a subject compared to a control.

[0834] Embodiment 38E. The peptide of any one of Embodiments 1E-33E, wherein the peptidedemonstrates increased selectivity for MC4R intracellular signaling to MC1R intracellular signaling as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0835] Embodiment 39E. The peptide of Embodiment 37E or 38E, wherein the peptide demonstratesan increased ratio of MC4R intracellular signaling to MC1R intracellular signaling by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when administered to a subject compared to a control.

[0836] Embodiment 40E. The peptide of Embodiment 37E or 38E, wherein the peptide demonstratesan increased ratio of MC4R intracellular signaling to MC1R intracellular signaling by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when administered to a subject compared to a control.

[0837] Embodiment 41E. The peptide of any one of Embodiments 1E-40E, wherein the peptidedemonstrates enhanced melanocortin 4 receptor (MC4R) function in a subject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control.

[0838] Embodiment 42E. The peptide of any one of Embodiments 1E-41E, wherein the peptidedemonstrates decreased melanocortin 1 receptor (MC1R) function in a subject when compared to before the peptide is administered or to a pre-treatment or non-treatment state, or a subject treated with control.

[0839] Embodiment 43E. The peptide of any one of Embodiments 1E-42E, wherein the peptidedemonstrates enhanced melanocortin 4 receptor (MC4R) function as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0840] Embodiment 44E. The peptide of any one of Embodiments 1E-43E, wherein the peptidedemonstrates decreased melanocortin 1 receptor (MC1R) function as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0841] Embodiment 45E. The peptide of any one of Embodiments 41E-44E, wherein the peptidedemonstrates enhanced MC4R function and / or decreased MC1R function by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state. 165123828-02-5133-WO

[0842] Embodiment 46E. The peptide of any one of Embodiments 41E-44E, wherein the peptidedemonstrates enhanced MC4R function and / or decreased MC1R function by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0843] Embodiment 47E. The peptide of any one of Embodiments 19E-46E, wherein the cyclic peptidedemonstrates increased selectivity for MC4R over MC1R by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0844] Embodiment 48E. The peptide of any one of Embodiments 19E-46E, wherein the cyclic peptidedemonstrates increased selectivity for MC4R over MC1R by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0845] Embodiment 49E. The peptide of any one of Embodiments 1E-48E, wherein the peptidecomprises a half-life extending moiety, optionally wherein the half-life extending moiety comprises polyethylene glycol (PEG), recombinant PEG mimetics, glycosylation of carbohydrates, Fc-fusion proteins or conjugates, albumin fusion proteins or conjugates, albumin-binding fusion proteins or conjugates, polypropylene glycol (PPG), XTEN fusion protein or conjugates, or a combination thereof.

[0846] Embodiment 50E. The peptide of any one of Embodiments 1E-49E, wherein the peptide furthercomprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, or at least 100 amino acids at the amino and / or carboxy terminus.

[0847] Embodiment 51E. The peptide of any one of Embodiments 1E-50E, wherein the peptide furthercomprises a therapeutic, diagnostic, and / or imaging moiety, optionally wherein the therapeutic, diagnostic, and / or imaging moiety comprises a small molecule, a biological (e.g., a biopolymer, a protein, a nucleic acid, a polysaccharide), or a radionuclide.

[0848] Embodiment 52E. The peptide of any one of Embodiments 1E-51E, wherein the peptide offormula (I) is conjugated to or co-formulated with an additional therapeutic agent or therapeutic moiety. 166123828-02-5133-WO

[0849] Embodiment 53E. The peptide of Embodiments 51E or 52E, wherein the additional therapeuticagent or therapeutic moiety comprises incretin, an incretin analogue, or a modulator of an incretin receptor.

[0850] Embodiment 54E. The peptide of Embodiment 53E, wherein the modulator is an agonist.

[0851] Embodiment 55E. The peptide of Embodiment 54E, wherein the agonist is an agonist of GLP-1,GIP, and / or glucagon receptor.

[0852] Embodiment 56E. The peptide of Embodiment 54E, wherein the agonist is a GLP-1 analogue.

[0853] Embodiment 57E. The peptide of Embodiment 56E, wherein the GLP-1 analogue comprises anon-canonical amino acid.

[0854] Embodiment 58E. The peptide of Embodiment 56E, wherein the GLP-1 analogue comprisestirzepatide, tirzepatide analogue, liraglutide, retatrutide, exenatide, lixisenatide, semaglutide or semaglutide derivative.

[0855] Embodiment 59E. A protein comprising the peptide of any one of Embodiments 1E to 58E.

[0856] Embodiment 60E. The protein of Embodiment 59E, wherein the protein has a size of at leastabout 10 amino acid residues, or at least about 15 resides, or at least about 20 residues, or at least about 25 residues, or at least about 30 residues, or at least about 35 residues, or at least about 40 residues, or at least about 45 residues, or at least about 50 residues, or at least about 60 residues, or at least about 70 residues, or at least about 80 residues, or at least about 90 residues, or at least about 100 residues, or at least about 250 residues, or at least about 500 residues, at least about 750 residues, at least about 1,000 residues, at least about 1,250 residues, at least about 1,500 residues, at least about 1,750 residues, at least about 2,000 residues, at least about 3,000 residues, at least about 4,000 residues, or at least about 5,000 residues.

[0857] Embodiment 61E. A nucleic acid encoding the peptide of any one of Embodiments 1E to 58E, orthe protein of Embodiment 59E or 60E.

[0858] Embodiment 62E. A solid synthesis device conjugated to the peptide of any one of Embodiments1E to 58E, the protein of Embodiment 59E or 60E, or the nucleic acid of Embodiment 61E.

[0859] Embodiment 63E. A pharmaceutical composition comprising a peptide of any one ofEmbodiments 1E to 58E, or the protein of Embodiment 59E or 60E, or the nucleic acid of Embodiment 61E, and a pharmaceutically acceptable excipient or carrier.

[0860] Embodiment 64E. The pharmaceutical composition of Embodiment 63E, wherein thepharmaceutical composition further comprises an additional therapeutic, diagnostic, and / or imaging moiety.

[0861] Embodiment 65E. The pharmaceutical composition of Embodiment 63E or 64E, wherein thepharmaceutical composition is conjugated to or co-formulated with an additional therapeutic agent or therapeutic moiety.

[0862] Embodiment 66E. The pharmaceutical composition of any one of Embodiments 63E or 64E,wherein the pharmaceutical composition is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, sub-lingually, vaginally or via an implanted reservoir. 167123828-02-5133-WO

[0863] Embodiment 67E. The pharmaceutical composition of any one of Embodiments 63E or 64E,wherein the pharmaceutical composition is administered via intravenous injection, intramuscular injection, subcutaneous injection, or depot injection.

[0864] Embodiment 68E. A method of selectively increasing the activity of MC4R over MC1R comprisingadministering a peptide of any one of Embodiments 1E to 58E or the pharmaceutical composition of Embodiments 63E to 67E to a subject in need thereof.

[0865] Embodiment 69E. The method of Embodiment 68E, wherein the method prevents, reduces, oreliminates hyperpigmentation in the subject when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0866] Embodiment 70E. The method of Embodiment 69E, wherein the hyperpigmentation is reducedby at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% when compared to an untreated or pre- treatment subject, or subject treated with a control.

[0867] Embodiment 71E. The method of Embodiment 69E, wherein the hyperpigmentation is reducedby at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold when compared to an untreated or pre-treatment subject, or subject treated with a control.

[0868] Embodiment 72E. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1E to 58E or the pharmaceutical composition of Embodiments 63E to 67E to a subject in need thereof.

[0869] Embodiment 73E. The method of Embodiment 72E, wherein the disease or disorder is selectedfrom genetic obesity, obesity, abnormal or excessive fat accumulation, hypothalamic obesity, surgically-acquired obesity, a metabolic disorder, an eating disorder, hypothyroidism, Cushing syndrome, obesity due to proopiomelanocortin (POMC) variance or deficiency, obesity due to proprotein convertase subtilisin / kexin type 1 (PCSK1) variance or deficiency, obesity due to leptin receptor (LEPR) variant or deficiency, Bardet-Biedl syndrome (BBS), MC4R allele variant or deficiency, and Prader-Willi syndrome.

[0870] Embodiment 74E. The method of Embodiment 72E or 73E, wherein the method furthercomprises co-administration of an additional therapeutic agent.

[0871] Embodiment 75E. The method of any one of Embodiments 72E to 74E, wherein the additionaltherapeutic agent comprises incretin, an incretin analogue, or a modulator of an incretin receptor.

[0872] Embodiment 76E. The method of Embodiment 75E, wherein the modulator is an agonist.

[0873] Embodiment 77E. The method of Embodiment 76E, wherein the agonist is an agonist of GLP-1,GIP, and / or glucagon receptor.

[0874] Embodiment 78E. The method of Embodiment 76E, wherein the agonist is a GLP-1 analogue.168123828-02-5133-WO

[0875] Embodiment 79E. The method of Embodiment 78E, wherein the GLP-1 analogue comprises anon-canonical amino acid.

[0876] Embodiment 80E. The method of Embodiment 78E, wherein the GLP-1 analogue comprisestirzepatide, tirzepatide analogue, liraglutide, retatrutide, exenatide, lixisenatide, semaglutide or semaglutide derivative.

[0877] Embodiment 81E. The method of Embodiment 75E, wherein the subject is receiving and / orpreviously received treatment comprising incretin, an incretin analogue, or a modulator of an incretin receptor.

[0878] Embodiment 82E. The method of Embodiment 75E, wherein the subject has not or is notreceiving treatment comprising incretin, an incretin analogue, or a modulator of an incretin receptor.

[0879] Embodiment 83E. A method of treating obesity or abnormal or excessive fat accumulationcomprising administering a peptide of any one of Embodiments 1E to 58E or the pharmaceutical composition of Embodiments 63E to 67E to a subject in need thereof.

[0880] Embodiment 84E. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1E to 58E or the pharmaceutical composition of Embodiments 63E to 67E to a subject receiving and / or previously received incretin.

[0881] Embodiment 85E. A method of treating a disease or disorder associated with MC4R functioncomprising administering a peptide of any one of Embodiments 1E to 58E or the pharmaceutical composition of Embodiments 63E to 67E to a subject not receiving incretin.

[0882] Embodiment 86E. The method of any one of Embodiments 68E to 85E, wherein the peptide orpharmaceutical composition is administered from a prefilled dosage form device, such as syringe or autoinjector.

[0883] Embodiments - Series F

[0884] Embodiment 1F. A peptide comprising the amino acid sequence of formula (FI):X1-X2-X3-X4-X5-X6-X7-X8formula (FI) wherein in formula (FI): X3 is Cycloleucine (Cyclo-Leu); X4 is 3-(3-Pyridyl)-L-alanine (3Pal); and X1, X2, X5, X6, X7, and X8 are each independently a canonical or non-canonical amino acid.

[0885] Embodiment 2F. The peptide of Embodiment 1, wherein the peptide of formula (FI) is a peptideof any one of formula (FIa), formula (FIb), formula (FIc), formula (FId), formula (FIe), or formula (FIf).

[0886] Embodiment 3F. The peptide of Embodiment 1F or 2F, wherein the peptide of formula (I) is apeptide of formula (FIa): X-4-X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (FIa) wherein in formula (FIa): 169123828-02-5133-WO X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table F1; or Table F1 or a linker.

[0887] Embodiment 4F. The peptide of Embodiment 1F or 2F, wherein the peptide of formula (FI) is apeptide of formula (FIb): X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8formula (FIb) wherein in formula (Ib): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table F1; or Table F1 or a linker.

[0888] Embodiment 5F. The peptide of Embodiment 1F or 2F, the peptide of formula (FI) is a peptideof formula (FIc): X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (FIc) wherein in formula (Ic): X-1, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table F1; or Table F1 or a linker.

[0889] Embodiment 6F. The peptide of Embodiment 1F or 2F, the peptide of formula (FI) is a peptideof formula (FId): X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (FId) wherein in formula (Id): X-1, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table F1; or Table F1 or a linker.

[0890] Embodiment 7F. The peptide of Embodiment 1F or 2F, the peptide of formula (FI) is a peptideof formula (FIe): X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 formula (FIe) wherein in formula (Ie): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10are each independently an amino acid selected from Table F1; or Table F1 or a linker.

[0891] Embodiment 8F. The peptide of Embodiment 1F or 2F, the peptide of formula (FI) is a peptideof formula (FIf): X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10formula (FIf) wherein in formula (Ie): X-1, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table F1; or Table F1 or a linker.

[0892] Embodiment 9F. The peptide of any one of Embodiments 1F-8F, wherein X5 is D-Phenylalanine(D-Phe).

[0893] Embodiment 10F. The peptide of any one of Embodiments 1F-9F, wherein X6 is Arginine (Arg).170123828-02-5133-WO

[0894] Embodiment 11F. The peptide of any one of Embodiments 1F-10F, wherein X7 is 6-Fluoro-L-Tryptophan (Trp(6-F)).

[0895] Embodiment 12F. The peptide of any one of Embodiments 1F-11F, wherein X8 is Cysteine (Cys).

[0896] Embodiment 13F. The peptide of any one of Embodiments 1F-12F, wherein X1 is selected fromD-Norarginine (D-Nar) and beta-homo-L-arginine (Beta-homoArg).

[0897] Embodiment 14F. The peptide of any one of Embodiments 1F-13F, wherein X1 is D-Nar.

[0898] Embodiment 15F. The peptide of any one of Embodiments 1F-14F, wherein X2 is Cys.

[0899] Embodiment 16F. The peptide of any one of Embodiments 1F-15F, wherein the peptide offormula (I) is selected from Table F1, Table F1A, Table F2, and Table F2A.

[0900] Embodiment 17F. The peptide of any one of Embodiments 1F-16F, wherein the peptide is acyclic peptide.

[0901] Embodiment 18F. The peptide of Embodiment 17F, wherein the cyclic peptide comprises adisulfide bridge or a lactam bridge.

[0902] Embodiment 19F. The peptide of Embodiment 17F or 18F, wherein the cyclic peptide has theformula (FII): eofula ulaormua (FIIa) wherein in formula (FIIa): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table F1; or Table F1 or a linker .

[0905] Embodiment 22F. The peptide of Embodiments 19F or 20F, wherein the cyclic peptide of formula(FII) is a cyclic peptide of formula (FIIb):formula (FIIb) 171123828-02-5133-WO wherein in formula (FIIb): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table F1; or Table F1 or a linker .

[0906] Embodiment 23F. The peptide of Embodiments 19F or 20F, wherein the cyclic peptide of formula(FII) is a cyclic peptide of formula (FIIc):wherein in formula (FIIc): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table F1; or Table F1 or a linker .

[0907] Embodiment 24F. The peptide of Embodiments 19F or 20F, wherein the cyclic peptide of formula(FII) is a cyclic peptide of formula (FIId):ula(FII) is a cyclic peptide of formula (FIIe):formula (FIIe) wherein in formula (FIIe): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10are each independently an amino ulaformula (FIIf) wherein in formula (FIIf): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table F1; or Table F1 or a linker . 172123828-02-5133-WO

[0910] Embodiment 27F. The peptide of any one of Embodiments 1F-26F, wherein the peptide furthercomprises one or more amino acids conjugated to X1 and / or X8, optionally wherein the one or more amino acids (Lys*).

[0911] Embodiment 28F. The peptide of any one of Embodiments 1F-27F, wherein the peptide furthercomprises one or more lipids conjugated to X1and / or X8.

[0912] Embodiment 29F. The peptide of any one of Embodiments 1F-28F, wherein the peptide iscapped with N-terminal acetyl and / or C-terminal amide groups.

[0913] Embodiment 30F. The peptide of any one of Embodiments 1F-29F, wherein the peptide isselected from Table F1, Table F1A, Table F2 or Table F2A.

[0914] Embodiment 31F. The peptide of any one of Embodiments 1F-30F, wherein the peptidedemonstrates increased selectivity for MC4R over MC1R when administered to a subject compared to a control.

[0915] Embodiment 32F. The peptide of any one of Embodiments 1F-31F, wherein the peptidedemonstrates increased selectivity for MC4R over MC1R as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0916] Embodiment 33F. The peptide of Embodiment 31F or 32F, wherein the peptide demonstratesincreased selectivity for MC4R over MC1R by at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 100% as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0917] Embodiment 34F. The peptide of Embodiment 31F or 32F, wherein the peptide demonstratesincreased selectivity for MC4R over MC1R by at least about 1 fold, or at least about 2 fold, or at least about 3 fold, or at least about 4 fold, or at least about 5 fold or at least about 6 fold or at least about 7 fold, or at least about 8 fold, or at least about 9 fold, or at least about 10 fold, or at least about 50 fold, or at least about 100 fold, or at least about 500 fold, or at least about 1000 fold as measured by an in vitro, ex vivo, or in vivo assay when compared to a control, or before the peptide is administered, or to a pre-treatment or non-treatment state.

[0918] Embodiment 35F. The peptide of any one of Embodiments 1F-30F, wherein the peptidedemonstrates an increased ratio of MC4R intracellular signaling to MC1R intracellular signaling when administered to a subject compared to a control.

[0919] Embodiment 36F. The peptide of any one of Embodiments 1F-31F, wherein the peptidedemonstrates increased selectivity for MC4R intracellular signaling to MC1R intracellular signaling as measured by an in vitro, ex vivo, or in vivo assay when compared to a control.

[0920] Embodiment 37F. The peptide of Embodiment 35F or 36F, wherein the peptide demonstrates anincreased ratio of MC4R intracellular signaling to MC1R intracellular signaling ...

Claims

123828-02-5133-WO CLAIMS What is claimed is:

1. A peptide comprising the amino acid sequence of formula (I): X1-X2-X3-X4-X5-X6-X7-X8 formula (I) wherein in formula (I): X3is 3-Aminooxetane-3-carboxylic acid (Aib(O-cyclic)); X4 is glutamine (Gln), homocitrulline (hCit), citrulline (Cit), 3-(3-pyridyl)-L-alanine (3-Pal), L-homoglutamine (hGln), histidine (His), or L-ornithine (Orn); andX1, X2, X5, X6, X7, and X8 are each independently a canonical or non-canonical amino acid.

2. The peptide of claim 1, wherein the peptide of formula (I) is a peptide of any one of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), or formula (If): X-4-X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (Ia) wherein in formula (Ia): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and Table A2A or a linker; X-3-X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (Ib) wherein in formula (Ib): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and Table A2A or a linker; X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8 formula (Ic) wherein in formula (Ic): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and Table A2A or a linker; X-1-X1-X2-X3-X4-X5-X6-X7-X8formula (Id) wherein in formula (Id): X-1, X1, X2, X3, X4, X5, X6, X7, and X8 are each independently an amino acid selected from Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and Table A2A or a linker; X-2-X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 228123828-02-5133-WO formula (Ie) wherein in formula (Ie): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and Table A2A or a linker; X-1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10formula (If) wherein in formula (If): X-1, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10 are each independently an amino acid selected from Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and Table A2A or a linker.

3. The peptide of any claim 1, wherein X4is Gln.

4. The peptide of claim 1, wherein X5 is selected from 4-fluoro-D-phenylalanine (D-Phe(4-F)), D- phenylalanine (D-Phe), and 4-methyl-D-phenylalanine (D-Phe(4-Me)), optionally wherein X5 is D-Phe(4-F).

5. The peptide of claim 1, wherein X6 is arginine (Arg).

6. The peptide of claim 1, wherein X7is 6-fluoro-L-tryptophan (Trp(6-F)).

7. The peptide of claim 1, wherein X8is penicillamine (Pen) or cysteine (Cys), optionally wherein X8is penicillamine (Pen).

8. The peptide of claim 1, wherein X1 is selected from D-norarginine (D-Nar) and beta-homo-L-arginine (Beta-homoArg), optionally wherein X1 is D-norarginine (D-Nar).

9. The peptide of claim 1, wherein X2is Cys.

10. The peptide of claim 1, wherein the peptide is a cyclic peptide, optionally wherein the cyclic peptide comprises a disulfide bridge or a lactam bridge.

11. The peptide of claim 9, wherein the cyclic peptide has the formula (II):

12. The peptide of claim 11, wherein the cyclic peptide of formula (II) is a cyclic peptide of any one of formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), or formula (IIf):formula (IIa) wherein in formula (IIa): X-1, X-2, X-3, X-4, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and Table A2A or a linker; 229123828-02-5133-WOwherein in formula (IIb): X-1, X-2, X-3, X1, X2, X3, X4, X5, X6, X7, and X8 are are each independently an amino acid selected from Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and Table A2A or a linker; formula (IIc) wherein in formula (IIc): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, and X8are each independently an amino acid selected from Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and Table A2A or a linker; rom acidormua ( ) wherein in formula (IIf): X-1, X-2, X1, X2, X3, X4, X5, X6, X7, X8, X9, and X10are each independently an amino acid selected from Table 1, Table 2, Table 3, Table A1, Table A1A, Table A2, and Table A2A or a linker.

13. The peptide of claim 1, wherein the peptide is capped with N-terminal acetyl and / or C-terminal amide groups.

14. The peptide of claim 1, wherein the peptide is selected from Table A1, Table A1A, Table A2, Table A2A, Table 1 and Table 2.

15. A peptide consisting of the amino acid sequence as set forth in formula (IV):123828-02-5133-WO formula (IV) wherein in formula (IV): X1 is D-norarginine (D-Nar); X2is cysteine (Cys); X3is 3-Aminooxetane-3-carboxylic acid (Aib(O-cyclic)); X4is glutamine (Gln); X5 is 4-fluoro-D-phenylalanine (D-Phe(4-F)); X6 is arginine (Arg); X7 is 6-fluoro-L-tryptophan (Trp(6-F)); and X8 is penicillamine (Pen), wherein represents a disulfide bridge, and the peptide is capped with N-terminal ace16. The peptide of claim 1, wherein the peptide demonstrates one or more of (a)-(h): (a) increased selectivity for MC4R over MC1R when administered to a subject compared to a control;(b) increased selectivity for MC4R over MC1R when administered to a subject as measured by an in vitro,ex vivo, or in vivo assay when compared to a control; (c) an increased ratio of MC4R intracellular signaling to MC1R intracellular signaling when administered to asubject compared to a control; (d) increased selectivity for MC4R intracellular signaling to MC1R intracellular signaling as measured by anin vitro, ex vivo, or in vivo assay when compared to a control; (e) enhanced melanocortin 4 receptor (MC4R) function in a subject when compared to before the peptide isadministered or to a pre-treatment or non-treatment state, or a subject treated with control; (f) decreased melanocortin 1 receptor (MC1R) function in a subject when compared to before the peptide isadministered or to a pre-treatment or non-treatment state, or a subject treated with control; (g) enhanced melanocortin 4 receptor (MC4R) function as measured by an in vitro, ex vivo, or in vivo assaywhen compared to a control; (h) decreased melanocortin 1 receptor (MC1R) function as measured by an in vitro, ex vivo, or in vivo assaywhen compared to a control.

17. A protein comprising the peptide of any one of claims 1 to 16.

18. A nucleic acid encoding the peptide of any one of claims 1 to 16, or the protein of claim 17.

19. A solid synthesis device conjugated to the peptide of any one of claims 1 to 16, or the protein of claim 17, or the nucleic acid of claim 18.

20. A pharmaceutical composition comprising a peptide of any one of claims 1 to 16, or the protein of claim 15 or 16, or the nucleic acid of claim 19, and a pharmaceutically acceptable excipient or carrier.

21. A method of selectively increasing the activity of MC4R over MC1R comprising administering a peptide of any one of claims 1 to 16 or the pharmaceutical composition of claim 18 to a subject in need thereof, optionally 231123828-02-5133-WO wherein the method prevents, reduces, or eliminates hyperpigmentation in the subject when compared to an untreated or pre-treatment subject, or subject treated with a control.

22. A method of treating a disease or disorder associated with MC4R function comprising administering a peptide of any one of claims 1 to 16 or the pharmaceutical composition of claim 18 to a subject in need thereof, optionally wherein the disease or disorder is selected from genetic obesity, obesity, abnormal or excessive fat accumulation, hypothalamic obesity, surgically-acquired obesity, a metabolic disorder, an eating disorder,hypothyroidism, Cushing syndrome, obesity due to proopiomelanocortin (POMC) variance or deficiency, obesitydue to proprotein convertase subtilisin / kexin type 1 (PCSK1) variance or deficiency, obesity due to leptin receptor (LEPR) variant or deficiency, Bardet-Biedl syndrome (BBS), MC4R allele variant or deficiency, and Prader-Willi syndrome. 232

Images