Peptide analogs and methods of using the same

Abstract

Provided herein are peptide analogs of gastrin releasing peptide (GRP), corresponding pharmaceutical compositions, and methods of using such peptide analogs of GRP in the treatment of a disease or disorder.

Description

PEPTIDE ANALOGS AND METHODS OF USING THE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 713,191, filed on October 29, 2024, U. S. Provisional Application No. 63 / 757,920, filed on February 13, 2025, and U. S. Provisional Application No. 63 / 784,599, filed on April 7, 2025, each of which is hereby incorporated by reference in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on September 30, 2025, is named 50339-761_601_SL.xml and is 517,117 bytes in size.BACKGROUND

[0003] Gastrin releasing peptide (GRP) is a 27 amino acid peptide that stimulates release of gastrin and regulates gastric acid secretion. GRP1-27can be further processed to give GRP18-27, also known as GRP-10 or neuromedin C. GRP receptors are widely distributed in mammals, especially in the central nervous system (CNS) and peripheral nervous system. GRP receptors regulate several functions including release of gastrointestinal hormones, smooth muscle cell contraction, and epithelial cell proliferation.SUMMARY

[0004] Described herein are peptide analogs of gastrin releasing peptide (GRP). In some embodiments, a peptide described herein is conjugated to a lipid. In some embodiments, a peptide described herein is a gastrin releasing peptide receptor (GRPR) agonist. In some embodiments, a peptide described herein is useful in the treatment of a disease or disorder. In some embodiments, the disease or disorder is gastrointestinal disease or a weight-related condition.

[0005] In one aspect, provided herein is a peptide comprising the amino acid sequence of Formula (I):X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nlewherein:XO is absent or a natural or non-natural amino acid or amino acid analog;XI, X2, X3, X5, X6, X8, and X9 are each independently a natural or non-natural amino acid or amino acid analog;X3 is not Leu; andwhen XO is a natural or non-natural amino acid or amino acid analog, X2 is not Leu;7MeTrp is 7-methyltryptophan;Nle is norleucine; andwherein the peptide is conjugated to one or more lipid moieties.

[0006] In some embodiments, the peptide of Formula (I) is a peptide of Formula (XI): X(-1)-X0-X1-X2-X3-7MeTrp-X5-X6-β-Ala-X8-X9-Nle, wherein X0 and X(-1) are each independently a natural or non-natural amino acid or amino acid analog; wherein X2 and X3 are not Leu.

[0007] In one aspect, provided herein is a peptide comprising the amino acid sequence of Formula (II):X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nle wherein:X0 is absent or a natural or non-natural amino acid or amino acid analog;XI, X2, X3, X5, X6, X8, and X9 are each independently a natural or non-natural amino acid or amino acid analog; X6 is not Thr; andwhen X0 is a natural or non-natural amino acid or amino acid analog, X5 is not Thr;7MeTrp is 7-methyltryptophan;Nle is norleucine; andwherein the peptide is conjugated to one or more lipid moieties.

[0008] In some embodiments, the peptide of Formula (II) is a peptide of Formula (XII): X(-1)-X0-X1-X2-X3-7MeTrp-X5-X6-β-Ala-X8-X9-Nle,wherein X0 and X(-1) are each independently a natural or non-natural amino acid or amino acid analog; andwherein X5 and X6 are not Thr.

[0009] In one aspect, provided herein is a peptide comprising the amino acid sequence of Formula (III):X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nle wherein:X0 is absent or a natural or non-natural amino acid or amino acid analog;X1, X2, X3, X5, X6, X8, and X9 are each independently a natural or non-natural amino acid or amino acid analog;X9 is not Phe; andwhen X0 is a natural or non-natural amino acid or amino acid analog, X8 is not Phe;7MeTrp is 7-methyltryptophan;Nle is norleucine; andwherein the peptide is conjugated to one or more lipid moieties.

[0010] In some embodiments, the peptide of Formula (III) is a peptide of Formula (XIII): X(-l)-X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nle, wherein XO and X(-l) are each independently a natural or non-natural amino acid or amino acid analog; and wherein X8 and X9 are not Phe.

[0011] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.INCORPORATION BY REFERENCE

[0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION

[0013] Bombesin receptors are a class of G protein-coupled receptors that regulate several functions of the gastrointestinal tract and central nervous system. The Bombesin receptor family includes gastrin releasing peptide (GRP) receptor (GRPR or BB2receptor), neuromedin B (NMB) receptor (NMBR or BB1receptor), and the orphan receptor, bombesin receptor subtype 3 (BRS-3) receptor (BB3receptor). Activation of GRPR induces a broad range of physiological effects, including smooth muscle cell contraction, tissue growth, gastrointestinal motility, feeding behavior, regulation of circadian rhythm, thermoregulation, and satiety.

[0014] Biologically active peptides are promising drug candidates due to high selectivity, high binding affinity, and low toxicity. However, the use of native peptides as drug candidates islimited due to their short half-lives, chemical and physical stability, and low bioavailability. Structural modifications of native peptides can enable compounds having improved pharmacological properties to the parent peptide.

[0015] Peptide lipidation or conjugation of lipids to peptides can be an attractive strategy to improve the therapeutic potential of peptide drugs. The presence of fatty acyl(s) increases the lipophilicity of peptides, affecting the secondary structure and binding properties of peptides. As such, conjugation of lipids to peptides as described herein, can alter absorption, distribution, metabolism, and excretion (ADME) properties. Described herein are lipidated peptide analogs of gastrin releasing peptide (GRP) for use in the treatment of a disease or disorder. The peptide analogs of the disclosure can comprise greater potency, selectivity, half-life or solubility compared with native or parent peptides.Peptides

[0016] In some embodiments, provided herein is a peptide that binds gastrin-releasing peptide receptor (GRPR).

[0017] In one aspect, provided herein is a peptide comprising the amino acid sequence of Formula (I):X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nlewherein:X0 is absent or a natural or non-natural amino acid or amino acid analog;XI, X2, X3, X5, X6, X8, and X9 are each independently a natural or non-natural amino acid or amino acid analog;X3 is not Leu; andwhen X0 is a natural or non-natural amino acid or amino acid analog, X2 is not Leu;7MeTrp is 7-methyltryptophan;Nle is norleucine; andwherein the peptide is conjugated to one or more lipid moieties.

[0018] In some embodiments, the peptide of Formula (I) is a peptide of Formula (XI): X(-l)-X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nle, wherein X0 and X(-l) are each independently a natural or non-natural amino acid or amino acid analog; wherein X2 and X3 are not Leu.

[0019] In one aspect, provided herein is a peptide comprising the amino acid sequence of Formula (II):X0-X1-X2-X3-7MeTrp-X5-X6-β-Ala-X8-X9-Nlewherein:X0 is absent or a natural or non-natural amino acid or amino acid analog;X1, X2, X3, X5, X6, X8, and X9 are each independently a natural or non-natural amino acid or amino acid analog; X6 is not Thr; andwhen X0 is a natural or non-natural amino acid or amino acid analog, X5 is not Thr;7MeTrp is 7-methyltryptophan;Nle is norleucine; andwherein the peptide is conjugated to one or more lipid moieties.

[0020] In some embodiments, the peptide of Formula (II) is a peptide of Formula (XII): X(-1)-X0-X1-X2-X3-7MeTrp-X5-X6-β-Ala-X8-X9-Nle, wherein X0 and X(-1) are each independently a natural or non-natural amino acid or amino acid analog; and wherein X5 and X6 are not Thr.

[0021] In one aspect, provided herein is a peptide comprising the amino acid sequence of Formula (III):X0-X1-X2-X3-7MeTrp-X5-X6-β-Ala-X8-X9-Nle wherein:X0 is absent or a natural or non-natural amino acid or amino acid analog;X1, X2, X3, X5, X6, X8, and X9 are each independently a natural or non-natural amino acid or amino acid analog;X9 is not Phe; andwhen X0 is a natural or non-natural amino acid or amino acid analog, X8 is not Phe;7MeTrp is 7-methyltryptophan;Nle is norleucine; andwherein the peptide is conjugated to one or more lipid moieties.

[0022] In some embodiments, the peptide of Formula (III) is a peptide of Formula (XIII): X(-1)-X0-X1-X2-X3-7MeTrp-X5-X6-β-Ala-X8-X9-Nle, wherein X0 and X(-1) are each independently a natural or non-natural amino acid or amino acid analog; and wherein X8 and X9 are not Phe.

[0023] In some embodiments, X(-l) is Glu, Ser, Arg, or Gly.

[0024] In some embodiments, X0 is absent, Glu, Ser, Arg, or Gly. In some embodiments, X0 is Glu or Gly. In some embodiments, X0 is Glu. In some embodiments, X0 is Gly. In some embodiments X0 is absent.

[0025] In some embodiments, XI is Glu, Gly, D-Ser, Pro, a-MePro, Hyp, P-MePhe, AeTyr, HypOaa, Ser, GalactarylLys, Cit, or Sar.

[0026] In some embodiments, X1 is Glu, Gly, or D-Ser. In some embodiments, X1 is Glu. In some embodiments, X1 is Gly. In some embodiments, X1 is D-Ser.

[0027] In some embodiments, X2 is is Glu, Asn, Ala, Trp, D-Ser, D-Phe, D-Ala, Gln, AeTyr, Gly, Dap(5CTMPA), Dap(2CE-PEG-TMEA), HypOaa, hGlu, or GalactarylLys.

[0028] In some embodiments, X2 is Glu, Asn, Ala, Trp, D-Ser, D-Phe, or D-Ala. In some embodiments, X2 is Glu. In some embodiments, X2 is Asn. In some embodiments, X2 is Ala. In some embodiments, X2 is Trp. In some embodiments, X2 is D-Ser. In some embodiments, X2 is D-Phe. In some embodiments, X2 is D-Ala.

[0029] In some embodiments, X3 is Ala, His, Gln, Asn, Phe, Lys, Arg, Glu, Ser, Tyr, Aib, DAP, Leu, Val, ThpGly, or Cpg. In some embodiments, X3 is Ala, His, Gln, Asn, Phe, Lys, Arg, Glu, Ser, Tyr, Aib, DAP, Val, ThpGly, or Cpg. In some embodiments, X3 is Ala, His, Gln, Asn, Phe, Lys, Arg, Glu, Ser, Tyr, Aib, or DAP. In some embodiments, X3 is Ala, His, Gln, Asn, Phe, Lys, Arg, Glu, or Aib. In some embodiments, X3 is Ala. In some embodiments, X3 is His. In some embodiments, X3 is Gln. In some embodiments, X3 is Asn. In some embodiments, X3 is Phe. In some embodiments, X3 is Lys. In some embodiments, X3 is Arg. In some embodiments, X3 is Glu. In some embodiments, X3 is Aib.

[0030] In some embodiments, X5 is Ala.

[0031] In some embodiments, X6 is Val, Ala, Ser, Ile, Leu, Thr, HOV, Abu, 3AP, AMBA, Tle, Cbg, Cpg, or Hva. In some embodiments, X6 is Val, Ala, Ser, Ile, Thr, HOV, Abu, Tle, 3AP, AMBA, Cbg, or Cpg. In some embodiments, X6 is Val, Ala, Ser, Ile, Leu, HOV, Abu, 3AP, AMBA, Tle, Cbg, Cpg, or Hva. In some embodiments, X6 is Val. In some embodiments, X6 is Ala. In some embodiments, X6 is Ser. In some embodiments, X6 is Ile. In some embodiments, X6 is Thr. In some embodiments, X6 is HOV. In some embodiments, X6 is Abu. In some embodiments, X6 is Tle. In some embodiments, X6 is 3AP. In some embodiments, X6 is AMBA. In some embodiments, X6 is Cbg. In some embodiments, X6 is Cpg.

[0032] In some embodiments, X8 is His or NMeHis. In some embodiments, X8 is His. In some embodiments, X8 is NMeHis.

[0033] In some embodiments, X9 is Ala, Leu, Tyr, Thr, Val, Ile, Phe, Aib, Cpa, Tle, Tba, Cbg, Fle, or β-MePhe. In some embodiments, X9 is Ala, Leu, Tyr, Thr, Val, Ile, Aib, Cpa, Tle, Tba, Cbg, Fle, or β-MePhe. In some embodiments, X9 is Ala, Leu, Tyr, Thr, Val, Ile, Phe, Aib, Cpa, Tle, Tba, or Cbg. In some embodiments, X9 is Ala, Leu, Tyr, Thr, Val, Ile, Phe, Tle, Aib, orCpa. In some embodiments, X9 is Leu or Phe. In some embodiments, X9 is Ala. In some embodiments, X9 is Leu. In some embodiments, X9 is Tyr. In some embodiments, X9 is Thr. In some embodiments, X9 is Vai. In some embodiments, X9 is He. In some embodiments, X9 is Phe. In some embodiments, X9 is Tie. In some embodiments, X9 is Aib. In some embodiments, X9 is Cpa.

[0034] In some embodiments, X0 is absent or Glu; X1 is Glu, Gly, D-Ser, Pro, α-MePro, Hyp, β-MePhe, AeTyr, HypOaa, Ser, GalactarylLys, Cit, or Sar; X2 is D-Ser, Asn, D-Phe, D-Ala, Ala, Trp, Glu, Gln, AeTyr, Gly, Dap(5CTMPA), Dap(2CE-PEG-TMEA), HypOaa, hGlu, or GalactarylLys; X3 is Glu, Aib, Phe, Arg, Lys, His, Gln, Asn, Aib, Ala, Val, ThpGly, or Cpg; X5 is Ala; X6 is Ala, Val, Ser, Abu, Tle, 3AP, AMBA, Tle, Cpg, Cbg, Ile, HOV, or Thr; X8 is His or NMeHis; and X9 is Leu, Aib, Thr, Val, Ile, Tle, Leu, Cpa, Tyr, Phe, Ala, Cbg, Fle, or β-MePhe.

[0035] In some embodiments, X0 is absent or Glu; X1 is Glu, Gly, D-Ser, Pro, α-MePro, Hyp, β-MePhe, AeTyr, HypOaa, Ser, GalactarylLys, Cit, or Sar; X2 is D-Ser, Asn, D-Phe, D-Ala, Ala, Trp, Glu, Gln, AeTyr, Gly, HypOaa, hGlu, or GalactarylLys; X3 is Glu, Aib, Phe, Arg, Lys, His, Gln, Asn, Aib, Ala, Leu, Val, ThpGly, or Cpg; X5 is Ala; X6 is Ala, Val, Ser, Abu, Tle, 3AP, AMBA, Tle, Cpg, Cbg, Ile, or HOV; X8 is His or NMeHis; and X9 is Leu, Aib, Thr, Val, Ile, Tle, Leu, Cpa, Tyr, Phe, Ala, Cbg, Fle, or β-MePhe.

[0036] In some embodiments, X0 is absent or Glu; X1 is Glu, Gly, D-Ser, Pro, α-MePro, Hyp, β-MePhe, AeTyr, HypOaa, Ser, GalactarylLys, Cit, or Sar; X2 is D-Ser, Asn, D-Phe, D-Ala, Ala, Trp, Glu, Gln, AeTyr, Gly, Dap(2CE-PEG-TMEA), HypOaa, hGlu, or GalactarylLys; X3 is Glu, Aib, Phe, Arg, Lys, His, Gln, Asn, Aib, Ala, Leu, Val, ThpGly, or Cpg; X5 is Ala; X6 is Ala, Val, Ser, Abu, Tle, 3AP, AMBA, Tle, Cpg, Cbg, Ile, HOV, or Thr; X8 is His or NMeHis; X9 is Leu, Aib, Thr, Val, Ile, Tle, Leu, Cpa, Tyr, Ala, Cbg, Fle, or β-MePhe.

[0037] In some embodiments, X0 is absent, Glu or Gly; X1 is Glu, Gly, D-Ser; X2 is Glu, Asn, Ala, Trp, D-Ser, D-Phe, D-Ala; X3 is D-Ala, His, Gln, Asn, Phe, Lys, Arg, Glu, or Aib; X5 is Ala; X6 is Val, Ala, Ser, Ile, Thr, HOV, Abu, Tle, 3AP, AMBA, Cbg, or Cpg; X8 is His; X9 is Ala, Leu, Tyr, Thr, Val, Ile, Phe, Tle, Aib, or Cpa.

[0038] In some embodiments, X5 is Ala; and X8 is His.

[0039] In some embodiments, the peptide further comprises X11 at the C-terminus, wherein X11 is a natural or non-natural amino acid or amino acid analog. In some embodiments, X11 is Sar, Aib, or Arg.

[0040] In some embodiments, the peptide is X1-X2-X3-7MeTrp-Ala-X6-β-Ala-His-X9-Nle (SEQ ID NO: 184).

[0041] In some embodiments, when X0 is natural or non-natural amino acid or amino acid analog, X2 is Ala, Asn, Glu, Trp, D-Ser, D-Phe, or D-Ala.

[0042] In some embodiments, when X0 is natural or non-natural amino acid or amino acid analog, X5 is Ala.

[0043] In some embodiments, when X0 is natural or non-natural amino acid or amino acid analog, X8 is His.

[0044] In some embodiments, X2 is Ala, Asn, Asp, Cys, Glu, Gin, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Vai, or a non-natural amino acid or amino acid analog. In some embodiments, X2 is not Arg.

[0045] In some embodiments, the peptide is not Eicosanedioyl-yGlu-OEG-OEG-Gly-Arg-His-7MethylTrp-Ala-Val-P-Ala-His-Leu-Nle-NH2(SEQ ID NO. 96).

[0046] In some embodiments, the peptide is X1-X2-X3-7MeTrp-X5-X6-β-Ala-X8-X9-Nle.

[0047] In some embodiments, the peptide is not Eicosanedioyl-yGlu-yGlu-OEG-OEG-Glu-D-Ser-Glu-His-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle-NH2(SEQ ID NO. 97).

[0048] In some embodiments, when X0 is absent, XI is not Arg. In some embodiments, when X0 is absent, X2 is not Arg.

[0049] In some embodiments, when X0 is a natural or non-natural amino acid or amino acid analog, XI is not Gly or Ser.Lipid Moiety

[0050] In some embodiments, the one or more lipid moieties are conjugated to the N-terminus of the peptide. In some embodiments, the one or more lipid moieties are conjugated to the C-terminus of the peptide. In some embodiments, the one or more lipid moieties are conjugated to the C-terminus of the peptide and the N-terminus of the peptide is substituted with an acetyl group.

[0051] In some embodiments, the one or more lipid moieties are conjugated to an amino acid residue of the peptide. In some embodiments, the one or more lipid moieties are conjugated to an internal amino acid residue of the peptide. In some embodiments, the one or more lipid moieties are conjugated to a lysine residue of the peptide. In some embodiments, the one or more lipid moieties are conjugated to an internal lysine residue of the peptide.

[0052] In some embodiments, the lipid moiety comprises a C2-C26 fatty acyl group. In some embodiments, the lipid moiety comprises a C18-C26 fatty acyl group.

[0053] In some embodiments, the lipid moiety comprises -(L1)p-(L2)q-(L3)r, wherein: each L1is OEG; OEG is -NH-PEG-PEG-CH2C(=O)-; PEG is -CH2CH2O-; each L2is independently a natural or unnatural amino acid or amino acid analog; each L3is independently a substituted or unsubstituted C2-C26fatty acyl group; p is 0-8; q is 0-6; and r is 1 or 2. In some embodiments, the lipid moiety comprises -(L1)p-(L2)q-(L3)r, wherein: each L1is OEG; OEG is -NH-PEG-PEG-CH2C(=O)-; PEG is -CH2CH2O-; each L2is Glu or γ-Glu; each L3is independently a substituted or unsubstituted C12-C24fatty acyl group; p is 0-4; q is 0-4; and r is 1 or 2.

[0054] In some embodiments, the lipid moiety comprises -(L1)p-(L2)q-(L3)r, wherein: each L1is independently -((CH2)vNR1)w-CO(CH2)xO(PEG)y(CH2)zNR1-; PEG is -CH2CH2O-; v is 2-6; w is 0-1; x is 1-4; y is 1-4; z is 2-24; R1is H or -CH3; each L2is independently a natural or unnatural amino acid or amino acid analog; each L3is independently a substituted or unsubstituted C2-C26fatty acyl group; p is 0-8; q is 0-6; and r is 1 or 2.

[0055] In some embodiments, the lipid moiety comprises -(L1)p-(L2)q-(L3)r, wherein: each L1is -CO(CH2)O(PEG)(CH2)2NH-; PEG is -CH2CH2O-; each L2is Glu or γ-Glu; each L3is independently a substituted or unsubstituted C12-C24fatty acyl group; p is 0-4; q is 0-4; and r is 1 or 2.

[0056] In some embodiments, the lipid moiety comprises -(OEG)p-(y-Glu)q-(L3)r, wherein: OEG(Eicosanedioyl -yGlu-yGlu-OEG-OEG-).Linker

[0058] In some embodiments, the lipid moiety or a lipid moiety of the two or more lipid moi eties comprises a linker attached to a fatty acyl.

[0059] In some embodiments, the linker is flexible. In some embodiments, the linker is rigid. In some embodiments, the linker comprises a linear structure. In some embodiments, the linker comprises a non-linear structure. In some embodiments, the linker comprises a branched structure. In some embodiments, the linker comprises a cyclic structure.

[0060] In some embodiments, the linker comprises one or more linear structures, one or more non-linear structures, one or more branched structures, one or more cyclic structures, one or more flexible moieties, one or more rigid moieties, or combinations thereof.

[0061] In some embodiments, a linker comprises one or more amino acid residues. In some embodiments, the linker comprises 1 to 3, 1 to 5, 1 to 10, 5 to 10, or 5 to 20 amino acid residues. In some embodiments, one or more amino acids of the linker are unnatural amino acids.

[0062] In some embodiments, the linker comprises a peptide linkage. In some embodiments, the peptide linkage comprises L-amino acids and / or D-amino acids.

[0063] In some embodiments, the linker is 1 to 100 atoms, 1 to 50 atoms, 1 to 30 atoms, 1 to 20 atoms, 1 to 15 atoms, 1 to 10 atoms, or 1 to 5 atoms in length. In some embodiments, the linker has 1 to 20 atoms in length. In some embodiments, the linker is 1 to 10 atoms in length.

[0064] In some embodiments, the linker comprises flexible and / or rigid regions. Exemplary flexible linker regions include those comprising Gly and Ser residues (“GS” linker), glycine residues, alkylene chain, PEG chain, and the like. Exemplary rigid linker regions include those comprising a-helix-forming sequences, proline-rich sequences, and regions rich in double and / or triple bonds.

[0065] In some embodiments, the linker comprises one or more of substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and substituted or unsubstituted heteroarylene. In some embodiments, the linker comprises one or more of substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

[0066] In some embodiments, the linker comprises a click chemistry residue. In some embodiments, the linker is attached to a peptide via click chemistry. For example, in some embodiments, a peptide comprises an azide group that reacts with an alkyne moiety of the linker. For example, in some embodiments, a peptide comprises an alkyne group that reacts with an azide of the linker. In some embodiments, the linker comprises an azide moiety, an alkyne moiety, or both. In some embodiments, the linker comprises a triazole moiety.

[0067] In some embodiments, the linker is hydrophilic. In some embodiments, the linker is hydrophobic.

[0068] Table 1 provides amino acid sequences of illustrative lipid moiety conjugated peptides of the disclosure. In some embodiments, a composition or method of the disclosure comprises a peptide comprising an amino acid sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one of the sequences of Table 1.

[0069] Table 1. Amino Acid Sequences of Lipid Moiety Conjugated Peptides

[0070] Table 2 provides amino acid sequences of illustrative peptides of the disclosure. In some embodiments, a composition or method of the disclosure comprises a peptide comprising an amino acid sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one of the sequences of Table 2, optionally wherein the peptide comprises one or more lipid moieties as described herein.

[0071] Table 2. Amino Acid Sequences of Peptides

[0072] In some embodiments, GRP-10 (human GRP 18-27, CAS Number: 81608-30-2) has the following sequence: Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met-NH2(SEQ ID NO. 98).

[0073] In some embodiments, human GRP (CAS Number: 93755-85-2) has the following sequence: Val-Pro-Leu-Pro-Ala-Gly-Gly-Gly-Thr-Val-Leu-Thr-Lys-Met-Tyr-Pro-Arg-Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met-NH2(SEQ ID NO. 99)

[0074] In some embodiments, the sequence identity of an amino acid sequence disclosed herein is determined by a BLASTP, CLUSTALW, MUSCLE, MAFFT algorithm, or a CLUSTALW algorithm with the Smith-Waterman homology search algorithm parameters.Pharmaceutical Compositions

[0075] In some embodiments, described herein is a pharmaceutical composition comprising: (i) a peptide described herein, or a pharmaceutically acceptable salt or solvate thereof, and (ii) a pharmaceutically acceptable carrier, diluent, or excipient.

[0076] In some embodiments, the pharmaceutical composition further comprises one or more absorption enhancer. In some embodiments, the absorption enhancer is for use in an oral formulation. In some embodiments, the absorption enhancer comprises sodium caprate, sodium caprylate, labrasol, sucrose laureate, sodium taurocholate, or sodium N-(8-[2-hydroxylbenzoyl] amino) caprylate.Methods of Treating

[0077] In some embodiments, described herein is a use of a peptide described herein, or a pharmaceutical composition comprising a peptide described herein, for the preparation of a medicament for the treatment of a disorder. In some embodiments, the disorder is a gastrointestinal disease. In some embodiments, the disorder is obesity.

[0078] In some embodiments of the methods described herein, the disorder is selected from the group consisting of: central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease / diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy; metabolic syndrome, obesity and co-morbidities including cardiovascular disease such as hypertension, heart failure and atrial fibrillation, dyslipidemia, sleep apnea, and osteoarthritis; and metabolic-associated steatohepatitis (MASH); eating and nutritional disorders including hyperphagia, cachexia, binge eating disorder, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, psoriasis, and celiac disease; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy; diseases / disorders ofgastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating / distension, functional diarrhea, functional constipation, and opioid-induced constipation; gastroparesis; nausea and vomiting; disorders related to microbiome dysbiosis, other conditions involving the gut-brain axis.

[0079] In some embodiments, the disorder is a metabolic condition including diabetes and its complications such as chronic kidney disease / diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy; metabolic syndrome, obesity and co-morbidities including cardiovascular disease such as hypertension, heart failure and atrial fibrillation, dyslipidemia, sleep apnea, and osteoarthritis; metabolic-associated steatohepatitis (MASH); eating and nutritional disorders including hyperphagia, cachexia, binge eating disorder, and other eating disorders. In some embodiments, the metabolic condition is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, or metabolic-associated steatohepatitis. In some embodiments, the metabolic condition is type 2 diabetes. In some embodiments, the metabolic condition is metabolic-associated steatohepatitis. In some embodiments, the metabolic condition is obesity.

[0080] In some embodiments, the disorder is weight loss or preventing weight gain or weight regain. In some embodiments, the disorder is weight loss or preventing weight gain or weight regain post-bariatric surgery. In some embodiments, the disorder is weight loss or preventing weight gain or weight regain, wherein the subject has had bariatric surgery.

[0081] In some embodiments, described herein is a method for treating a disorder in a subject in need thereof, the method comprising: administering a therapeutically effective amount of a peptide of described herein or a pharmaceutical composition comprising a peptide described herein. The disorder can be a gastrointestinal disease. The disorder can be obesity.

[0082] In some embodiments, described herein is a method for weight management in a subject in need thereof, the method comprising: administering a therapeutically effective amount of a peptide described herein or a pharmaceutical composition comprising a peptide described herein.

[0083] In some embodiments, described herein is a method for reducing body weight of a subject in need thereof, the method comprising: administering a therapeutically effective amount of a peptide described herein or a pharmaceutical composition comprising a peptide described herein.

[0084] In some embodiments, described herein is a method for treating obesity in a subject in need thereof, the method comprising: administering a therapeutically effective amount of apeptide of described herein or a pharmaceutical composition comprising a peptide described herein.

[0085] In some embodiments, the administering occurs weekly. In some embodiments, the administering occurs every 7-14 days, every two weeks, every three weeks, or every four weeks. In some embodiments, the administering occurs semimonthly or monthly. In some embodiments, the administering occurs monthly.

[0086] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0087] In some embodiments, the subject is overweight. In some embodiments, the subject is obese.

[0088] In some embodiments, the subject has at least one weight-related comorbid condition selected from the group consisting of: hypertension, type 2 diabetes mellitus, dyslipidemia, metabolic-associated steatohepatitis, sleep apnea, and urinary incontinence.

[0089] In some embodiments, the subject has received at least one previous treatment of a weight management therapy.

[0090] In some embodiments, administering the peptide reduces a body weight of the subject by at least 5% compared to a body weight of an otherwise identical subject that is not administered the peptide. In some embodiments, administering the peptide reduces body weight of a subject by at least about 5%, at least about 10%, at least about 15%, at least about 20%, or at least about 30% compared to the body weight of an otherwise identical subject that is not administered the peptide. In some embodiments, administering the peptide reduces a body weight of the subject by at least 5% compared to the body weight of the subject at baseline. In some embodiments, administering the peptide reduces body weight of a subject by at least about 5%, at least about 10%, at least about 15%, at least about 20%, or at least about 30% compared to the body weight of the subject at baseline. In some embodiments, the baseline is the body weight of the subject before the subject begins administration of the peptide. For example, baseline can be the body weight of the subject on Day 0 if peptide administration begins on Day 1.

[0091] In some embodiments, administering the peptide reduces cumulative food intake of the subject (e.g., within a 24-hour period) by at least about: 5%, 10%, 15%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% compared to food intake of the same subject when not administered the peptide.

[0092] In some embodiments, a peptide described herein comprises a half-life that is longer than the half-life of an otherwise identical peptide that is not conjugated to the lipid moiety. Forexample, the half-life can be at least 5-fold, 10-fold, 100-fold, 1000-fold, 1500-fold, or 2000-fold higher. In some embodiments, the half-life of a peptide described herein is at least 100-fold higher compared to a half-life of an otherwise identical peptide with no lipid conjugation. In some embodiments, the half-life of the peptide is at least 1000-fold higher compared to a halflife of an otherwise identical peptide with no lipid conjugation. In some embodiments, the halflife of the peptide is at least 1500-fold higher compared to a half-life of an otherwise identical peptide with no lipid conjugation.

[0093] In some embodiments, a peptide described herein comprises a half-life that is longer than the half-life of a reference peptide, for example a GRP peptide (SEQ ID NO. 99) or a GRP-10 peptide (SEQ ID NO. 98). For example, the half-life can be at least 5-fold, 10-fold, 100-fold, 1000-fold, 1500-fold, or 2000-fold higher. In some embodiments, the half-life of a peptide described herein is at least 100-fold higher compared to the half-life of GRP-10 (SEQ ID NO.98). In some embodiments, the half-life of the peptide is at least 1000-fold higher compared to a half-life of a GRP peptide (SEQ ID NO. 99) or a GRP-10 peptide (SEQ ID NO. 98). In some embodiments, the half-life of the peptide is at least 1500-fold higher compared to a half-life of a GRP peptide (SEQ ID NO. 99) or a GRP-10 peptide (SEQ ID NO. 98).

[0094] In some embodiments, a peptide described herein has a reduced clearance as compared to a reference peptide. In some embodiments, the clearance is reduced by at least 2-fold, 5-fold, 10-fold, 100 fold, or 1000-fold. In some embodiments, the reference peptide is GRP (SEQ ID NO. 99), GRP-10 (SEQ ID NO. 98), or a non-lipidated analog.

[0095] In some embodiments, a peptide described herein has a solubility between about 1 mg / mL and about 100 mg / mL. In some embodiments, a peptide described herein has a solubility between about 1 mg / mL and 50 mg / mL. In some embodiments, a peptide described herein has a solubility of about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, or about 20 mg / mL. In some embodiments, a peptide described herein has a solubility of about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, or about 50 mg / mL. In some embodiments, the solubility is measured in a buffer. In some embodiments, the buffer is an aqueous buffer. In some embodiments, the buffer is an aqueous phosphate buffer. In some embodiments, the solubility is measured at a pH range of about 4-9. In some embodiments, the solubility is measured at a neutral pH (i.e., pH of about 7). In some embodiments, the solubility is measured at a physiological pH (i.e., pH of about 7.4). In some embodiments, the solubility is measured at a pH of about 8. In some embodiments, the solubility is measured at a pH of about 9. In some embodiments, the solubility is measured at a pH of about 10. In some embodiments,the solubility is measured at a pH of about 4. In some embodiments, the solubility is measured at a pH of about 5. In some embodiments, the solubility is measured at a pH of about 6.

[0096] In some embodiments, a peptide described herein is stable in a buffer for up to 2 weeks or greater. In some embodiments, a peptide described herein is stable in a buffer for up to 4 weeks or greater. In some embodiments, a peptide described herein is stable in a buffer for up to 6 weeks or greater. In some embodiments, a peptide described herein is stable in a buffer for up to 12 weeks or greater. In some embodiments, a peptide described herein is stable in a buffer for up to 6 months or greater. In some embodiments, a peptide described herein is stable in a buffer for up to 1 year or greater. In some embodiments, the buffer is an aqueous buffer. In some embodiments, the buffer is an aqueous phosphate buffer. In some embodiments, the buffer has a pH range of about 4-9. In some embodiments, the buffer is at a neutral pH (i.e., pH of about 7). In some embodiments, the buffer is at a physiological pH (i.e., pH of about 7.4). In some embodiments, the buffer has a pH of about 8. In some embodiments, the buffer has a pH of about 9. In some embodiments, the buffer has a pH of about 10. In some embodiments, the buffer has a pH of about 4. In some embodiments, the buffer has a pH of about 5. In some embodiments, the buffer has a pH of about 6.

[0097] In some embodiments, a peptide described herein is stable in a buffer at a temperature of about 25 °C. In some embodiments, a peptide described herein is stable in a buffer at a temperature of about 30 °C. In some embodiments, a peptide described herein is stable in a buffer at a temperature of about 35 °C. In some embodiments, a peptide described herein is stable in a buffer at a temperature of about 40 °C. In some embodiments, a peptide described herein is stable in a buffer at a temperature of about 45 °C. In some embodiments, a peptide described herein is stable in a buffer at a temperature of about 50 °C. In some embodiments, the buffer is an aqueous buffer. In some embodiments, the buffer is an aqueous phosphate buffer. In some embodiments, the buffer has a pH range of about 4-9. In some embodiments, the buffer is at a neutral pH (i.e., pH of about 7). In some embodiments, the buffer is at a physiological pH (i.e., pH of about 7.4). In some embodiments, the buffer has a pH of about 8. In some embodiments, the buffer has a pH of about 9. In some embodiments, the buffer has a pH of about 10. In some embodiments, the buffer has a pH of about 4. In some embodiments, the buffer has a pH of about 5. In some embodiments, the buffer has a pH of about 6.

[0098] In some embodiments, a peptide described herein is stable and soluble in a buffer. In some embodiments, a peptide described herein has a solubility of at least 50 mg / mL and is stable for up to 4 weeks or greater at 25 °C in a phosphate buffer at pH 8. In some embodiments, apeptide described herein has a solubility of at least 75 mg / mL and is stable for up to 4 weeks or greater at 25 °C in a phosphate buffer at pH 8. In some embodiments, a peptide described herein has a solubility of at least 50 mg / mL and is stable for up to 12 weeks or greater at 25 °C in a phosphate buffer at pH 8. In some embodiments, a peptide described herein has a solubility of at least 75 mg / mL and is stable for up to 12 weeks or greater at 25 °C in a phosphate buffer at pH 8.

[0099] In some embodiments, a peptide described herein has a stability (e.g., plasma stability) of greater than about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours. In some embodiments, a peptide described herein has a plasma stability of greater than about 12 hours. In some embodiment, a peptide described herein has a plasma stability of greater than about 18 hours. In some embodiments, a peptide described herein has a plasma stability of greater than about 24 hours. In some embodiments, a peptide described herein has a plasma stability of greater than about 30 hours. In some embodiments, a peptide described herein is stable in plasma at a temperature of about 25 °C. In some embodiments, a peptide described herein is stable in plasma at a temperature of about 30 °C. In some embodiments, a peptide described herein is stable in plasma at a temperature of about 35 °C. In some embodiments, a peptide described herein is stable in plasma at a temperature of about 40 °C. In some embodiments, the plasma is from a subject, wherein the subject is a human. In some embodiments, the plasma is from a subject, wherein the subject is a mammal. In some embodiments, the plasma is from a subject, wherein the subject is a mouse.

[0100] In some embodiments, stability is measured as a function of the percentage peptide remaining at a given time or after a given time interval. In some embodiments, the percentage peptide remaining at a given time or after a given time interval is greater than about 25%. In some embodiments, the percentage peptide remaining at a given time or after a given time interval is greater than about 50%. In some embodiments, the percentage peptide remaining at a given time or after a given time interval is greater than about 75%. In some embodiments, the percentage peptide remaining at a given time or after a given time interval is greater than about 80%. In some embodiments, the percentage peptide remaining at a given time or after a given time interval is greater than about 85%. In some embodiments, the percentage peptide remaining at a given time or after a given time interval is greater than about 90%. In some embodiments, the percentage peptide remaining at a given time or after a given time interval is greater than about 95%. In some embodiments, the percentage peptide remaining at a given time or after a given time interval is greater than about 99%.

[0101] In some embodiments, the peptide is administered intravenously. In some embodiments, the peptide is administered subcutaneously. In some embodiments, the peptide is administered orally.

[0102] In some embodiments, a method described herein further comprises administering an absorption enhancer. In some embodiments, the absorption enhancer is for use in an oral formulation. In some embodiments, the absorption enhancer is selected from the group consisting of: sodium caprate, sodium caprylate, labrasol, and sodium N-(8-[2-hydroxylbenzoyl] amino) caprylate.

[0103] In some embodiments, a method described herein further comprises administering a therapeutically effective amount of another weight loss agent.Certain Terminology

[0104] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0105] As used herein, C1-Cx includes C1-C2, C1-C3 . . . C1-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0106] The term “acyl,” as used herein refers to the group -C(=O)-R, where R is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon. An “acetyl” group refers to a -C(=O)CH3 group.

[0107] The term “alkenyl,” as used herein refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, alkenyl includes 2 to 6 carbon atoms. The term “alkenylene” refers to a divalent alkenyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and –CH2CH=CH2.

[0108] The term “alkoxy” refers to a (alkyl)-O- group, where alkyl is as defined herein. In some embodiments, the alkoxy group is a C1-C6alkoxy, which refers to a (C1-C6alkyl)-O- group.Examples of alkyl groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0109] An “alkyl” group refers to an aliphatic hydrocarbon group. In some embodiments, the alkyl is a straight-chain or branched-chain aliphatic hydrocarbon group containing from 1 to 20 carbon atoms. In certain embodiments, alkyl includes 1 to 10 carbon atoms. In further embodiments, the alkyl includes 1 to 8 carbon atoms. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl, and the like. In some embodiments, an alkyl is a C1-C6alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, ort-butyl. The term “alkylene” refers to a divalent alkyl, such as methylene (-CH2-). In some embodiments, an alkylene is a C1-C6alkylene. In other embodiments, an alkylene is a C1-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0110] The term “amino,” as used herein refers to -NRR, wherein R and R are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R’ may combine to form heterocycloalkyl, either of which may be optionally substituted. In one aspect, “amino” as used herein refers to an -NH2 group.

[0111] The term “alkynyl,” as used herein refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms. In one embodiment, an alkenyl group has the formula -C=C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -C=CH, -C≡CCH3, -C≡CCH2CH3, -CH2C≡CH. The term “alkynylene” refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C=C-).Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-l-yl, butyneyl, pentyn-l-yl, 3-methylbutyn-l-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term “alkynyl” may include “alkynylene” groups.

[0112] The term “aromatic” refers to a planar ring having a delocalized π-electron system containing 4n+2π electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”)groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0113] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls.

[0114] The term “aryl” as used herein means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together. The term "aryl" embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, an aryl is a C6-C10aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0115] The terms “benzo” and “benz,” as used herein refer to fused bicyclic or polycyclic ring system that is formed with benzene as one of the rings. Examples include benzofuran, benzothiophene, and benzimidazole.

[0116] The term “cycloalkyl,” as used herein refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. In some embodiments, cycloalkyl groups include groups having from 3 to 10 ring atoms. In certain embodiments, said cycloalkyl will comprise from 5 to 7 carbon atoms. In certain embodiments, said cycloalkyl will comprise from 3 to 6 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-lH-indenyl, adamantly, and the like. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[l,l,l]pentane, camphor, adamantane, and bicyclo[3,2,l]octane. In some embodiments, a cycloalkyl is a C3-C6cycloalkyl. In some embodiments, a cycloalkyl is a C3-C4cycloalkyl.

[0117] The term "heterocycle" or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1, 3-dionyl, 3,4-dihydroisoquinolin-l(2H)-onyl, 3,4-dihydroquinolin-2(lH)-onyl, isoindoline-1, 3-dithionyl, benzo[d]oxazol-2(3H)-onyl, lH-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=0) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0118] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the term "heteroaryl," as used herein refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom selected from N, O, and S. In certain embodiments, said heteroaryl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said heteroaryl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, said heteroaryl will comprise from 5 to 7 atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings. Examples of heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotri azolyl, benzodi oxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadi azolyl, benzofuranyl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like.Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1 O atom in the ring. In some embodiments, a heteroaryl contains 1 S atom in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9heteroaryl.

[0119] A “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the term “heterocycloalkyl” as used herein each refer to a saturated, partially unsaturated, or fully unsaturated (but nonaromatic) monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each said heteroatom may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In further embodiments, said hetercycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments,said hetercycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, said hetercycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, said hetercycloalkyl will comprise from 5 to 6 ring members in each ring. “Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Examples of heterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited. In one aspect, a heterocycloalkyl is a C2-C10heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C10heterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3 or 4-membered ring. In some embodiments, a heterocycloalkyl contains 1-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 1-20 atoms. In some embodiments, a heterocycloalkyl contains 1 S atom. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

[0120] The term “carbamate,” as used herein refers to an ester of carbamic acid (-NHCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.

[0121] The term “carboxyl” or “carboxy,” as used herein, refers to -C(=O)OH or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt.

[0122] The term “cyano,” as used herein refers to -CN.

[0123] The term “ester,” as used herein refers to a carboxy group bridging two moieties linked at carbon atoms.

[0124] The term “ether,” as used herein refers to an oxy group bridging two moieties linked at carbon atoms.

[0125] The term “halo,” or “halogen,” as used herein refers to fluorine, chlorine, bromine, or iodine. In some embodiments, halo is fluoro, chloro, or bromo.

[0126] The term “haloalkyl,” as used herein refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, di chloroethyl and dichloropropyl. “Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHC1-), and the like. In one aspect, a haloalkyl is a C1-C6haloalkyl. In another aspect, a haloalkyl is a C1-C4haloalkyl.

[0127] The term “haloalkoxy,” as used herein refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom. In one aspect, the haloalkoxy is a C1-C6haloalkoxy, which refers to a (C1-C6haloalkyl)-O- group. In another aspect, the haloalkoxy is a C1-C4haloalkoxy, which refers to a (C1-C4haloalkyl)-O- group.

[0128] The term “heteroalkyl” refers to an alkyl wherein 1 or more carbon atoms are replaced with a heteroatom. In some embodiments, “heteroalkyl” refers to an alkyl wherein 1 or more carbon atoms are replaced with one or more heteroatoms that are independently selected from NH, -N(alkyl), O, S, S(=O) and S(=O)2. The attachment of the heteroatom(s) to the remainder of the compound is at a carbon atoms of the heteroalkyl. In some embodiments, up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3. In some embodiments, “heteroalkyl” is an “alkoxyalkyl”, “alkylthioalkyl”, or “alkylaminoalkyl”. “Alkoxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by an alkoxy group, as defined herein. In some embodiments, an alkoxyalkyl is a (C1-C6alkoxy)-C1-C6alkyl. Typical alkoxyalkyl groups include, but are not limited to, -CH2OCH3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2CH2CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2CH2OCH2CH3, and the like. “Alkylthioalkyl” refers to an alkyl in which one hydrogen atom is replaced by an alkylthio group, as defined herein. In some embodiments, an alkoxyalkyl is a (C1-C6alkylthio)-C1-C6alkyl. Typical alkoxyalkyl groups include, but are not limited to, -CH2SCH3, -CH2CH2SCH3, -CH2CH2CH2SCH3, -CH2CH2CH2CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH2CH3, -CH2CH2CH2SCH2CH3, -CH2CH2CH2CH2SCH2CH3, and the like. “Alkylaminoalkyl” refers to an alkyl in which one hydrogen atom is replaced by analkylamino group, as defined herein. In some embodiments, an alkoxyalkyl is a (C1-C6alkylamino)-C1-C6alkyl. Typical alkoxyalkyl groups include, but are not limited to, -CH2NHCH3, -CH2CH2NHCH3, -CH2CH2CH2NHCH3, -CH2CH2CH2CH2NHCH3, -CH2NHCH2CH3, -CH2CH2NHCH2CH3, -CH2CH2CH2NHCH2CH3, -CH2CH2CH2CH2NHCH2CH3, and the like.

[0129] The term “hydroxy,” or “hydroxyl,” as used herein refers to -OH.

[0130] The term “hydroxyalkyl,” as used herein refers to a hydroxy group attached to the parent molecular moiety through an alkyl group. In some embodiments, a hydroxyalkyl is a C1-C4hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

[0131] The phrase “linear chain of atoms” refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0132] The term “nitro,” as used herein refers to -NO2.

[0133] The term “oxo,” as used herein refers to =0.

[0134] The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein refer the -SO3H group and its anion as the sulfonic acid is used in salt formation.

[0135] The term “sulfanyl,” as used herein refers to -S-.

[0136] The term “sulfinyl,” as used herein refers to -S(=O)-.

[0137] The term “sulfonyl,” as used herein refers to a -S(=O)2-, -S(=O)2R, or -S(=O)2R- group, with R as defined herein.

[0138] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

[0139] When a group is defined to be “null,” what is meant is that said group is absent.

[0140] In some embodiments, the term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide,alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(Ci-C4alkyl), -C(=O)N(Ci-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1-C4alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).

[0141] The term “bond” refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

[0142] The term “amino acid” as used herein refers to both natural and non-natural amino acids. The term “non-natural amino acid” as used herein refers to an amino acid other than the 20 amino acids that occur naturally in protein. The term “amino acid analog” as used herein refers to a molecule which is structurally similar to an amino acid and which can be substituted for an amino acid in a peptide disclosed herein. Amino acid analogs include, without limitation, P-amino acids and amino acids where the amino or carboxy group is substituted by a similarly reactive group (e.g., substitution of the primary amine with a secondary or tertiary amine, or substitution of the carboxy group with an ester).

[0143] The term “internal amino acid residue” as used herein refers to an amino acid residue that is not the C-terminal residue or the N-terminal residue.

[0144] The term “peptide” as used herein refers to a compound that includes two or more amino acids. A peptide described herein can comprise one or more non-natural amino acids.

[0145] As used herein, amino acid residue refers to an amino acid formed upon chemical digestion (hydrolysis) of a polypeptide at its peptide linkages. The amino acid residues described herein are, in certain embodiments, in the “L” isomeric form. Residues in the “D” isomeric form can be substituted for any “L” amino acid residue, as long as the desired functional property is retained by the polypeptide. “-NH2” refers to the free amino group present at the amino terminus of a polypeptide or the free amino group of a primary amide group present at the carboxylterminus of a polypeptide. In addition, the phrase “amino acid residue” is broadly defined to include the amino acids listed in Table A and modified and unusual amino acids, such as those listed in Table B and referred to in 37 C. F. R. §§1.821-1.822 and incorporated herein by reference.

[0146] Table A: Amino Acids and Abbreviations

[0147] Table B: Non-Natural Amino Acids or Amino Acid Analogs and Abbreviations

[0148] The term “identity” as used herein can refer to the subunit sequence identity between two polymeric molecules particularly between two amino acid molecules, such as, between two polypeptide molecules, two peptide molecules, or two polynucleotide molecules. When two amino acid sequences have the same residues at the same positions, e.g., if a position in each of two polypeptide molecules is occupied by an arginine, then they are identical at that position. The identity or extent to which two amino acid sequences have the same residues at the same positions in an alignment is often expressed as a percentage. The identity between two amino acid sequences is a direct function of the number of matching or identical positions, e.g., if half (e.g., five positions in a polymer ten amino acids in length) of the positions in two sequences are identical, the two sequences are 50% identical; if 90% of the positions (e.g., 9 of 10), are matched or identical, the two amino acids sequences are 90% identical. In embodiments, “percent sequence identity” means that two nucleotide sequences or two amino acid sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least, e.g., 70% sequence identity, or at least 80% sequence identity, or at least 85% sequence identity, or at least 90% sequence identity, or at least 95% sequence identity or more. For sequence comparison, one sequence can act as a reference sequence (e.g., parent sequence), to which test sequences are compared. When using a sequence comparison algorithm, test andreference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm can then calculate the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters.

[0149] The term “percent identity” refers to a comparison between two nucleic acid or amino acid sequences. Such comparisons are measured using any number of alignment methods known in the art, including but not limited to global (e.g., Needleman-Wunsch algorithm) or local alignments (e.g., Smith-Waterman, Sellers, or other algorithm). Percent identity often refers to the percentage of matching positions of two sequences for a contiguous section of positions, wherein the two sequences are aligned in such a way to maximize matching positions and minimize gaps of non-matching positions. In some instances, alignments are conducted wherein there are no gaps between the two sequences. In some instances, the alignment results in less than 5% gaps, less than 3% gaps, or less than 1% gaps. Additional methods of sequence comparison or alignment are also consistent with the disclosure.

[0150] The term “substantially identical” means a polypeptide or nucleic acid molecule exhibiting at least 50% identity to a reference amino acid sequence (for example, any one of the amino acid sequences described herein) or nucleic acid sequence (for example, any one of the nucleic acid sequences described herein). In some embodiments, such a sequence is at least 50%, least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, at least 99.99% or 100% identical at the amino acid level or nucleic acid to the sequence used for comparison. Sequence identity is typically measured using sequence analysis software. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection (see generally Ausubel etal., Current Protocols in Molecular Biology). Conservative substitutions may include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine.

[0151] The term “disease” or “disorder” as used herein refers to any condition that impairs the normal functioning of the body, such as a functional abnormality or disturbance that impairs normal functioning.

[0152] The term “combination therapy” means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure.

[0153] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint.

[0154] The term “therapeutically acceptable” refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use.

[0155] As used herein, “treating,” “treatment,” and the like means ameliorating a disease, so as to reduce, ameliorate, or eliminate its cause, its progression, its severity, or one or more of its symptoms, or otherwise beneficially alter the disease in a subject. In certain embodiments, reference to “treating” or “treatment” of a subject at risk for developing a disease, or at risk of disease progression to a worse state, is intended to include prophylaxis. Prevention of a disease may involve complete protection from disease or may involve prevention of disease progression. Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease.

[0156] The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, non-human primates such as chimpanzees, and other apes and monkey species; livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0157] In some embodiments, a lipid moiety described herein comprises a fatty acid group, or corresponding fatty acyl group, as shown in Table C.

[0158] Table C: Fatty AcidsFurther Forms of Peptides

[0159] In one aspect, peptides described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these peptides having the same type of activity are included in the scope of the present disclosure. In addition, the peptides described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the peptides presented herein are also considered to be disclosed herein.

[0160] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the peptide, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0161] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. A summary of pharmaceutically acceptable salts described herein is found, for example, in S. M. Berge, L. D. Bighley, D. C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble than non-ionic species. In some embodiments, a pharmaceutically acceptable salt of a peptide disclosed herein is for oral administration. In some embodiments, a pharmaceutically acceptable salt of a peptide disclosed herein is for intravenous administration. In some embodiments, a pharmaceutically acceptable salt of a peptide disclosed herein is for subcutaneous administration. In some embodiments,pharmaceutically acceptable salts are obtained by reacting a peptide disclosed herein with an acid. In some embodiments, the peptide disclosed herein (i.e., free base form) is basic and is reacted with an organic acid or an inorganic acid.

[0162] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a peptide disclosed herein with a base. In some embodiments, the peptide disclosed herein is acidic and is reacted with a base. In such situations, an acidic proton of the peptide disclosed herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, peptides described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, peptides described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with peptides that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the peptides provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.

[0163] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of peptides described herein are conveniently prepared or formed during the processes described herein. In addition, the peptides provided herein optionally exist in unsolvated as well as solvated forms.

[0164] In some embodiments, sites on the organic radicals (e.g., alkyl groups, aromatic rings) of peptides disclosed herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize, or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.

[0165] In another embodiment, the peptides described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0166] Peptides described herein include isotopically-labeled peptides, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present peptides include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example,2H,3H,13C,14C,15N,18O,17O,35S,18F,36C1,123I,124I,125I,131I,32P and33P. In one aspect, isotopically-labeled peptides described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0167] In some embodiments, the peptides disclosed herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The peptides presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The peptides and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents.Pharmaceutical Compositions and Formulations

[0168] Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, forming the resulting mixture into a desired shape.

[0169] Conventional excipients, such as binding agents, fillers, acceptable wetting agents, tableting lubricants and disintegrants may be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueousor oily suspensions and syrups. Alternatively, the oral preparations may be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use.Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants may be added to the liquid preparations. Parenteral dosage forms may be prepared by dissolving the compound provided herein in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.

[0170] A compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et. al.).

[0171] The compounds provided herein, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical formulations and unit dosages thereof and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

[0172] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.Examples of such dosage units are capsules, tablets, powders, granules, or a suspension, with conventional additives such as lactose, mannitol, com starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate. In some embodiments, the pharmaceutical composition further comprises one or more absorption enhancer. In some embodiments, the absorption enhancer comprises sodium caprate, sodium caprylate, labrasol, sucrose laureate, sodium taurocholate, and sodium N-(8-[2-hydroxylbenzoyl] amino) caprylate.

[0173] The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose, or water may be used as a suitable pharmaceutically acceptable carrier. Compounds provided herein or a salt, solvate, or hydrate thereof can be used as active ingredients in pharmaceutical compositions. The term “active ingredient,” defined in the context of a “pharmaceutical composition,” refers to a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an “inactive ingredient” which would generally be recognized as providing no pharmaceutical benefit.

[0174] The dose when using the compounds provided herein can vary within wide limits and as is customary and is known to the physician or other clinician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated, or prophylaxis conducted, or on whether further active compounds are administered in addition to the compounds provided herein. Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3, or 4 doses. Depending on the individual and as deemed appropriate from the healthcare provider it may be necessary to deviate upward or downward from the doses described herein.

[0175] The amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician. In general, one skilled in the art understands how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human. In some circumstances, these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors. Representative factors include the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, on whether an acute or chronic disease state is being treated, or prophylaxis conducted, or on whether further active compounds are administered in addition to the compounds provided herein and as part of a drug combination. The dosage regimen for treating a disease condition with the compounds and / or compositions providedherein is selected in accordance with a variety of factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods provided herein.

[0176] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.

[0177] Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.

[0178] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0179] For topical administration to the epidermis the compounds provided herein may be formulated as ointments, creams, or lotions, or as a transdermal patch.

[0180] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.

[0181] The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.Methods of Dosing and Treatment Regimens

[0182] In one embodiment, the compounds disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, are used in the preparation of medicaments for the treatment of diseasesor conditions in a mammal. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound disclosed herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.

[0183] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0184] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, in order to prevent a return of the symptoms of the disease or condition.

[0185] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0186] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which theimproved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0187] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0188] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD₅₀ and the ED₅₀. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and / or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED₅₀ with minimal toxicity. In certain embodiments, the daily dosage range and / or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

[0189] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by injection to the mammal; and / or (e) administered topically to the mammal; and / or (f) administered subcutaneously to the mammal; and / or (g) administered non-systemically or locally to the mammal.

[0190] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.

[0191] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii)the time between multiple administrations is every 24 hours; (iii) the compound is administered to the mammal every week; (iv) the compound is administered to the mammal every 7-14 days; (v) the compound is administered to the mammal every two weeks; (vi) the compound is administered to the mammal every three weeks; (vii) the compound is administered to the mammal every 4 weeks; (viii) the compound is administered to the mammal semimonthly; (ix) the compound is administered to the mammal every month. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0192] In certain instances, it is appropriate to administer at least one compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more other therapeutic agents.Synthesis of Peptides

[0193] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0194] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC are employed.

[0195] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc. Compounds may also be prepared using solid-phase peptide synthesis techniques such as those described in, for example, Solid Phase Peptide Synthesis, 2ndEdition, The Pierce Chemical Co., Rockford, Ill. (1984). Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions.

[0196] A peptide of the present disclosure may be prepared through known methods, including solid-phase peptide synthesis (SPPS). (see Palomo, Jose M. (2014). “Solid-phase peptide synthesis: an overview focused on the preparation of biologically relevant peptides” RSC Adv. 4 (62): 32658-32672; Krchnak, V; Holladay, Mark W. (2002). “Solid Phase Heterocyclic Chemistry” Chemical Reviews. 102 (1): 61-92; Merrifield, B. (1986-04-18). “Solid phase synthesis” Science. 232 (4748): 341-347; Guillier, F; et al., (2000). “Linkers and Cleavage Strategies in Solid-Phase Organic Synthesis and Combinatorial Chemistry.” Chemical Reviews.100 (6): 2091-2158; Amblard M, et al., “Methods and protocols of modern solid phase Peptide synthesis.” Mol Biotechnol. 2006 Jul;33(3):239-54).

[0197] In some embodiments, the solid-phase peptide synthesis is Fmoc solid-phase peptide synthesis, (see, e.g., Behrendt, R., etal., (2016) Advances in Fmoc solid-phase peptide synthesis. J. Pept. Sci., 22: 4–27).Numbered Embodiments

[0198] Embodiment 1. A peptide comprising the amino acid sequence of Formula (I):X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nleor a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X0 is absent or a natural or non-natural amino acid or amino acid analog;XI, X2, X3, X5, X6, X8, and X9 are each independently a natural or non-natural amino acid or amino acid analog;X3 is not Leu; andwhen X0 is a natural or non-natural amino acid or amino acid analog, X2 is not Leu;7MeTrp is 7-methyltryptophan;Nle is norleucine; andwherein the peptide is conjugated to one or more lipid moieties.

[0199] Embodiment 2. A peptide comprising the amino acid sequence of Formula (II):X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nleor a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X0 is absent or a natural or non-natural amino acid or amino acid analog;XI, X2, X3, X5, X6, X8, and X9 are each independently a natural or non-natural amino acid or amino acid analog;X6 is not Thr; andwhen X0 is a natural or non-natural amino acid or amino acid analog, X5 is not Thr;7MeTrp is 7-methyltryptophan;Nle is norleucine; andwherein the peptide is conjugated to one or more lipid moieties.

[0200] Embodiment 3. A peptide comprising the amino acid sequence of Formula (III):X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nleor a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X0 is absent or a natural or non-natural amino acid or amino acid analog;X1, X2, X3, X5, X6, X8, and X9 are each independently a natural or non-natural amino acid or amino acid analog;X9 is not Phe; andwhen X0 is a natural or non-natural amino acid or amino acid analog, X8 is not Phe;7MeTrp is 7-methyltryptophan;Nle is norleucine; andwherein the peptide is conjugated to one or more lipid moieties.

[0201] Embodiment 4. The peptide of any one of embodiments 1-3, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XO is absent, Glu, Ser, Arg, or Gly.

[0202] Embodiment 5. The peptide of any one of embodiments 1-3, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XO is absent.

[0203] Embodiment 6. The peptide of any one of embodiments 1-3, wherein:X0 is Glu or Gly.

[0204] Embodiment 7. The peptide of any one of embodiments 1-3, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X0 is Glu.

[0205] Embodiment 8. The peptide of any one of embodiments 1-7, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XI is Glu, Gly, D-Ser, Pro, a-MePro, Hyp, P-MePhe, AeTyr, HypOaa, Ser, GalactarylLys, Cit, or Sar.

[0206] Embodiment 9. The peptide of any one of embodiments 1-7, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XI is Glu, Gly, or D-Ser.

[0207] Embodiment 10. The peptide of any one of embodiments 1-9, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X2 is Glu, Asn, Ala, Trp, D-Ser, D-Phe, D-Ala, Gln, AeTyr, Gly, Dap(5CTMPA), Dap(2CE-PEG-TMEA), HypOaa, hGlu, or GalactarylLys.

[0208] Embodiment 11. The peptide of any one of embodiments 1-9, wherein:X2 is Glu, Asn, Ala, Trp, D-Ser, D-Phe, or D-Ala.

[0209] Embodiment 12. The peptide of any one of embodiments 2-11, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X3 is Ala, His, Gln, Asn, Phe, Lys, Arg, Glu, Ser, Tyr, Aib, DAP, Leu, Val, ThpGly, or Cpg.

[0210] Embodiment 13. The peptide of any one of embodiments 1-11, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X3 is Ala, His, Gln, Asn, Phe, Lys, Arg, Glu, Ser, Tyr, Aib, DAP, Val, ThpGly, or Cpg.

[0211] Embodiment 14. The peptide of any one of embodiments 1-11, wherein:X3 is Ala, His, Gln, Asn, Phe, Lys, Arg, Glu, Ser, Tyr, Aib, or DAP.

[0212] Embodiment 15. The peptide of any one of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X5 is Ala.

[0213] Embodiment 16. The peptide of any one of embodiments 1 or 3-15, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X6 is Val, Ala, Ser, Ile, Leu, Thr, HOV, Abu, 3AP, AMBA, Tle, Cbg, Cpg, or Hva.

[0214] Embodiment 17. The peptide of any one of embodiments 1-15, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X6 is Val, Ala, Ser, Ile, Leu, HOV, Abu, 3AP, AMBA, Tle, Cbg, Cpg, or Hva.

[0215] Embodiment 18. The peptide of any one of embodiments 1-15, wherein:X6 is Val, Ala, Ser, Ile, Thr, HOV, Abu, Tle, 3AP, AMBA, Cbg, or Cpg.

[0216] Embodiment 19. The peptide of any one of embodiments 1-15, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X6 is Val.

[0217] Embodiment 20. The peptide of any one of embodiments 1-19, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X8 is His or NMeHis.

[0218] Embodiment 21. The peptide of any one of embodiments 1-19, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X8 is His.

[0219] Embodiment 22. The peptide of any one of embodiments 1, 2, or 4-21, or any one of embodiments 4-17, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X9 is Ala, Leu, Tyr, Thr, Val, Ile, Phe, Aib, Cpa, Tle, Tba, Cbg, Fle, or β-MePhe.

[0220] Embodiment 23. The peptide of any one of embodiments 1-21, or any one of embodiments 4-17, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X9 is Ala, Leu, Tyr, Thr, Val, Ile, Aib, Cpa, Tle, Tba, Cbg, Fle, or β-MePhe.

[0221] Embodiment 24. The peptide of any one of embodiments 1, 2, or 4-21, or any one of embodiments 4-17, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X9 is Leu or Phe.

[0222] Embodiment 25. The peptide of any one of embodiments 1, 2, or 4-21, wherein:X9 is Ala, Leu, Tyr, Thr, Val, Ile, Phe, Aib, Cpa, Tle, Tba, or Cbg.

[0223] Embodiment 26. The peptide of any one of embodiments 1, 2, or 4-21, wherein:X9 is Ala, Leu, Tyr, Thr, Val, Ile, Phe, Tle, Aib, or Cpa.

[0224] Embodiment 27. The peptide of embodiment 1, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X0 is absent or Glu;XI is Glu, Gly, D-Ser, Pro, a-MePro, Hyp, P-MePhe, AeTyr, HypOaa, Ser, GalactarylLys, Cit, or Sar;X2 is D-Ser, Asn, D-Phe, D-Ala, Ala, Trp, Glu, Gin, AeTyr, Gly, Dap(5CTMPA), Dap(2CE- PEG-TMEA), HypOaa, hGlu, or GalactarylLys;X3 is Glu, Aib, Phe, Arg, Lys, His, Gin, Asn, Aib, Ala, Val, ThpGly, or Cpg;X5 is Ala;X6 is Ala, Val, Ser, Abu, Tie, 3AP, AMBA, Tie, Cpg, Cbg, He, HOV, or Thr;X8 is His or NMeHis; andX9 is Leu, Aib, Thr, Val, He, Tie, Leu, Cpa, Tyr, Phe, Ala, Cbg, Fle, or P-MePhe.

[0225] Embodiment 28. The peptide of embodiment 2, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X0 is absent or Glu;XI is Glu, Gly, D-Ser, Pro, a-MePro, Hyp, P-MePhe, AeTyr, HypOaa, Ser, GalactarylLys, Cit, or Sar;X2 is D-Ser, Asn, D-Phe, D-Ala, Ala, Trp, Glu, Gin, AeTyr, Gly, HypOaa, hGlu, or GalactarylLys;X3 is Glu, Aib, Phe, Arg, Lys, His, Gin, Asn, Aib, Ala, Leu, Val, ThpGly, or Cpg;X5 is Ala;X6 is Ala, Val, Ser, Abu, Tie, 3 AP, AMBA, Tie, Cpg, Cbg, He, or HOV;X8 is His or NMeHis; andX9 is Leu, Aib, Thr, Val, He, Tie, Leu, Cpa, Tyr, Phe, Ala, Cbg, Fle, or P-MePhe.

[0226] Embodiment 29. The peptide of embodiment 3, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XO is absent or Glu;XI is Glu, Gly, D-Ser, Pro, a-MePro, Hyp, P-MePhe, AeTyr, HypOaa, Ser, GalactarylLys, Cit, or Sar;X2 is D-Ser, Asn, D-Phe, D-Ala, Ala, Trp, Glu, Gin, AeTyr, Gly, Dap(2CE-PEG-TMEA), HypOaa, hGlu, or GalactarylLys;X3 is Glu, Aib, Phe, Arg, Lys, His, Gin, Asn, Aib, Ala, Leu, Vai, ThpGly, or Cpg;X5 is Ala;X6 is Ala, Vai, Ser, Abu, Tie, 3 AP, AMBA, Tie, Cpg, Cbg, He, HOV, or Thr;X8 is His or NMeHis;X9 is Leu, Aib, Thr, Vai, He, Tie, Leu, Cpa, Tyr, Ala, Cbg, Fie, or P-MePhe.

[0227] Embodiment 30. The peptide of embodiment 1, wherein:XO is absent, Glu or Gly;XI is Glu, Gly, or D-Ser;X2 is Glu, Asn, Ala, Trp, D-Ser, D-Phe, D-Ala;X3 is Ala, His, Gin, Asn, Phe, Lys, Arg, Glu, or Aib;X5 is Ala;X6 is Vai, Ala, Ser, lie, Thr, HOV, Abu, Tie, 3 AP, AMBA, Cbg, or Cpg;X8 is His; andX9 is Ala, Leu, Tyr, Thr, Vai, lie, Phe, Tie, Aib, or Cpa.

[0228] Embodiment 31. The peptide of any one of embodiments 1-30, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X5 is Ala; andX8 is His or NMeHis.

[0229] Embodiment 32. The peptide of any one of embodiments 1-31, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein the peptide is: X1-X2-X3-7MeTrp-Ala-X6-β-Ala-His-X9-Nle (SEQ ID NO: 184).

[0230] Embodiment 33. The peptide of embodiment 1, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:when X0 is natural or non-natural amino acid or amino acid analog, X2 is Ala, Asn, Glu, Trp, D-Ser, D-Phe, or D-Ala.

[0231] Embodiment 34. The peptide of embodiment 2, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:when X0 is natural or non-natural amino acid or amino acid analog, X5 is Ala.

[0232] Embodiment 35. The peptide of embodiment 3, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:when X0 is natural or non-natural amino acid or amino acid analog, X8 is His.

[0233] Embodiment 36. The peptide of any one of embodiments 1-3, wherein:X2 is Ala, Asn, Asp, Cys, Glu, Gin, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, Vai, or a non-natural amino acid or amino acid analog.

[0234] Embodiment 37. The peptide of any one of embodiments 1-3, wherein:X2 is not Arg.

[0235] Embodiment 38. The peptide of any one of embodiments 1-3, wherein the peptide is not SEQ ID NO. 98.

[0236] Embodiment 39. The peptide of any one of embodiments 1-3, wherein the peptide is:X1-X2-X3-7MeTrp-X5-X6-β-Ala-X8-X9-Nle.

[0237] Embodiment 40. The peptide of any one of embodiments 1-3, wherein the peptide is not SEQ ID NO. 97.

[0238] Embodiment 41. The peptide of any one of embodiments 1 or 4-19, wherein the peptide of Formula (I) is a peptide of Formula (XI): X(-l)-X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nle,wherein X0 and X(-l) are each independently a natural or non-natural amino acid or amino acid analog; andwherein X2 and X3 are not Leu.

[0239] Embodiment 42. The peptide of any one of embodiments 2 or 4-19, wherein the peptide of Formula (II) is a peptide of Formula (XII): X(-l)-X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nle,wherein X0 and X(-l) are each independently a natural or non-natural amino acid or amino acid analog; andwherein X5 and X6 are not Thr.

[0240] Embodiment 43. The peptide of any one of embodiments 3-19, wherein the peptide of Formula (III) is a peptide of Formula (XIII): X(-l)-X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nle,wherein X0 and X(-l) are each independently a natural or non-natural amino acid or amino acid analog; andwherein X8 and X9 are not Phe.

[0241] Embodiment 44. The peptide of any one of embodiments 41-43, wherein:X(-l) is Glu, Ser, Arg, or Gly.

[0242] Embodiment 45. The peptide of any one of embodiments 1-44, or a pharmaceutically acceptable salt, solvate, or isomer thereof, whereinthe one or more lipid moieties are conjugated to the N-terminus of the peptide.

[0243] Embodiment 46. The peptide of any one of embodiments 1-44, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the one or more lipid moieties are conjugated to the C-terminus of the peptide.

[0244] Embodiment 47. The peptide of any one of embodiments 1-44, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the one or more lipid moieties are conjugated to the C-terminus of the peptide and the N- terminus of the peptide is substituted with an acetyl group.

[0245] Embodiment 48. The peptide of any one of embodiments 1-44, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the one or more lipid moieties are conjugated to an amino acid residue of the peptide.

[0246] Embodiment 49. The peptide of any one of embodiments 1-44, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the one or more lipid moieties are conjugated to a lysine residue of the peptide.

[0247] Embodiment 50. The peptide of any one of embodiments 1-49, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the lipid moiety comprises a C2-C26 fatty acyl group.

[0248] Embodiment 51. The peptide of any one of embodiments 1-49, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the lipid moiety comprises a C18-C26 fatty acyl group.

[0249] Embodiment 52. The peptide of any one of embodiments 1-51, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the lipid moiety comprises -(L1)p-(L2)q-(L3)r, wherein:each L1is independently -((CH2)vNR1)w-CO(CH2)xO(PEG)y(CH2)zNR1-;PEG is -CH2CH2O-; v is 2-6; w is 0-1; x is 1-4; y is 1-4; z is 2-24; R1is H or -CH3; each L2is independently a natural or unnatural amino acid or amino acid analog; each L3is independently a substituted or unsubstituted C2-C26 fatty acyl group;p is 0-8;q is 0-6; andr is 1 or 2.

[0250] Embodiment 53. The peptide of any one of embodiments 1-52, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the lipid moiety comprises -wherein:each L1is -CO(CH2)O(PEG)(CH2)2NH-;PEG is -CH2CH2O-;each L2is Glu or y-Glu;each L3is independently a substituted or unsubstituted Ci2-C24 fatty acyl group;p is 0-4;q is 0-4; andr is 1 or 2.

[0251] Embodiment 54. The peptide of any one of embodiments 1-53, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the lipid moiety comprises -(OEG)p-(y-Glu)q-(L3)r, wherein:OEGis -NH-PEG-PEG-CH2C(=O)-;PEG is -CH2CH2O-;p is 1, 2, 3, or 4;q is 1, 2, 3, or 4; andr is 1.

[0252] Embodiment 55. The peptide of any one of embodiments 1-53, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the lipid moiety comprises -(OEG)p-(y-Glu)q-(L3)r, wherein:OEGis -NH-PEG-PEG-CH2C(=O)-;PEG is -CH2CH2O-;p is 1, 2, 3, or 4;q is 1, 2, 3, or 4; andr is 1.

[0253] Embodiment 56. The peptide of any one of embodiments 1-54, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein -(L^p^L^q^L3^ is(Eicosanedioyl-yGlu-yGlu-OEG-OEG-).

[0254] Embodiment 57. The peptide of any one of embodiments 1-56, wherein:the peptide comprises an amino acid sequence comprising at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one of SEQ ID NOs 101-182.

[0255] Embodiment 58. The peptide of any one of embodiments 1-56, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the peptide comprises the amino acid sequence of any one of SEQ ID NOs 101-182.

[0256] Embodiment 59. The peptide of any one of embodiments 1-56, wherein:the peptide comprises the amino acid sequence of any one of SEQ ID NOs 101-140.

[0257] Embodiment 60. The peptide of any one of embodiments 1-56, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the peptide consists of the amino acid sequence of any one of SEQ ID NOs 101-182.

[0258] Embodiment 61. The peptide of any one of embodiments 1-56, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the peptide comprises an amino acid sequence comprising at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one of SEQ ID NOs 1-82.

[0259] Embodiment 62. The peptide of any one of embodiments 1-56, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the peptide comprises an amino acid sequence of any one of SEQ ID NOs 1-82.

[0260] Embodiment 63. The peptide of any one of embodiments 1-56, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the peptide comprises an amino acid sequence of any one of SEQ ID NOs 1-40.

[0261] Embodiment 64. The peptide of any one of embodiments 1-56, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the peptide consists of the amino acid sequence of any one of SEQ ID NOs 1-82.

[0262] Embodiment 65. The peptide of embodiment 57 or embodiment 61, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein the sequence identity isdetermined by a BLASTP, CLUSTALW, MUSCLE, MAFFT algorithm, or a CLUSTALW algorithm with the Smith-Waterman homology search algorithm parameters.

[0263] Embodiment 66. A peptide selected from:Eicosanedioyl-yGlu-yGlu-OEG-OEG-Glu-D-Ser-Glu-7MeTrp-Ala-Ala-P-Ala-His-Leu-Nle- NH2(SEQ IDNO 1);Eicosanedioyl-YGlu-yGlu-OEG-OEG-Gly-Asn-Aib-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 2);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Phe-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 3);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Arg-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 4);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Lys-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 5);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Glu-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 6);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Ser-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 7);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Abu-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 8);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Tle-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 9);Eicosanedioyl-YGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-3AP-P-Ala-His-Leu-Nle- NH2(SEQ IDNO 10);Eicosanedioyl-YGlu-YGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-AMBA-P-Ala-His-Leu- Nle-NH2(SEQ ID NO 11);Eicosanedioyl-YGlu-YGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Val-P-Ala-His-Aib-Nle- NH2(SEQ IDNO 12);Eicosanedioyl-YGlu-YGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Val-P-Ala-His-Thr-Nle- NH2(SEQ IDNO 13);Eicosanedioyl-YGlu-YGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Val-P-Ala-His-Val-Nle- NH2(SEQ IDNO 14);Eicosanedioyl-YGlu-YGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Val-P-Ala-His-Ile-Nle-NH2(SEQ ID NO 15);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Val-P-Ala-His-Tle-Nle- NH2(SEQ IDNO 16);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Gln-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ IDNO 17);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Phe-Gln-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 18);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Gln-7MeTrp-Ala-Ala-P-Ala-His-Leu-Nle- NH2(SEQ IDNO 19);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Gln-7MeTrp-Ala-Ala-P-Ala-His-Ile-Nle- NH2(SEQ ID NO 20);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Gln-7MeTrp-Ala-Tle-P-Ala-His-Thr-Nle- NH2(SEQ ID NO 21);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Phe-7MeTrp-Ala-Cpg-P-Ala-His-Ile-Nle- NH2(SEQ ID NO 22);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Ala-Asn-7MeTrp-Ala-Ile-P-Ala-His-Cpa-Nle- NH2(SEQ ID NO 23);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Ala-Gln-7MeTrp-Ala-Cbg-P-Ala-His-Tyr-Nle- NH2(SEQ ID NO 24);Eicosanedi oyl-(yEyE)OEG-OEG-Gly-D-Phe-Gln-7MeTrp-Ala-Val-P-Ala-His-Ile-Nle-NH2(SEQ ID NO 25);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Phe-Gln-7MeTrp-Ala-Ile-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 26);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-HOV-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 27);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Gln-7MeTrp-Ala-HOV-P-Ala-His-Phe- Nle-NH2(SEQ ID NO 28);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Gln-7MeTrp-Ala-Val-P-Ala-His-Phe-Nle- NH2(SEQ ID NO 29);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Gln-7MeTrp-Ala-Thr-P-Ala-His-Ile-Nle- NH2(SEQ ID NO 30);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Trp-Gln-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 31);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Trp-Gln-7MeTrp-Ala-Val-P-Ala-His-Phe-Nle- NH2(SEQ ID NO 32);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Aib-7MeTrp-Ala-Ile-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 33);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Phe-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 34);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Aib-7MeTrp-Ala-Thr-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 35);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-His-7MeTrp-Ala-Thr-P-Ala-His-Phe-Nle- NH2(SEQ ID NO 41);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-His-7MeTrp-Ala-Ile-P-Ala-His-Phe-Nle-NH2(SEQ ID NO 42);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-His-7MeTrp-Ala-Thr-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 43);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Ala-Asn-7MeTrp-Ala-Val-P-Ala-His-Cbg-Nle- NH2(SEQ ID NO 44);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-His-7MeTrp-Ala-Val-P-Ala-His-Cbg-Nle- NH2(SEQ ID NO 45);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Leu-7MeTrp-Ala-Ile-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 46);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Leu-7MeTrp-Ala-Ile-P-Ala-His-Val-Nle- NH2(SEQ ID NO 47);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Leu-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 48);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-Leu-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 49);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-Val-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 50);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-Val-7MeTrp-Ala-Val-P-Ala-His-Phe-Nle- NH2(SEQ IDNO 51);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-Leu-7MeTrp-Ala-Val-P-Ala-His-Phe-Nle- NH2(SEQ ID NO 52);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Ala-Asn-7MeTrp-Ala-Val-P-Ala-His-Fle-Nle- NH2(SEQ ID NO 53);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-His-7MeTrp-Ala-Val-P-Ala-His-Fle-Nle- NH2(SEQ ID NO 54);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-ThpGly-7MeTrp-Ala-Val-P-Ala-His-Leu- Nle-NH2(SEQ ID NO 55);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-AeTyr-His-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 56);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Pro-Gly-His-7MeTrp-Ala-Val-β-Ala-His-Leu-Nle- NH2(SEQ ID NO 57);Eicosanedioyl-yGlu-yGlu-OEG-OEG-α-MePro-Gly-His-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 58);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Hyp-Gly-His-7MeTrp-Ala-Val-β-Ala-His-Leu-Nle- NH2(SEQ ID NO 59);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Cpg-7MeTrp-Ala-Val-β-Ala-His-Leu-Nle- NH2(SEQ ID NO 60);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Cpg-7MeTrp-Ala-Val-β-Ala-His-Leu-Nle- NH2(SEQ ID NO 61);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Gln-7MeTrp-Ala-Val-β-Ala-His-β-MePhe- Nle-NH2(SEQ ID NO 62);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Gln-7MeTrp-Ala-Thr-β-Ala-His-β-MePhe- Nle-NH2(SEQ ID NO 63);Eicosanedioyl-yGlu-yGlu-OEG-OEG-β-MePhe-Asn-His-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 64);Eicosanedioyl-yGlu-yGlu-OEG-OEG-AeTyr-D-Ala-Gln-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 65);Eicosanedioyl-yGlu-yGlu-OEG-OEG-AeTyr-D-Ala-Gln-7MeTrp-Ala-Val-β-Ala-His-Phe- Nle-NH2(SEQ ID NO 66);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Dap(5CTMPA)-Gln-7MeTrp-Ala-Thr-β-Ala-His- Phe-Nle-NH2(SEQ ID NO 67);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Dap(2CE-PEG-TMEA)-Gln-7MeTrp-Ala-Thr-β-Ala-His-Leu-Nle-NH2(SEQ ID NO 68);Eicosanedioyl-yGlu-yGlu-OEG-OEG-HypOaa-D-Ala-Gln-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 69);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-HypOaa-Ala-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 70);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-hGlu-Aib-7MeTrp-Ala-Val-β-Ala-His-Leu-Nle- NH2(SEQ ID NO 71);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Glu-Aib-7MeTrp-Ala-Val-β-Ala-NMeHis-Leu- Nle-NH2(SEQ ID NO 72);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Glu-ThpGly-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 73);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Sar-Glu-ThpGly-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 74);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Ser-Glu-ThpGly-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 75);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Glu-ThpGly-7MeTrp-Ala-HOV-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 76);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-GalactarylLys-Aib-7MeTrp-Ala-Val-|3-Ala-His- Leu-Nle-NH2(SEQ ID NO 77);Eicosanedioyl-yGlu-yGlu-OEG-OEG-GalactarylLys-Ala-Gln-7MeTrp-Ala-Val-β-Ala-His- Leu-Nle-NH2(SEQ ID NO 78);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Cit-Ala-Gln-7MeTrp-Ala-Val-β-Ala-His-Leu-Nle- NH2(SEQ ID NO 79);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Sar-Glu-Aib-7MeTrp-Ala-Val-β-Ala-NMeHis-Leu- Nle-NH2(SEQ ID NO 80);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Hyp-Glu-Aib-7MeTrp-Ala-Val-β-Ala-NMeHis-Leu- Nle-NH2(SEQ ID NO 81); andEicosanedioyl-yGlu-yGlu-OEG-OEG-Hyp-Glu-ThpGly-7MeTrp-Ala-Val-β-Ala-NMeHis- Leu-Nle-NH2(SEQ ID NO 82),or a pharmaceutically acceptable salt, solvate, or isomer thereof.

[0264] Embodiment 67. A peptide selected from:Eicosanedioyl-yGlu-yGlu-OEG-OEG-Glu-D-Ser-Glu-Ala-7MeTrp-Ala-Val-β-Ala-His-Ala- Nle-NH2(SEQ ID NO 36);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Glu-D-Ser-Glu-Ala-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 37);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Glu-D-Ser-Glu-Ala-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 38);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Glu-D-Ser-Glu-His-7MeTrp-Ala-Ala-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 39); orEicosanedioyl-yGlu-yGlu-OEG-OEG-Glu-D-Ser-Glu-His-7MeTrp-Ala-Val-β-Ala-His-Ala- Nle-NH2(SEQ ID NO 40); or apharmaceutically acceptable salt, solvate, or isomer thereof.

[0265] Embodiment 68. A pharmaceutical composition comprising:the peptide of any one of embodiments 1-67, or a pharmaceutically acceptable salt or solvate thereof, anda pharmaceutically acceptable carrier, diluent, or excipient.

[0266] Embodiment 69. The pharmaceutical composition of embodiment 68, wherein the pharmaceutical composition further comprises an absorption enhancer.

[0267] Embodiment 70. The pharmaceutical composition of embodiment 69, wherein the absorption enhancer is for use in an oral formulation.

[0268] Embodiment 71. The pharmaceutical composition of any one of embodiments 69-70, wherein the absorption enhancer is selected from the group consisting of sodium caprate, sodium caprylate, labrasol, and sodium N-(8-[2-hydroxylbenzoyl] amino)caprylate.

[0269] Embodiment 72. Use of the peptide of any one of embodiments 1-67, or a pharmaceutically acceptable salt, solvate, or isomer thereof, or the pharmaceutical composition of any one of embodiments 68-71, for the preparation of a medicament for the treatment of a disorder.

[0270] Embodiment 73. The use of embodiment 72, wherein the disorder is a gastrointestinal disease.

[0271] Embodiment 74. The use of embodiment 72, wherein the disorder is obesity.

[0272] Embodiment 75. A method for weight management in a subject in need thereof, the method comprising: administering a therapeutically effective amount of a peptide of any one of embodiments 1-67, or the pharmaceutical composition of any one of embodiments 68-71.

[0273] Embodiment 76. A method for reducing body weight of a subject in need thereof, the method comprising: administering a therapeutically effective amount of a peptide of any one of embodiments 1-67, or the pharmaceutical composition of any one of embodiments 68-71.

[0274] Embodiment 77. A method for treating obesity in a subject in need thereof, the method comprising: administering a therapeutically effective amount of a peptide of any one of embodiments 1-67, or the pharmaceutical composition of any one of embodiments 68-71.

[0275] Embodiment 78. The method of any one of embodiments 75-77, wherein the administering occurs weekly.

[0276] Embodiment 79. The method of any one of embodiments 75-77, wherein the administering occurs every 7-14 days, every two weeks, every three weeks, or every four weeks.

[0277] Embodiment 80. The method of any one of embodiments 75-77, wherein the administering occurs semimonthly or monthly.

[0278] Embodiment 81. The method of any one of embodiments 75-77, wherein the administering occurs monthly.

[0279] Embodiment 82. The method of any one of embodiments 75-81, wherein the subject is a human.

[0280] Embodiment 83. The method of any one of embodiments 75-82, wherein the subject is overweight.

[0281] Embodiment 84. The method of any one of embodiments 75-83, wherein the subject is obese.

[0282] Embodiment 85. The method of any one of embodiments 75-84, wherein the subject has at least one weight-related comorbid condition selected from the group consisting of: hypertension, type 2 diabetes mellitus, dyslipidemia, metabolic-associated steatohepatitis, sleep apnea, and urinary incontinence.

[0283] Embodiment 86. The method of any one of embodiments 75-85, wherein the subject has received at least one previous treatment of a weight management therapy.

[0284] Embodiment 87. The method of any one of embodiments 75-86, wherein administering the peptide reduces a body weight of the subject by at least 5% compared to a body weight of an otherwise identical subject not administered the peptide.

[0285] Embodiment 88. The method of any one of embodiments 75-87, wherein the peptide is administered intravenously.

[0286] Embodiment 89. The method of any one of embodiments 75-87, wherein the peptide is administered subcutaneously.

[0287] Embodiment 90. The method of any one of embodiments 75-87, wherein the peptide is administered orally.

[0288] Embodiment 91. The method of embodiment 90, further comprising administering with an absorption enhancer.

[0289] Embodiment 92. The method of embodiment 91, wherein the absorption enhancer is for use in an oral formulation.

[0290] Embodiment 93. The method of embodiment 90, wherein: the absorption enhancer is selected from the group consisting of: sodium caprate, sodium caprylate, labrasol, and sodium N-(8-[2 -hydroxylbenzoyl] amino) caprylate.

[0291] Embodiment 94. The method of any one of embodiments 75-93, further comprising administering a therapeutically effective amount of another weight loss agent.EXAMPLES

[0292] The following examples are provided to further illustrate some embodiments of the present disclosure but are not intended to limit the scope of the disclosure.

[0293] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

[0294] AbbreviationsACN or MeCN or CH3CN: acetonitrile;AC2O: acetic anhydride;AEEA: 8-amino-3,6-dioxaoctanoic acidbrine: saturated aqueous NaCl solution;DCM: dichloromethane;Dde: l-(4,4-dimethyl-2,6-dioxocyclohex-l-ylidene)ethylDIEA or DIPEA: N, N-diisopropylethylamine;DMF: dimethylformamide;DMSO: dimethyl sulfoxide;EtOAc or EA: ethyl acetate;Fmoc: fluorenylmethoxycarbonyl;HATU: l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;HC1: hydrochloric acid or hydrochloride;Hex: hexanes;H2O: water;HBTU: N, N, N', N'-tetramethyl-O-(lH-benzotriazol-l-yl)uronium hexafluorophosphate;HPLC: high-performance liquid chromatography;H2O: waterivDde: 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl; LCMS: liquid chromatography-mass spectrometry;MBHA resin: methylbenzhydryl amine resin;MeOH: methanol;3 -MPA: 3 -mercaptopropionic acid;MS: mass spectrometry;MTBE: methyl tert-butyl ether;NMP: N-methyl-2-pyrrolidone;N2: nitrogen;OEG: -NH-PEG-PEG-CH2C(=O)-;PBS: phosphate-buffered saline;PE: petroleum ether;PEG: -CH2CH2O-;Prep-HPLC: preparative high-performance liquid chromatography; RP-HPLC: reversed-phase high-performance liquid chromatography; SPPS: solid-phase peptide synthesis;TFA: trifluoroacetic acid;TFP: tetrafluorophenyl;THF: tetrahydrofuran;Tis: triisopropylsilane;t-Bu: tert-butyl;TSTU: 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate; rt: room temperature;min: minute;h or hr: hour;mg: milligrams; kg: kilograms;mL or ml: milliliter;eq: equivalents;mol: mole;mmol: millimole;UV: ultraviolet;v / v: volume / volume.Example 1: Synthesis of Peptide 23 (SEQ ID NO. 23)

[0295] Sequence: Eicosanedioyl -yGlu-yGlu-OEG-OEG-Gly-Ala-Asn-7MeTrp-Ala-Ile-P-Ala-His-Cpa-Nle-NH2(SEQ ID NO. 23)

[0296] Peptide 23 was synthesized by standard solid-phase peptide synthesis (SPPS). The assembly was performed on a Rink-amide MBHA resin (100-200Mesh, loading 0.8 mmol / g) in a peptide solid phase synthesis vessel. The constructed peptide was isolated from the resin and protecting groups removed by cleavage with strong acid followed by precipitation. Peptide purification was performed prep-HPLC. Lyophilization of pure fractions gave the final product.

[0297] Swell Resin: 125 mg of Rink-amide MBHA solid phase resin (0.8 mmol / g loading) was transferred to a 7-mL reaction vessel and placed on the TETRAS™ multiple channel synthesizer. The resin was swelled with 4 mL of DMF (1 x 30 min).

[0298] Step 1: Coupling of Fmoc-Nle-OH: To the reaction vessel was added piperidine (3 mL, 20% purity in DMF). The mixture was shaken for 10 min, and then the solution was drained.The process was repeated once. The resin (filter cake) was washed with DMF (3 mL x 6). To the reaction vessel was added the Fmoc-Nle-OH (0.2M in DMF, 2 mL, 4.00 equiv.), then Oxyma pure (0.4M in DMF, 1 mL, 4.00 equiv.) and DIC (0.4M in DMF, 1 mL, 4.00 equiv.).The mixture was shaken at 25 °C for 60 min. The mixture was drained and washed with DMF (3 mL x 3) prior to starting the next deprotection or coupling cycle.

[0299] Steps 2~15: Step 1 was repeated sequentially using the acid derivatives and coupling reagents in Table D.

[0300] Table D: Amino acid derivatives and coupling reagents used in SPPS.

[0301] Step 16: TFA Cleavage and Ether precipitation: After coupling of the last amino acid, the resin was washed with DMF (3 mL x 5), DCM (3 mL x 5) and MeOH (3 mL x 5), then dried to give eicosanedioyl(OtBu)-yGlu(OtBu)-yGlu(OtBu)-OEG-OEG-Gly-Ala-Asn(Trt)-7MeTrp-Ala-Ile-P-Ala-His(Trt)-Cpa-Nle-NH2-resin(450 mg) (SEQ ID NO: 183). A fresh solution of Tips (0.125 mL), DODT (0.125 mL) and water (0.125 mL) in TFA (4.625 mL) (TFA / Tips / DODT / water v / v / v / v / v, 92.5% / 2.5% / 2.5% / 2.5%, 5 mL, 10 mL / g) was stirred at 0 °C for 15 min, and then the fully protected peptide-bound resin was added to the mixture at 0 °C. The resulting mixture was shaken at 25 °C for 2 hrs. The reaction mixture was filtered, and the filtrate was added to cold MTBE (25 mL) to form a white precipitate. The white precipitate was filtered to give the crude peptide. The crude peptide was purified by prep-HPLC (column: SP-100-8ODS-P C18 250 × 50 × 8 um; mobile phase: [A: water (0.1% TFA), B: ACN]; B%: 40% -60%, 40 min) to give Peptide 23 (SEQ ID NO. 23) as a white solid. LCMS: (ES+) m / z (M+H)+= 1950.1; (M / 2+H)+= 975.6.

[0302] The peptides below were prepared in a similar manner to Peptide 23.

[0303] Example A-l: In Vitro Testing of Peptides for IP1 GRPR Activity

[0304] U2OS cells stably expressing human GRP receptors (DiscoverX, #93-0229C3) were cultured according to manufacturer’s instructions. Cells were cultured to 85% confluency, then collected using AccuTase (Innovative Cell Technologies, #AT104). Cells were washed and plated on a poly-d-lysine-coated 384-well plate (ThermoFisher, #A3890401) at a density of 2,500 cells / well in 15 mL assay buffer (AssayComplete Cell Plating 5 Reagent, DiscoverX # 93-0563R5), then incubated overnight at 37 °C and 5% CO2.

[0305] The following morning, a homogenous time-resolved fluorescence (HTRF) assay was performed in a 384-well plate format using the IPl-Gq assay kit (Cisbio, 62IPAPEB). Test compounds were made as a stock in DMSO, then serially diluted to generate 10-point dose response curves in IP1 stimulation buffer. Five microliters of the prepared compounds were then added to the plate containing cells and assay buffer in duplicate, and the cells were incubated at 37 °C and 5% CO2 for 90 minutes. Following compound incubation, 8 mL of IP1 lysis / detection buffer (prepared according to manufacturer’s instructions) was added to each well, and the plates were incubated at room temperature for 1 hour.

[0306] HTRF signals were measured using a plate reader (ClarioSTAR), calculating the ratio between emissions at 665 nm and 620 nm (HTRF ratio). HTRF ratio for positive (Max, 1 pM GRP; SEQ ID NO. 99) and negative (Min, DMSO) controls were used to normalize HTRF data and generate values for % activity. EC50and Max activity values were determined using a standard 4-parameter fit using GraphPad Prism.

[0307] Table A-l: IP1 GRPR Activity Data

[0308] GRP is SEQ ID NO. 99.Example A-2: In Vivo Testing of Peptides

[0309] Male C57BL / 6J mice, approximately 10 weeks old (Jackson Laboratory), will be group housed in a 12-h light cycle room (6:00 AM on, 6:00 PM off) upon arrival and will be acclimated to the facility for a minimum of 1 week prior to the study. Animals will be provided standard rodent chow (PicoLab Rodent Diet, 5053) ad libitum. Animals will be single caged for a minimum of 3 days prior to the study. During the period prior to the study day, mice will be exposed to one pellet of high fat diet (Research Diets D12492i) to avoid any effects of novelty in the study. On three separate days during this run-in period, mice will be given one dose of phosphate-buffered saline (PBS; 5 mL / kg) by subcutaneous injection to acclimate them to the procedure. For baseline measures, pre-weighed meals of standard rodent chow will be provided to each animal following acclimation dosing in the afternoon, and body weight will be recorded. The next morning, food intake and body weight measurements will be recorded at 16 hours following the presentation of the pre-weighed meal. These measurements and the resulting body weight changes will then be used to assign mice to balanced cohorts.

[0310] On the day of the study, mice will be weighed and given a subcutaneous dose of either vehicle (e.g., PBS, 5 mL / kg; pH 5.0-8.5) or a peptide of the disclosure (e.g., 500 nmol / kg; pH 5.0-8.5). Following dosing, a pre-weighed high fat diet will be provided. Food intake and body weight measurements will be taken at 16 hours following the provision of the pre-weighed high fat diet.

[0311] Mice administered a peptide of the disclosure may demonstrate a reduction in food intake compared to the amount consumed by mice administered vehicle and may also show a reduction in body weight relative to mice administered vehicle.Example A-3. Pharmacokinetics After Intravenous Peptide Administration

[0312] The pharmacokinetics for peptides of the disclosure can be determined in C57BL / 6 mice. GPR-10 and peptides can be dosed IV at, e.g., 2 mg / kg as a formulation of, e.g., 0.4 mg / mL in 5% DMSO + 30% PEG400+ 65% water (pH 6-7). Following IV administration, lipid-conjugated peptides of the disclosure may have a significantly longer half-life (T1 / 2) and reduced clearance (CL) relative to GRP 10 and a non-lipidated peptide control.Example A-4: Solubility in Buffer

[0313] Solubility can be measured in an appropriate buffer as follows. A known amount of compound, e.g., 20 mg, will be placed in a vessel equipped with a stirring bar. A measured amount of buffer (e.g., 200 - 400 pL of 200 mM phosphate buffer) will be added, and in some cases, additional surfactants, e.g., polysorbate 80 (PS80), polyethylene glycol (15)-hydroxystearate (Solutol® HS15), etc., can be added. A measured amount of purified water (e.g., 1.6 mL) will be added, and the pH will be adjusted to the desired pH, e.g., pH 8, by addition of 0.5 N aqueous NaOH or 0.5 N aqueous HC1. The volume of added acid or base will be recorded. The mixture will be stirred at 300 rpm for 10 min. Additional purified water will be added to reach a given volume, e.g., 4 mL, of solution. After stirring the sample at 300 rpm at room temperature for 1 h or 24 h, the appearance will be observed and the pH will be measured. A portion of the sample will be taken to filter or centrifuge for testing the 1- or 24-hour solubility by HPLC. Following this procedure, the solubility of a peptide disclosed herein in 20 mM pH 8.0 phosphate buffer with 0.3% PS80 + 10% HS15 will be measured.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A peptide comprising the amino acid sequence of Formula (I):X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nleor a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XO is absent or a natural or non-natural amino acid or amino acid analog;XI, X2, X3, X5, X6, X8, and X9 are each independently a natural or non-natural amino acid or amino acid analog;X3 is not Leu; andwhen XO is a natural or non-natural amino acid or amino acid analog, X2 is not Leu;7MeTrp is 7-methyltryptophan;Nle is norleucine; andwherein the peptide is conjugated to one or more lipid moieties.

2. A peptide comprising the amino acid sequence of Formula (II):X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nleor a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XO is absent or a natural or non-natural amino acid or amino acid analog;XI, X2, X3, X5, X6, X8, and X9 are each independently a natural or non-natural amino acid or amino acid analog;X6 is not Thr; andwhen XO is a natural or non-natural amino acid or amino acid analog, X5 is not Thr;7MeTrp is 7-methyltryptophan;Nle is norleucine; andwherein the peptide is conjugated to one or more lipid moieties.

3. A peptide comprising the amino acid sequence of Formula (III):X0-Xl-X2-X3-7MeTrp-X5-X6-P-Ala-X8-X9-Nleor a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XO is absent or a natural or non-natural amino acid or amino acid analog;X1, X2, X3, X5, X6, X8, and X9 are each independently a natural or non-natural amino acid or amino acid analog;X9 is not Phe; andwhen X0 is a natural or non-natural amino acid or amino acid analog, X8 is not Phe;7MeTrp is 7-methyltryptophan;Nle is norleucine; andwherein the peptide is conjugated to one or more lipid moieties.

4. The peptide of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XO is absent, Glu, Ser, Arg, or Gly.

5. The peptide of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XO is absent.

6. The peptide of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XO is Glu.

7. The peptide of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XI is Glu, Gly, D-Ser, Pro, a-MePro, Hyp, P-MePhe, AeTyr, HypOaa, Ser, GalactarylLys, Cit, or Sar.

8. The peptide of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XI is Glu, Gly, or D-Ser.

9. The peptide of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X2 is Glu, Asn, Ala, Trp, D-Ser, D-Phe, D-Ala, Gln, AeTyr, Gly, Dap(5CTMPA), Dap(2CE-PEG-TMEA), HypOaa, hGlu, or GalactarylLys.

10. The peptide of any one of claims 2-9, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X3 is Ala, His, Gln, Asn, Phe, Lys, Arg, Glu, Ser, Tyr, Aib, DAP, Leu, Val, ThpGly, or Cpg.

11. The peptide of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X3 is Ala, His, Gln, Asn, Phe, Lys, Arg, Glu, Ser, Tyr, Aib, DAP, Val, ThpGly, or Cpg.

12. The peptide of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X5 is Ala.

13. The peptide of any one of claims 1 or 3-12, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X6 is Vai, Ala, Ser, He, Leu, Thr, HOV, Abu, 3AP, AMBA, Tie, Cbg, Cpg, or Hva.

14. The peptide of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X6 is Val, Ala, Ser, Ile, Leu, HOV, Abu, 3AP, AMBA, Tle, Cbg, Cpg, or Hva.

15. The peptide of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X6 is Val.

16. The peptide of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X8 is His or NMeHis.

17. The peptide of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X8 is His.

18. The peptide of any one of claim 1 or claim 2, or any one of claims 4-17, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X9 is Ala, Leu, Tyr, Thr, Val, Ile, Phe, Aib, Cpa, Tle, Tba, Cbg, Fle, or β-MePhe.

19. The peptide of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X9 is Ala, Leu, Tyr, Thr, Val, Ile, Aib, Cpa, Tle, Tba, Cbg, Fle, or β-MePhe.

20. The peptide of any one of claim 1 or claim 2, or any one of claims 4-17, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X9 is Leu or Phe.

21. The peptide of claim 1, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X0 is absent or Glu;XI is Glu, Gly, D-Ser, Pro, a-MePro, Hyp, P-MePhe, AeTyr, HypOaa, Ser, GalactarylLys, Cit, or Sar;X2 is D-Ser, Asn, D-Phe, D-Ala, Ala, Trp, Glu, Gin, AeTyr, Gly, Dap(5CTMPA), Dap(2CE- PEG-TMEA), HypOaa, hGlu, or GalactarylLys;X3 is Glu, Aib, Phe, Arg, Lys, His, Gin, Asn, Aib, Ala, Vai, ThpGly, or Cpg;X5 is Ala;X6 is Ala, Vai, Ser, Abu, Tie, 3AP, AMBA, Tie, Cpg, Cbg, lie, HOV, or Thr;X8 is His or NMeHis; andX9 is Leu, Aib, Thr, Vai, He, Tie, Leu, Cpa, Tyr, Phe, Ala, Cbg, Fie, or P-MePhe.

22. The peptide of claim 2, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XO is absent or Glu;XI is Glu, Gly, D-Ser, Pro, a-MePro, Hyp, P-MePhe, AeTyr, HypOaa, Ser, GalactarylLys, Cit, or Sar;X2 is D-Ser, Asn, D-Phe, D-Ala, Ala, Trp, Glu, Gin, AeTyr, Gly, HypOaa, hGlu, or GalactarylLys;X3 is Glu, Aib, Phe, Arg, Lys, His, Gin, Asn, Aib, Ala, Leu, Vai, ThpGly, or Cpg;X5 is Ala;X6 is Ala, Vai, Ser, Abu, Tie, 3 AP, AMBA, Tie, Cpg, Cbg, He, or HOV;X8 is His or NMeHis; andX9 is Leu, Aib, Thr, Vai, lie, Tie, Leu, Cpa, Tyr, Phe, Ala, Cbg, Fie, or P-MePhe.

23. The peptide of claim 3, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:XO is absent or Glu;XI is Glu, Gly, D-Ser, Pro, a-MePro, Hyp, P-MePhe, AeTyr, HypOaa, Ser, GalactarylLys, Cit, or Sar;X2 is D-Ser, Asn, D-Phe, D-Ala, Ala, Trp, Glu, Gin, AeTyr, Gly, Dap(2CE-PEG-TMEA), HypOaa, hGlu, or GalactarylLys;X3 is Glu, Aib, Phe, Arg, Lys, His, Gin, Asn, Aib, Ala, Leu, Vai, ThpGly, or Cpg;X5 is Ala;X6 is Ala, Vai, Ser, Abu, Tie, 3 AP, AMBA, Tie, Cpg, Cbg, lie, HOV, or Thr;X8 is His or NMeHis;X9 is Leu, Aib, Thr, Vai, He, Tie, Leu, Cpa, Tyr, Ala, Cbg, Fie, or P-MePhe.

24. The peptide of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:X5 is Ala; andX8 is His or NMeHis.

25. The peptide of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein the peptide is: X1-X2-X3-7MeTrp-Ala-X6-β-Ala-His-X9-Nle (SEQ ID NO: 184).

26. The peptide of claim 1, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:when XO is natural or non-natural amino acid or amino acid analog, X2 is Ala, Asn, Glu, Trp, D-Ser, D-Phe, or D-Ala.

27. The peptide of claim 2, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:when XO is natural or non-natural amino acid or amino acid analog, X5 is Ala.

28. The peptide of claim 3, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:when XO is natural or non-natural amino acid or amino acid analog, X8 is His.

29. The peptide of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or isomer thereof, whereinthe one or more lipid moieties are conjugated to the N-terminus of the peptide.

30. The peptide of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the one or more lipid moieties are conjugated to the C-terminus of the peptide.

31. The peptide of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the one or more lipid moieties are conjugated to the C-terminus of the peptide and the N- terminus of the peptide is substituted with an acetyl group.

32. The peptide of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the one or more lipid moieties are conjugated to an amino acid residue of the peptide.

33. The peptide of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the one or more lipid moieties are conjugated to a lysine residue of the peptide.

34. The peptide of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the lipid moiety comprises a C2-C26 fatty acyl group.

35. The peptide of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the lipid moiety comprises a C18-C26 fatty acyl group.

36. The peptide of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the lipid moiety comprises -(L^p-lL^q-lL3^, wherein:each L1is independently -((CH2)vNR1)w-CO(CH2)xO(PEG)y(CH2)zNR1-;PEG is -CH2CH2O-; V is 2-6; w is 0-1; x is 1-4; y is 1-4; z is 2-24; R1is H or -CH3; each L2is independently a natural or unnatural amino acid or amino acid analog; each L3is independently a substituted or unsubstituted C2-C26 fatty acyl group;p is 0-8;q is 0-6; andr is 1 or 2.

37. The peptide of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the lipid moiety comprises -(L^p-lL^q-lL3^, wherein:each L1is -CO(CH2)O(PEG)(CH2)2NH-;PEG is -CH2CH2O-;each L2is Glu or y-Glu;each L3is independently a substituted or unsubstituted Ci2-C24 fatty acyl group;p is 0-4;q is 0-4; andr is 1 or 2.

38. The peptide of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the lipid moiety comprises -(OEG)p-(Y-Glu)q-(L3)r, wherein:OEGis -NH-PEG-PEG-CH2C(=O)-;PEG is -CH2CH2O-;p is 1, 2, 3, or 4;q is 1, 2, 3, or 4; andr is 1.

39. The peptide of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein -(Eicosanedioyl -yGlu-yGlu-OEG-OEG-).

40. The peptide of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the peptide comprises an amino acid sequence comprising at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one of SEQ ID NOs 101-182.

41. The peptide of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the peptide comprises an amino acid sequence of any one of SEQ ID NOs 101-182.

42. The peptide of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the peptide comprises an amino acid sequence comprising at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any one of SEQ ID NOs 1-82.

43. The peptide of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the peptide comprises an amino acid sequence of any one of SEQ ID NOs 1-82.

44. The peptide of any one of claims 40 or 42, or a pharmaceutically acceptable salt, solvate, or isomer thereof, wherein:the sequence identity is determined by a BLASTP, CLUSTALW, MUSCLE, MAFFT algorithm, or a CLUSTALW algorithm with the Smith -Waterman homology search algorithm parameters.

45. A peptide selected from:Eicosanedioyl-yGlu-yGlu-OEG-OEG-Glu-D-Ser-Glu-7MeTrp-Ala-Ala-P-Ala-His-Leu-Nle- NH2(SEQ IDNO 1);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Aib-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 2);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Phe-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 3);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Arg-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 4);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Lys-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 5);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Glu-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 6);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Ser-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 7);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Abu-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 8);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Tle-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 9);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-3AP-P-Ala-His-Leu-Nle- NH2(SEQ IDNO 10);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-AMBA-P-Ala-His-Leu- Nle-NH2(SEQ ID NO 11);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Val-P-Ala-His-Aib-Nle- NH2(SEQ IDNO 12);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Val-P-Ala-His-Thr-Nle- NH2(SEQ IDNO 13);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Val-P-Ala-His-Val-Nle- NH2(SEQ IDNO 14);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Val-P-Ala-His-Ile-Nle-NH2(SEQ ID NO 15);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-Val-P-Ala-His-Tle-Nle- NH2(SEQ IDNO 16);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Gln-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ IDNO 17);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Phe-Gln-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 18);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Gln-7MeTrp-Ala-Ala-P-Ala-His-Leu-Nle- NH2(SEQ IDNO 19);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Gln-7MeTrp-Ala-Ala-P-Ala-His-Ile-Nle- NH2(SEQ ID NO 20);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Gln-7MeTrp-Ala-Tle-P-Ala-His-Thr-Nle- NH2(SEQ ID NO 21);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Phe-7MeTrp-Ala-Cpg-P-Ala-His-Ile-Nle- NH2(SEQ ID NO 22);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Ala-Asn-7MeTrp-Ala-Ile-P-Ala-His-Cpa-Nle- NH2(SEQ ID NO 23);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Ala-Gln-7MeTrp-Ala-Cbg-P-Ala-His-Tyr-Nle- NH2(SEQ ID NO 24);Eicosanedi oyl-(yEyE)OEG-OEG-Gly-D-Phe-Gln-7MeTrp-Ala-Val-P-Ala-His-Ile-Nle-NH2(SEQ ID NO 25);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Phe-Gln-7MeTrp-Ala-Ile-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 26);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-His-7MeTrp-Ala-HOV-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 27);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Gln-7MeTrp-Ala-HOV-P-Ala-His-Phe- Nle-NH2(SEQ ID NO 28);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Gln-7MeTrp-Ala-Val-P-Ala-His-Phe-Nle- NH2(SEQ ID NO 29);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Gln-7MeTrp-Ala-Thr-P-Ala-His-Ile-Nle- NH2(SEQ ID NO 30);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Trp-Gln-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 31);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Trp-Gln-7MeTrp-Ala-Val-P-Ala-His-Phe-Nle- NH2(SEQ ID NO 32);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Aib-7MeTrp-Ala-Ile-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 33);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Phe-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 34);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Aib-7MeTrp-Ala-Thr-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 35);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-His-7MeTrp-Ala-Thr-P-Ala-His-Phe-Nle- NH2(SEQ ID NO 41);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-His-7MeTrp-Ala-Ile-P-Ala-His-Phe-Nle-NH2(SEQ ID NO 42);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-His-7MeTrp-Ala-Thr-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 43);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Ala-Asn-7MeTrp-Ala-Val-P-Ala-His-Cbg-Nle- NH2(SEQ ID NO 44);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-His-7MeTrp-Ala-Val-P-Ala-His-Cbg-Nle- NH2(SEQ ID NO 45);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Leu-7MeTrp-Ala-Ile-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 46);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Leu-7MeTrp-Ala-Ile-P-Ala-His-Val-Nle- NH2(SEQ ID NO 47);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Leu-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 48);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-Leu-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 49);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-Val-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 50);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-Val-7MeTrp-Ala-Val-P-Ala-His-Phe-Nle- NH2(SEQ IDNO 51);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-Leu-7MeTrp-Ala-Val-P-Ala-His-Phe-Nle- NH2(SEQ ID NO 52);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Ala-Asn-7MeTrp-Ala-Val-P-Ala-His-Fle-Nle- NH2(SEQ ID NO 53);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Gln-His-7MeTrp-Ala-Val-P-Ala-His-Fle-Nle- NH2(SEQ ID NO 54);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-ThpGly-7MeTrp-Ala-Val-P-Ala-His-Leu- Nle-NH2(SEQ ID NO 55);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-AeTyr-His-7MeTrp-Ala-Val-P-Ala-His-Leu-Nle- NH2(SEQ ID NO 56);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Pro-Gly-His-7MeTrp-Ala-Val-β-Ala-His-Leu-Nle- NH2(SEQ ID NO 57);Eicosanedioyl-yGlu-yGlu-OEG-OEG-α-MePro-Gly-His-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 58);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Hyp-Gly-His-7MeTrp-Ala-Val-β-Ala-His-Leu-Nle- NH2(SEQ ID NO 59);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Cpg-7MeTrp-Ala-Val-β-Ala-His-Leu-Nle- NH2(SEQ ID NO 60);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Asn-Cpg-7MeTrp-Ala-Val-β-Ala-His-Leu-Nle- NH2(SEQ ID NO 61);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Gln-7MeTrp-Ala-Val-β-Ala-His-β-MePhe- Nle-NH2(SEQ ID NO 62);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-D-Ala-Gln-7MeTrp-Ala-Thr-β-Ala-His-β-MePhe- Nle-NH2(SEQ ID NO 63);Eicosanedioyl-yGlu-yGlu-OEG-OEG-β-MePhe-Asn-His-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 64);Eicosanedioyl-yGlu-yGlu-OEG-OEG-AeTyr-D-Ala-Gln-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 65);Eicosanedioyl-yGlu-yGlu-OEG-OEG-AeTyr-D-Ala-Gln-7MeTrp-Ala-Val-β-Ala-His-Phe- Nle-NH2(SEQ ID NO 66);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Dap(5CTMPA)-Gln-7MeTrp-Ala-Thr-β-Ala-His- Phe-Nle-NH2(SEQ ID NO 67);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Dap(2CE-PEG-TMEA)-Gln-7MeTrp-Ala-Thr-β-Ala-His-Leu-Nle-NH2(SEQ ID NO 68);Eicosanedioyl-yGlu-yGlu-OEG-OEG-HypOaa-D-Ala-Gln-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 69);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-HypOaa-Ala-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 70);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-hGlu-Aib-7MeTrp-Ala-Val-β-Ala-His-Leu-Nle- NH2(SEQ ID NO 71);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Glu-Aib-7MeTrp-Ala-Val-β-Ala-NMeHis-Leu- Nle-NH2(SEQ ID NO 72);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Glu-ThpGly-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 73);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Sar-Glu-ThpGly-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 74);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Ser-Glu-ThpGly-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 75);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-Glu-ThpGly-7MeTrp-Ala-HOV-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 76);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Gly-GalactarylLys-Aib-7MeTrp-Ala-Val-β-Ala-His- Leu-Nle-NH2(SEQ ID NO 77);Eicosanedioyl-yGlu-yGlu-OEG-OEG-GalactarylLys-Ala-Gln-7MeTrp-Ala-Val-β-Ala-His- Leu-Nle-NH2(SEQ ID NO 78);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Cit-Ala-Gln-7MeTrp-Ala-Val-β-Ala-His-Leu-Nle- NH2(SEQ ID NO 79);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Sar-Glu-Aib-7MeTrp-Ala-Val-β-Ala-NMeHis-Leu- Nle-NH2(SEQ ID NO 80);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Hyp-Glu-Aib-7MeTrp-Ala-Val-β-Ala-NMeHis-Leu- Nle-NH2(SEQ ID NO 81); andEicosanedioyl-yGlu-yGlu-OEG-OEG-Hyp-Glu-ThpGly-7MeTrp-Ala-Val-β-Ala-NMeHis- Leu-Nle-NH2(SEQ ID NO 82),or a pharmaceutically acceptable salt, solvate, or isomer thereof.

46. A peptide selected from:Eicosanedioyl-yGlu-yGlu-OEG-OEG-Glu-D-Ser-Glu-Ala-7MeTrp-Ala-Val-β-Ala-His-Ala- Nle-NH2(SEQ ID NO 36);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Glu-D-Ser-Glu-Ala-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 37);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Glu-D-Ser-Glu-Ala-7MeTrp-Ala-Val-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 38);Eicosanedioyl-yGlu-yGlu-OEG-OEG-Glu-D-Ser-Glu-His-7MeTrp-Ala-Ala-β-Ala-His-Leu- Nle-NH2(SEQ ID NO 39); orEicosanedioyl-yGlu-yGlu-OEG-OEG-Glu-D-Ser-Glu-His-7MeTrp-Ala-Val-β-Ala-His-Ala- Nle-NH2(SEQ ID NO 40); or apharmaceutically acceptable salt, solvate, or isomer thereof.

47. A pharmaceutical composition comprising:the peptide of any one of claims 1-46, or a pharmaceutically acceptable salt or solvate thereof, anda pharmaceutically acceptable carrier, diluent, or excipient.

48. The pharmaceutical composition of claim 47, wherein the pharmaceutical composition further comprises an absorption enhancer.

49. The pharmaceutical composition of claim 47, wherein the absorption enhancer is for use in an oral formulation.

50. The pharmaceutical composition of any one of claims 48-49, wherein:the absorption enhancer is selected from the group consisting of sodium caprate, sodium caprylate, labrasol, and sodium N-(8-[2-hydroxylbenzoyl] amino)caprylate.

51. Use of the peptide of any one of claims 1-47, or a pharmaceutically acceptable salt, solvate, or isomer thereof, or the pharmaceutical composition of any one of claims 48-50, for the preparation of a medicament for the treatment of a disorder.

52. The use of claim 51, wherein the disorder is a gastrointestinal disease.

53. The use of claim 51, wherein the disorder is obesity.

54. A method for weight management in a subject in need thereof, the method comprising: administering a therapeutically effective amount of a peptide of any one of claims 1-47, or the pharmaceutical composition of any one of claims 48-50.

55. A method for reducing body weight of a subject in need thereof, the method comprising:administering a therapeutically effective amount of a peptide of any one of claims 1-47, or the pharmaceutical composition of any one of claims 48-50.

56. A method for treating obesity in a subject in need thereof, the method comprising:administering a therapeutically effective amount of a peptide of any one of claims 1-47, or the pharmaceutical composition of any one of claims 48-50.

57. The method of any one of claims 54-56, wherein the administering occurs weekly.

58. The method of any one of claims 54-56, wherein the administering occurs every 7-14 days, every two weeks, every three weeks, or every four weeks.

59. The method of any one of claims 54-56, wherein the administering occurs semimonthly or monthly.

60. The method of any one of claims 54-56, wherein the administering occurs monthly.

61. The method of any one of claims 54-60, wherein the subject is a human.

62. The method of any one of claims 54-61, wherein the subject is overweight.

63. The method of any one of claims 54-62, wherein the subject is obese.

64. The method of any one of claims 54-63, wherein the subject has at least one weight-related comorbid condition selected from the group consisting of: hypertension, type 2 diabetes mellitus, dyslipidemia, metabolic-associated steatohepatitis, sleep apnea, and urinary incontinence.

65. The method of any one of claims 54-64, wherein the subject has received at least one previous treatment of a weight management therapy.

66. The method of any one of claims 54-65, wherein administering the peptide reduces a body weight of the subject by at least 5% compared to a body weight of an otherwise identical subject not administered the peptide.

67. The method of any one of claims 54-66, wherein the peptide is administered intravenously.

68. The method of any one of claims 54-66, wherein the peptide is administered subcutaneously.

69. The method of any one of claims 54-66, wherein the peptide is administered orally.

70. The method of claim 69, further comprising administering with an absorption enhancer.

71. The method of claim 70, wherein the absorption enhancer is for use in an oral formulation.

72. The method of claim 70, wherein: the absorption enhancer is selected from the group consisting of: sodium caprate, sodium caprylate, labrasol, and sodium N-(8-[2- hydroxylbenzoyl] amino) caprylate.

73. The method of any one of claims 54-72, further comprising administering a therapeutically effective amount of another weight loss agent.

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