Dual GIP / GLP-1 peptide conjugates and methods of use

Abstract

Provided herein are peptides and peptide conjugates comprising a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist. The peptides may be used for blood glucose management and treating conditions such as diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

Description

DUAL GIP / GLP-1 PEPTIDE CONJUGATES AND METHODS OF USE CROSS REFERENCE This application claims the benefit of PCT / CN2024 / 079615, filed March 1, 2024, and PCT / CN2024 / 122704, filed September 30, 2024 which are hereby incorporated by reference in their entirety. BACKGROUND OF THE INVENTION The development of therapeutic agents is often hampered by short half-lives. The biological half-life of an agent is the time it takes for the agent to lose half of its pharmacologic, physiologic, or radiologic activity. As a result, patients are often administered higher dosages of a therapeutic agent more frequently, which can lead to reduced compliance, higher costs and greater risk of side effects. Accordingly, there is a need for generation of therapeutic agents with extended half-lives. SUMMARY OF THE INVENTION In an aspect, disclose herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof:Formula (V) wherein: each R3is independently hydrogen or methyl; R10is -OH or -NH2; R11is hydrogen, -OH, or -P(=O)(OH)2; n0is 0 or 1; n1and n2are each independently 1-4; and m is 6-20. In another aspect, disclosed herein is a peptide conjugate comprising: a) a peptide; and b) a staple attached to the peptide at a second amino acid and a third amino acid, wherein the second and third amino acid are each cysteine, wherein the staple is of Formula (IIb):Formula (IIb) wherein: each R3is independently hydrogen or methyl; R10is -OH or -NH2; R11is hydrogen, -OH, or -P(=O)(OH)2; n0 is 0 or 1; n1 and n2 are each independently 1-4; m is 6-20; and each * denotes the attachment point to a sulfur atom of the second and third amino acid. In another aspect, disclosed herein is a compound comprising Formula (I*), or a pharmaceutically acceptable salt or solvate thereof:wherein: each R4is independently hydrogen, -CH3, -CH2CH3,, , ,R5is –(CHR5a-NHC(=O))0-2-(La)t-RQ; wherein each R5ais hydrogen, -C(=O)OH, or -CH2CH2C(=O)OH; each Lais independently -(CR7R7)w-, -alkylene-O-, -O-alkylene-, -NR8-alkylene-, - alkylene-NR8-, - C(=O)NR8-, -NR8C(=O)-, -alkylene-C(=O)NR8-, -C(=O)NR8-alkylene-, -alkylene-NR8C(=O)-, or -NR8C(=O)-alkylene, wherein each R7is independently hydrogen or -CH(=O)OH; each R8is independently hydrogen; w is 1-10;RQis -CH3, -C(=O)OH, -P(=O)(OH)2, phenyl, 5-membered heteroaryl, 2-amino-5-methyl-5,6,7,8- tetrahydropteridin-4(3H)-one, or tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen; and t is 1-10; f is 0 or 1; R9is hydrogen or methyl; and RXis a nitrogen of an amine containing amino acid. In another aspect, provided herein is a peptide conjugate comprising: a) a peptide; and b) a prodrug moiety attached to the peptide at an amine containing side chain residue of a first amino acid; wherein the prodrug moiety is of Formula (I):Formula (I) wherein: each R4is independently hydrogen, -CH3, -CH2CH3,, , ,R5is –(CHR5a-NHC(=O))0-2-(La)t-RQ; wherein; each R5ais hydrogen, -CH(=O)OH, or -CH2CH2C(=O)OH; each Lais independently -(CR7R7)w-, -alkylene-O-, -O-alkylene-, -NR8-alkylene-, - alkylene- NR8-, -C(=O)NR8-, -NR8C(=O)-, -alkylene-C(=O)NR8-, -C(=O)NR8-alkylene-, -alkylene- NR8C(=O)-, or -NR8C(=O)-alkylene, wherein each R7is independently hydrogen or -CH(=O)OH; each R8is independently hydrogen; w is 1-10; RQis -CH3, -C(=O)OH, -P(=O)(OH)2, phenyl, 5-membered heteroaryl, 2-amino-5-methyl- 5,6,7,8-tetrahydropteridin-4(3H)-one, or tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen; t is 1-10; f is 0 or 1; p and q are each 1; anddenotes the attachment of the prodrug to the first amino acid. In some embodiments, the peptide conjugate further comprises a staple attached to the peptide at a second amino acid and a third amino acid, wherein the second and third amino acid are each cysteine and wherein the staple is of Formula (IIa):wherein: ZAis a 5-membered heteroaryl, -CO2H, or -P(=O)(OH)2; each R3is independently hydrogen or methyl; R10is -OH or -NH2; R11is hydrogen, -OH, or -P(=O)(OH)2; n0 is 0 or 1; n1 and n2 are each independently 1-4; m is 6-20; and each * denotes the attachment point to a sulfur atom of the second and third amino acid. In some embodiments, the peptide is an incretin. In some embodiments, the peptide binds to a GIP receptor. In some embodiments, the peptide binds to a GLP-1 receptor. In some embodiments, the peptide binds to both a GLP-1 receptor and a GIP receptor. In some embodiments, the peptide comprises a sequence: Tyr-X2-Glu-Gly-Thr-X6-Thr-Ser-X9-X10-X11-Ile-X13-X14-Asp-Lys-X17-Ala-Ala-Aib-Glu-Phe-Val- X24-X25-X26-X27-X28-Gly-Gly-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-NH2, wherein: X2is Aib, D-Pro, Gly, or D-Ala; X6is Phe, αMe-Phe, or αMe-Phe2F; X9is Asp or αMe-Asp; X10is Tyr, Val, Leu, Ile, Ala, Val(3-OH), or 4Pal; X11is Ser, αMe-Ser, or Val(3-OH); X13is Tyr, αMe-Leu, Cha, or Nle; X14is Leu or αMe-Leu; X17is Cys or Lys; X24is Cys or Lys; X25is Trp, Tyr, αMe-Trp, or αMe-Tyr; X26is Leu, Val, or αMe-Leu;X27is Ile, Leu, αMe-Leu, Tle, cpA, or Lys; X28is Ala, Glu, Hgl, or Lys; X31is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X32is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X33is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X34is Gly, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X35is Ala, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X36is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X37is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X38is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X39is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; and X40is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent. Also provided herein is a pharmaceutical composition comprising the peptide conjugate described herein and a pharmaceutically acceptable excipient. Also provided herein is a method for treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a peptide or peptide conjugate described herein. In some embodiments, the disease or condition is diabetes or obesity. In some embodiments, the diabetes is Type 1 diabetes mellitus, Type 2 diabetes mellitus, gestational diabetes, neonatal diabetes, maturity onset diabetes of the young, or latent autoimmune diabetes in adults, or any combination thereof. In some embodiments, the disease or condition is non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis, or cardiovascular disease. In some embodiments, the disease or condition is short bowel syndrome (SBS). In some embodiments, the disease or condition is inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), or psoriasis. In some embodiments, the disease or condition is Alzheimer’s disease, Parkinson’s disease or Huntington’s disease. BRIEF DESCRIPTION OF THE FIGURES FIG.1A and FIG.1B display example components of a peptide, such as amino acids. DETAILED DESCRIPTION OF THE INVENTION G protein-coupled receptors (GPCRs) are membrane-bound proteins that have seven transmembrane domains linked by three intracellular and three extracellular loops. Their ligand-binding sites are highly specialized so that each receptor responds only to a limited variety of chemicals which bind with high affinity. Examples of GPCR ligands are peptides, proteins, lipid-derived molecules, small organic compounds and ions. GPCRs have been of long-standing interest as pharmaceutical drug targets, as they are involved in a plethora of pathophysiological processes, including the regulation of neuronal excitability, metabolism, reproduction, hormonal homeostasis, and behavior. It is estimated that aroundfamily. GPCRs are generally classified into multiple superfamilies. Family B GPCRs, or the so-called secretin receptor family, are a small but structurally and functionally diverse set of receptors. These proteins are vital to many physiological functions and serve as key drug targets for several human diseases such as type 2 diabetes mellitus (T2DM), migraine, osteoporosis, depression, and anxiety. Members of this family include receptors for polypeptide hormones of 27–141 residues in length. Nine of these receptors are targeted by ligands that are structurally related to one another, examples of which include glucagon-like peptides (GLP-1 and GLP-2), glucagon, glucose-dependent insulinotropic polypeptide (GIP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase- activating polypeptide (PACAP) and growth hormone-releasing hormone (GHRH). Glucagon-like peptide 1 (GLP-1) is a naturally-occurring incretin hormone released into the circulation by the L cells of the gut in response to ingested nutrients. By binding to its cognate receptor (GLP-1R) GLP-1 is able to promote insulin secretion while suppressing glucagon secretion, but only when glucose levels are raised, thus offering the potential to lower plasma glucose levels while reducing the risk of hypoglycemia. Furthermore, GLP-1 decreases the rate of gastric emptying, and reduces appetite, thus resulting in weight loss. GLP-1 receptor agonists (GLP-1RAs) represent a unique approach to the treatment of diabetes, with benefits beyond glucose control, including favorable effects on body weight, blood pressure, cholesterol levels, and beta-cell function. Two short-acting (exenatide and liraglutide; once- or twice- daily administration) and three long-acting (albiglutide, dulaglutide, and exenatide LAR; weekly administration) GLP-1RAs are currently approved in the United States. In particular, exenatide, a GLP-1 analog originally isolated from the saliva of the Gila monster, has a half-life of 30 min after i.v. administration and a half-life of 2–3 h after s.c. administration in humans. These drugs mimic the effects of the naturally occurring incretin hormone GLP-1 by activating GLP-1 receptors in the pancreas, which leads to enhanced insulin release and reduced glucagon release in a glucose-dependent manner—with a consequently low risk of hypoglycemia. The effects of these GLP-1RAs on GLP-1 receptors in the CNS and the gastrointestinal tract also lead to reduced appetite and delayed glucose absorption, with concomitant weight loss. Given their limited oral bioavailability, these GLP-1RAs are currently given as a s.c. injection. In some aspects, provided herein are GLP-1RAs connected to a fatty-acid derived side- chain staple to increase half-life. GIP is also characterized as an incretin that stimulates insulin secretion in a glucose-dependent manner. A GIP and GLP-1 receptor dual agonist has been shown to reduce fasting serum glucose compared to placebo and to reduce body weight. This dual agonist, LY3298176, is administered once- weekly subcutaneously. In certain embodiments, further provided herein are GIPR and GLP-1R dual agonists comprising a stapled feature to increase serum stability and half-life. Provided herein are peptides and peptide conjugates comprising a therapeutic peptide stapled to a molecule, such as a half-life extending molecule. In certain embodiments, the stapled peptides comprise incretin peptides or incretin peptide mimetics. Incretin peptides generally bind to their cognate receptors in an α-helical conformation,therefore certain embodiments herein provide for modifications that stabilize the α-helix, which in some cases may increase binding affinity to their receptors. Moreover, proteolytic stability may also be enhanced in a helical rather than an extended conformation. In some aspects, provided herein are such conjugated peptides having increased circulatory half-life and potency toward their cognate receptors. In some aspects, described herein is a peptide engineering strategy used to generate stapled long-acting peptide analogs with comparable potency as native peptides and significantly enhanced pharmacokinetic properties. Peptides In one aspect, provided herein are peptides and peptide conjugates comprising a peptide that modulates the GLP-1 receptor and / or the GIP receptor. In some embodiments, the peptide modulates both the GLP-1 receptor and the GIP receptor. In some embodiments, a peptide that modulates the GLP- 1 receptor is a GLP-1 receptor agonist. In some embodiments, a peptide that modulates the GIP receptor is a GIP receptor agonist. The binding affinity of the peptide conjugate as described herein may be within about 5% of the binding affinity of an unmodified form of the peptide to a receptor (e.g., GLP-1 and / or GIP receptor). The binding affinity of the peptide conjugate as described herein may be within about 10% of the binding affinity of an unmodified form of the peptide. The binding affinity of the peptide conjugate as described herein may be within about 15% of the binding affinity of an unmodified form of the peptide. The binding affinity of the peptide conjugate as described herein may be within about 20% of the binding affinity of an unmodified form of the peptide. The peptide may comprise one or more sulfhydryl containing amino acid residues. The one or more sulfhydryl containing amino acid residues may be used for connecting a staple. The one or more sulfhydryl containing amino acid residues may be naturally occurring in the peptide. The one or more sulfhydryl containing amino acid residues may be inserted into the peptide. The one or more sulfhydryl containing amino acid residues may replace one or more amino acid residues in the peptide. Methods for amino acid substitution and / or insertion are known in the art. The peptide may comprise one or more amine containing residues. Non-limiting examples of amine containing residues include lysine, ornithine, diaminobutyric acid, diaminopropionic acid and homolysine. The one or more amine containing residues may be used for connecting a staple. The one or more one or more amine containing residues may be naturally occurring in the peptide. The one or more one or more amine containing residues may be inserted into the peptide. The one or more one or more amine containing residues may replace one or more amino acid residues in the peptide. The peptide may comprise one or more amine containing amino acid residues. An amine containing residue may be used for connecting to a prodrug moiety. The peptide may comprise at least a portion of a wild-type peptide comprising one or more amino acid mutations. The one or more amino acid mutations may comprise a deletion, substitution, addition or a combination thereof. The one or more amino acid mutations may comprise adding one ormore amino acid residues to a wild-type peptide. The one or more amino acid mutations may comprise deletion of one or more amino acid residues of the wild-type peptide. The one or more amino acid mutations may comprise substitution of one or more amino acid residues of the wild-type peptide. The one or more amino acid mutations may comprise substituting one or more amino acid residues of the wild-type peptide with one or more cysteine, lysine or other sulfhydryl or amine containing residues. The one or more amino acid mutations may comprise substituting one or more amino acid residues of the wild-type peptide with one or more D-amino acid residues. The one or more amino acid residues of the wild-type peptide may comprise one or more alanines, methionines, arginines, serines, threonines, and tyrosines. The peptide may be modified with, for example, acetylation, phosphorylation, and methylation. The peptide modification may comprise a chemical modification. Peptide modifications may occur on the N-terminus of the peptide. Peptide modifications may comprise acetyling the amino group at the N- terminus of the peptide. Alternatively, or additionally, peptide modifications may occur on the C- terminus of the peptide. Peptide modifications may occur at one or more internal amino acids of the peptide. Peptide modifications may comprise replacing the carboxyl group at the C-terminus of the peptide. Peptide modifications may comprise modifying the carboxyl group at the C-terminus of the peptide. The carboxyl group at the C-terminus of the peptide may be modified to produce an amide group. The carboxyl group at the C-terminus of the peptide may be modified to produce an amine group. In some embodiments, the peptide may be a modified peptide with a D-serine in place of L- serine. In some embodiments, the peptide may be a modified with an aminoisobutyric acid [Aib] in place of L-serine. In some embodiments, the peptide may be a modified peptide with a neuroleucine [Nle] in place of leucine (Leu). In some embodiments, the peptide comprises aMeF (alpha-methyl Phe). In some embodiments, the peptide comprises 4Pal (4-pyridyl-Ala). In some embodiments, the peptide comprises aMeL (alpha-methyl Leu). In some embodiments, the peptide comprises Orn (ornithine). In some embodiments, the peptide comprises aMeY (alpha-methyl tyrosine). In some embodiments, the peptide comprises one or more of the following amino acids: N- methyl-Phe, D-Phe, alpha-methyl-Phe, Phe (2-F), Phe (3-F), Phe (4-F), 4-Pyridyl-Ala, Aib, N-methyl- Leu, D-Leu, alpha-methyl-Leu, beta-3-Leu, beta-3-Phe, beta-3-Asn, beta-3-Trp, D-Asn, D-Glu, D-Gln, D-Asp. In some embodiments, the peptide comprises an amino acid of FIGS.1A-1B. In some embodiments, the peptide comprising a sequence: Tyr-X2-X3-Gly-Thr-X6-Thr-Ser-X9-X10-X11-Ile-X13-X14-Asp-Lys-X17-Ala-Ala-Aib-Glu-Phe-Val-X24- X25-X26-X27-X28-Gly-Gly-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-NH2 wherein: X2is Aib, D-Pro, Gly, or D-Ala; X3is Asp or Glu; X6is Phe, αMe-Phe, or αMe-Phe2F; X9is Asp or αMe-Asp; X10is Tyr, Val, Leu, Ile, Ala, Val(3-OH), or 4Pal;X11is Ser, αMe-Ser, or Val(3-OH); X13is Tyr, αMe-Leu, Cha, or Nle; X14is Leu or αMe-Leu; X17is Cys or Lys; X24is Cys or Lys; X25is Trp, Tyr, αMe-Trp, or αMe-Tyr; X26is Leu, Val, or αMe-Leu; X27is Ile, Leu, αMe-Leu, Tle, cpA, or Lys; X28is Ala, Glu, Hgl, or Lys; X31is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X32is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X33is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X34is Gly, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X35is Ala, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X36is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X37is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X38is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X39is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; and X40is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent In some embodiments, the peptide comprising a sequence: Tyr-X2-Glu-Gly-Thr-X6-Thr-Ser-X9-X10-X11-Ile-X13-X14-Asp-Lys-X17-Ala-Ala-Aib-Glu-Phe-Val- X24-X25-X26-X27-X28-Gly-Gly-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-NH2wherein: X2is Aib, D-Pro, Gly, or D-Ala; X6is Phe, αMe-Phe, or αMe-Phe2F; X9is Asp or αMe-Asp; X10is Tyr, Val, Leu, Ile, Ala, Val(3-OH), or 4Pal; X11is Ser, αMe-Ser, or Val(3-OH); X13is Tyr, αMe-Leu, Cha, or Nle; X14is Leu or αMe-Leu; X17is Cys or Lys; X24is Cys or Lys; X25is Trp, Tyr, αMe-Trp, or αMe-Tyr; X26is Leu, Val, or αMe-Leu; X27is Ile, Leu, αMe-Leu, Tle, cpA, or Lys; X28is Ala, Glu, Hgl, or Lys; X31is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X32is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent;X33is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X34is Gly, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X35is Ala, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X36is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X37is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X38is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X39is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; and X40is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent. In some embodiments, X2is Aib. In some embodiments, X2is D-Pro. In some embodiments, X2is D-Ala. In some embodiments, X2is Gly. In some embodiments, X3is Asp. In some embodiments, X3is Glu. In some embodiments, X6is Phe. In some embodiments, X6is αMe-Phe. In some embodiments, X6is αMe-Phe2F. In some embodiments, X9is Asp . In some embodiments, X9is αMe-Asp. In some embodiments, X10is Tyr. In some embodiments, X10is Val. In some embodiments, X10is Leu. In some embodiments, X10is Ile. In some embodiments, X10is Ala. In some embodiments, X10is 4Pal. In some embodiments, X10is Val(3-OH). In some embodiments, X11is Ser. In some embodiments, X11is αMe-Ser. In some embodiments, X11is Val(3-OH). In some embodiments, X13is Tyr. In some embodiments, X13is αMe-Leu. In some embodiments, X13is Cha. In some embodiments, X13is Nle. In some embodiments, X14is Leu. In some embodiments, X14is αMe-Leu. In some embodiments, X17is Cys. In some embodiments, X17is Lys. In some embodiments, X24is Cys. In some embodiments, X24is Lys. In some embodiments, X25is Trp. In some embodiments, X25is Tyr. In some embodiments, X25is αMe-Trp. In some embodiments, X25is αMe-Tyr. In some embodiments, X26is Leu. In some embodiments, X26is Val. In some embodiments, X26is αMe-Leu. In some embodiments, X27is Ile. In some embodiments, X27is Leu. In some embodiments, X27is αMe-Leu. In some embodiments, X27is Tle. In some embodiments, X27is cpA. In some embodiments, X27is Lys. In some embodiments, X28is Ala. In some embodiments, X28is Glu. In some embodiments, X28is Hgl. In some embodiments, X28is Lys. In some embodiments, X31is Pro. In some embodiments, X31is Lys of D-Lys. In some embodiments, X31is Orn or D-Orn. In some embodiments, X31is Dab or D-Dab. In some embodiments, X31is Dap or D-Dap. In some embodiments, X31is absent. In some embodiments, X32is Ser. In some embodiments, X32is absent.In some embodiments, X33is Ser. In some embodiments, X33is Lys. In some embodiments, X33is D-Lys. In some embodiments, X33is Orn. In some embodiments, X33is D-Orn. In some embodiments, X33is Dab. In some embodiments, X33is D-Dab In some embodiments, X33is Dap. In some embodiments, X33is D-Dap. In some embodiments, X33is absent. In some embodiments, X34is Gly. In some embodiments, X34is Lys or D-Lys. In some embodiments, X34is Orn or D-Orn. In some embodiments, X34is Dab or D-Dab. In some embodiments, X34is Dap or D-Dap. In some embodiments, X34is absent. In some embodiments, X35is Ala. In some embodiments, X35is Lys or D-Lys. In some embodiments, X35is Orn or D-Orn. In some embodiments, X35is Dab or D-Dab. In some embodiments, X35is Dap or D-Dap. In some embodiments, X35is absent. In some embodiments, X36is Pro. In some embodiments, X36is Lys or D-Lys. In some embodiments, X36is Orn or D-Orn. In some embodiments, X36is Dab or D-Dab. In some embodiments, X36is Dap or D-Dap. In some embodiments, X36is absent. In some embodiments, X37is Pro. In some embodiments, X37is Lys or D-Lys. In some embodiments, X37is Orn or D-Orn. In some embodiments, X37is Dab or D-Dab. In some embodiments, X37is Dap or D-Dap. In some embodiments, X37is absent. In some embodiments, X38is Pro. In some embodiments, X38is Lys or D-Lys. In some embodiments, X38is Orn or D-Orn. In some embodiments, X38is Dab or D-Dab. In some embodiments, X38is Dap or D-Dap. In some embodiments, X38is absent. In some embodiments, X39is Ser. In some embodiments, X39is Thr. In some embodiments, X39is Lys or D-Lys. In some embodiments, X39is Orn or D-Orn. In some embodiments, X39is Dab or D- Dab. In some embodiments, X39is Dap or D-Dap. In some embodiments, X39is absent. In some embodiments, the protein comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO.1 (Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSX40), wherein X40is absent, serine, threonine, L or D-lysine, L- or D-ornithine, or L- or D-diaminobutyric acid. In some embodiments, X40is Ser. In some embodiments, X40is Thr. In some embodiments, X40is Lys or D-Lys. In some embodiments, X40is Orn or D-Orn. In some embodiments, X40is Dab or D- Dab. In some embodiments, X40is Dap or D-Dap. In some embodiments, X40is absent. In some embodiments, the peptide comprises a sequence of any one of SEQ ID NOs: 1-115. In some cases, the peptide comprises a sequence at least about 79%, about 80%, about 81%, about 8%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to any one of SEQ ID NOs: 1-115. In some cases, the peptide comprises a sequence at least about 90% identical to any one of SEQ ID NOs: 1-115. In some cases, the peptide comprises a sequence at least about 95% identical to any one of SEQ ID NOs: 1-115. In some cases, the peptide comprises a sequence at least about 99% identical to any one of SEQ ID NOs: 1-115. In some cases, the peptidecomprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to any one of SEQ ID NOS: 1-115. In some embodiments, the protein comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO.2 (Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS). In some embodiments, the peptide sequence does not include SEQ ID NO.2 (Y(Aib)EGT- FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS). Non-limiting examples of peptides are shown in Table 1. Table 1. Peptide SEQ IDConjugates In an aspect, disclosed herein is a peptide conjugate comprising:a) a peptide; and b) a prodrug moiety attached to the peptide at a first amino acid. In some embodiments, the peptide conjugate further comprises a staple attached to the peptide at a second amino acid and a third amino acid. In an aspect, disclosed herein is a peptide conjugate comprising: a) a peptide; b) a prodrug moiety attached to the peptide at a first amino acid; and c) a staple attached to the peptide at a second amino acid and a third amino acid. In an aspect, disclosed herein is a peptide conjugate comprising: c) a peptide; and d) a staple attached to the peptide at a second amino acid and a third amino acid. Prodrug moiety In some embodiments, the prodrug moiety is a diketopeptide moiety. In some embodiments, the prodrug moiety is attached to the peptide at a first amino acid. In some embodiments, the prodrug moiety is of Formula (I):wherein: each R4is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, or C3-C10 heterocycloalkyl, each of which is optionally substituted with one, two, or three R6; or two R4together with the carbon to which they are attached to form a C3-C7 cycloalkyl or C3-C7 heterocycloalkyl which is optionally substituted with one, two, or three R6; each R6is independently halogen, -ORa, -SRa, -NO2, -NRcRd, -CO2Ra, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one, two, or three halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORa, or -NRcRd; R5is –(CHR5a-NHC(=O))0-2-(La)t-RQ; RQis -CH3, -C(=O)OH, -P(=O)(OH)2, phenyl, 5-membered heteroaryl, 2-amino-5-methyl-5,6,7,8- tetrahydropteridin-4(3H)-one, or tetrahydro-1H-thieno[3,4-d- 17 -midazolel-2(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen; R5ais hydrogen or C1-C6 alkyl, which is optionally substituted with one, two, or three R6a; each R6ais independently -ORa, -SRa, -NRcRd, -CO2Ra, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroarylare each optionally substituted with one, two, or three halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORa, or -NRcRd; each Lais independently -(CR7R7)w-, -alkylene-O-, -O-alkylene-, -C(=O)-alkylene-, - alkylene-C(=O)-, - NR8-alkylene-, - alkylene-NR8-, -S-alkylene-, -alkylene-S-, -S(=O)-alkylene-, - alkylene-S(=O)-, - S(=O)2-alkylene, - alkylene-S(=O)2-, -C(=O)-, -C(=O)NR8-, -NR8C(=O)-, -NR8C(=O)NR8-, - NR8C(=O)NR8-alkylene-, -NR8C(=O)-alkylene-NR8-, -alkylene-C(=O)NR8-, -C(=O)NR8-alkylene-, - alkylene-NR8C(=O)-, -NR8C(=O)-alkylene-, or phenylene; f is 0 or 1; p is 0 or 1; q is 0 or 1; t is 1-10; each R7is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rf, -NRaC(=O)ORa, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, - ORa, -NRcRd, or -C(=O)NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6alkyl, C1-C6haloalkyl, -ORa, or - NRcRd; each R8is independently hydrogen, -S(=O)Rb, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, - C(=O)NRcRd, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6alkyl, C1-C6haloalkyl, -ORa, or -NRcRc; R9is hydrogen, C1-C6alkyl, or C3-C10cycloalkyl; w is 1-20; Rais hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1- C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2; Rbis C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1- C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2; andeach Rcand Rdis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2; or Rcand Rd, together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. In some embodiments, the prodrug moiety is of Formula (I),Formula (I) wherein: each R4is independently hydrogen, -CH3, -CH2CH3,,R5is –(CHR5a-NHC(=O))0-2-(La)t-RQ; wherein; each R5ais hydrogen, -CH(=O)OH, or -CH2CH2C(=O)OH; each Lais independently -(CR7R7)w-, -alkylene-O-, -O-alkylene-, -NR8-alkylene-, - alkylene-NR8-, - C(=O)NR8-, -NR8C(=O)-, -alkylene-C(=O)NR8-, -C(=O)NR8-alkylene-, -alkylene-NR8C(=O)-, or -NR8C(=O)-alkylene, wherein each R7is independently hydrogen or -CH(=O)OH; each R8is independently hydrogen; and w is 1-10; RQis -CH3, -C(=O)OH, -P(=O)(OH)2, phenyl, 5-membered heteroaryl, 2-amino-5-methyl-5,6,7,8- tetrahydropteridin-4(3H)-one, or tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen; t is 1-10; R9is hydrogen or methyl; f is 0 or 1; p and q are each 1; and denotes the attachment of the prodrug to the nitrogen atom of the peptide.In some embodiments of Formula (I), p is 0. In some embodiments of Formula (I), p is 1. In some embodiments of Formula (I), q is 0. In some embodiments of Formula (I), q is 1. In some embodiments, the prodrug moiety of Formula (I) has the structure of Formula (Ia), (Ib), (Ic), or (Id):In some embodiments of Formula (I), each R4is independently C1-C6alkyl or C1-C6heteroalkyl each of which is optionally substituted with one, two, or three R6. In some embodiments of Formula (I), each R4is independently C1-C6alkyl. In some embodiments of Formula (I), each R4is independently C1-C6heteroalkyl. In some embodiments of Formula (I), each R4is independently hydrogen, methyl, ethyl, isopropyl, n-propyl, isobutyl, sec-butyl, tert-butyl, or n-butyl. In some embodiments of Formula (I), each R4is independently methyl, ethyl, or isopropyl. In some embodiments of Formula (I), each R4is methyl. In some embodiments of Formula (I), each R4is ethyl. In some embodiments of Formula (I), each R4is isopropyl. In some embodiments of Formula (I), each R4is independently C3-C10 cycloalkyl or C3-C10 heterocycloalkyl, each of which is optionally substituted with one, two, or three R6. In some embodiments of Formula (I), each R4is independently C3-C10 cycloalkyl. In some embodiments of Formula (I), each R4is independently C3-C6 cycloalkyl. In some embodiments of Formula (I), each R4is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of Formula (I), each R4is hydrogen. In another aspect, provided herein is a composition comprising Formula (I*), or a pharmaceutically acceptable salt or solvate thereof:Formula (I*)wherein: each R4is independently hydrogen, -CH3, -CH2CH3,,R5is –(CHR5a-NHC(=O))0-2-(La)t-RQ; wherein each R5ais hydrogen, -C(=O)OH, or -CH2CH2C(=O)OH; each Lais independently -(CR7R7)w-, -alkylene-O-, -O-alkylene-, -NR8-alkylene-, - alkylene-NR8-, - C(=O)NR8-, -NR8C(=O)-, -alkylene-C(=O)NR8-, -C(=O)NR8-alkylene-, -alkylene-NR8C(=O)-, or -NR8C(=O)-alkylene, wherein each R7is independently hydrogen or -CH(=O)OH; each R8is independently hydrogen; w is 1-10; RQis -CH3, -C(=O)OH, -P(=O)(OH)2, phenyl, 5-membered heteroaryl, 2-amino-5-methyl-5,6,7,8- tetrahydropteridin-4(3H)-one, or tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen; and t is 1-10; f is 0 or 1; R9is hydrogen or methyl; and RXis a nitrogen of an amine containing amino acid. In some embodiments of Formula (I*), RXis the nitrogen of an amine containing amino acid. In further embodiments, RXis a nitrogen containing amino acid of an incretin. In some embodiments, the compound further comprises a peptide comprising the amino containing amino acid. In some embodiments, the peptide is of SEQ ID NOS: 1-115. In some embodiment, the amino acid is a lysine. In some embodiments, the amino acid is a homolysine. In some embodiments, the amino acid is D or L- diaminobutyric acid. In some embodiments, the compound of Formula (I*) is an adduct to the peptide. In some embodiments, the composition comprising Formula (I*) improves the stability of the peptide. In some embodiments, the compound of Formula (I*) improves the metabolic stability of the peptide. In some embodiments, the peptide is more stable with the adduct of Formula (I*) than without the attachment. In some embodiments of Formula (I) or (I*), each R4is independently hydrogen, -CH3, -embodiments of Formula (I) or (I*), each R4is independently hydrogen, -CH3, or. In some embodiments of Formula (I) or (I*), each R4is independently hydrogen or -CH3. In some embodiments of Formula (I) or (I*), each R4is independently hydrogen or. In some embodiments of Formula(I) or (I*), each R4is independently hydrogen, , , or . In some embodiments of Formula (I) or (I*), each R4is independently hydrogen or. In some embodiments of Formula (I) or (I*) each R4is -CH3. In some embodiments of Formula (I) or (I*), each R4is hydrogen. In some embodiments of Formula (I), two R4together with the carbon atom to which they are attached form a C3-C7cycloalkyl. In some embodiments of Formula (I), two R4together with the carbon atom to which they are attached form a C2-C7heterocycloalkyl. In some embodiments of Formula (I), each R6is independently halogen, -ORa, -SRa, -NO2, - NRcRd, -CO2Ra, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one, two, or three halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORa, or -NRcRd. In some embodiments of Formula (I), each R6is independently halogen, -ORa, or -NRcRd. In some embodiments of Formula (I), each R6is independently -ORa. In some embodiments of Formula (I), each R6is independently -NRcRd. In some embodiments of Formula (I), each R6is independently C3-C8 cycloalkyl or C2-C8 heterocycloalkyl. In some embodiments of Formula (I), each R6is independently C3-C8 cycloalkyl. In some embodiments of Formula (I), each R6is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of Formula (I), each R6is independently C2-C8 heterocycloalkyl. In some embodiments of Formula (I), each R6is independently C6-C10 aryl or 5- to 10- membered heteroaryl. In some embodiments of Formula (I), each R6is independently C6-C10 aryl. In some embodiments of Formula (I), each R6is independently phenyl or naphthyl. In some embodiments of Formula (I), each R6is independently 5- to 10-membered heteroaryl. In some embodiments of Formula (I), each R6is independently 5- to 8-membered heteroaryl comprising one, two, or three heteroatoms selected from N, O, and S. In some embodiments of Formula (I), each R6is independently a 5 or 6-membered heteroaryl. In some embodiments of Formula (I), each R6is independently a 5- membered heteroaryl selected from pyrrole, imidazole, or triazole. In some embodiments of Formula (I), each R6is pyrrole. In some embodiments of Formula (I), each R6is imidazole. In some embodiments of Formula (I), each R6is triazole. In some embodiments of Formula (I), each R6is independently a bicyclic heteroaryl comprising one, two, or three heteroatoms selected from N, O, and S. In some embodiments of Formula (I), each R6is indole. In some embodiments of Formula (I), each R6is independently halogen, -ORa, -NRcRd, or 5- membered heteroaryl. In some embodiments of Formula (I), each R6is independently selected from -NH2or imidazole. In some embodiments of Formula (I) or (I*), R9is hydrogen or C1-C6alkyl. In some embodiments of Formula (I) or (I*), R9is C1-C6alkyl. In some embodiments of Formula (I) or (I*), R9is methyl, ethyl, or isopropyl. In some embodiments of Formula (I), R9is C3-C10cycloalkyl. In someembodiments of Formula (I), R9is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of Formula (I) or (I*), R9is hydrogen. In some embodiments of Formula (I) or (I*), f is 0. In some embodiments of Formula (I) or (I*), f is 1. In some embodiments of Formula (I) or (I*), the prodrug moiety comprises:In some embodiments of Formula (I) or (I*), the prodrug moiety comprises:In some embodiments of Formula (I) or (I*), R5is –(CHR5a-NHC(=O))0-2-(La)t-RQ. In some embodiments of Formula (I) or (I*), R5is –(CHR5a-NHC(=O))2-(La)t-RQ. In some embodiments of Formula (I) or (I*), R5is –(CHR5a-NHC(=O))1-(La)t-RQ. In some embodiments of Formula (I) or (I*), R5is -(La)t-RQ. OH. Inof Formula (I) or (I*), R5is -(La)t-C(=O)OH. In some embodiments of Formula (I) or (I*), R5ais hydrogen or C1-C6alkyl, which is optionally substituted with one, two, or three R6a. In some embodiments of Formula (I) or (I*), R5ais C1- C6alkyl. In some embodiments of Formula (I) or (I*), R5ais methyl, ethyl, or isopropyl. In some embodiments of Formula (I) or (I*), R5ais methyl. In some embodiments of Formula (I) or (I*), R5ais ethyl. In some embodiments of Formula (I) or (I*), R5ais isopropyl. In some embodiments of Formula (I) or (I*), R5ais -CH2CH2C(=O)OH. In some embodiments of Formula (I) or (I*), R5ais -CH2C(=O)OH. In some embodiments of Formula (I) or (I*), R5ais - CH2OH. In some embodiments of Formula (I) or (I*), R5ais -CH2CH2COH. In some embodiments of Formula (I), each R6ais independently -ORa, -SRa, -NRcRd, -CO2Ra, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one, two, or three halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORa, or -NRcRd. In some embodiments of Formula (I), each R6ais independently -ORaor -NRgRh. In some embodiments of Formula (I), each R6ais independently -CO2Ra. In some embodiments of Formula (I), each R6ais independently C3-C8 cycloalkyl or C2-C8 heterocycloalkyl.In some embodiments of Formula (I), each R6ais independently C6-C10 aryl or 5- to 10- membered heteroaryl. In some embodiments of Formula (I), each R6ais independently C6-C10 aryl. In some embodiments of Formula (I), each R6ais independently phenyl or naphthyl. In some embodiments of Formula (I), each R6ais independently 5- to 10-membered heteroaryl. In some embodiments of Formula (I), each R6ais independently 5- to 8-membered heteroaryl comprising one, two, or three heteroatoms selected from N, O, and S. In some embodiments of Formula (I), each R6ais independently 5 or 6-membered heteroaryl. In some embodiments of Formula (I), each R6ais independently a 5- membered heteroaryl selected from pyrrole, imidazole, or triazole. In some embodiments of Formula (I), each R6ais pyrrole. In some embodiments of Formula (I), each R6ais imidazole. In some embodiments of Formula (I), each R6ais a triazole. In some embodiments of Formula (I), each R6ais independently a bicyclic heteroaryl comprising one, two, or three heteroatoms selected from N, O, and S. In some embodiments of Formula (I), each R6ais indole In some embodiments of Formula (I) or (I*) each Lais independently -(CR7R7)w-, -alkylene-O-, -O-alkylene-, -C(=O)-alkylene-, - alkylene-C(=O)-, -NR8-alkylene-, - alkylene-NR8-, -C(=O)-, - C(=O)NR8-, -NR8C(=O)-, -NR8C(=O)NR8-, -NR8C(=O)NR8-alkylene-, -NR8C(=O)-alkylene-NR8-, - alkylene-C(=O)NR8-, -C(=O)NR8-alkylene-, -alkylene-NR8C(=O)-, -NR8C(=O)-alkylene, or phenylene. In some embodiments of Formula (I) or (I*), each Lais independently -(CR7R7)w-, -alkylene-O-, -O- alkylene-, -NR8-alkylene-, - alkylene-NR8-, -C(=O)NR8-, -NR8C(=O)-, -alkylene-C(=O)NR8-, - C(=O)NR8-alkylene-, -alkylene-NR8C(=O)-, or -NR8C(=O)-alkylene-. In some embodiments of Formula (I) or (I*), each Lais independently -(CR7R7)w-, -alkylene-O-, -O-alkylene-, -C(=O)NR8-, or -NR8C(=O)- . In some embodiments of Formula (I) or (I*), each Lais independently -(CR7R7)w-. In some embodiments of Formula (I) or (I*), each Lais independently -CH(NH2)CH2CH2CH2CH2-, - CH2CH2CH(C(=O)OH)-, -CH2CH2CH2CH2-, -CH2CH2CH2-, or - CH2CH2-. In some embodiments of Formula (I) or (I*), each Lais independently -CH(CH2CH2C(=O)NRcRd, wherein each Rcand Rdeach independently hydrogen or C1-C6alkyl substituted with one, two, three, or more -OH. In some embodiments of Formula (I), each Lais -alkylene-O- or -O-alkylene-. In some embodiments of Formula (I) or (I*), each Lais -C(=O)NH-, or -NHC(=O)-. In some embodiments of Formula (I) or (I*), each Lais phenylene. In some embodiments of Formula (I) or (I*), each R7is independently hydrogen, -ORa, or - NRcRd. In some embodiments of Formula (I) or (I*), each R7is independently -ORa. In some embodiments of Formula (I) or (I*), each R7is independently -NRcRd. In some embodiments of Formula (I) or (I*), each R7is independently -CO2Raor -C(=O)NRcRd. In some embodiments of Formula (I) or (I*), each R7is independently -CO2Ra. In some embodiments of Formula (I), each R7is independently - C(=O)NRcRd. In some embodiments of Formula (I) or (I*), each R7is independently hydrogen, -NH2, or -CO2H. In some embodiments of Formula (I) or (I*), each R7is hydrogen. In some embodiments of Formula (I) or (I*), each R8is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd. In some embodiments ofFormula (I) or (I*), each R8is independently hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl. In some embodiments of Formula (I) or (I*), each R8is independently hydrogen or C1-C6 alkyl. In some embodiments of Formula (I) or (I*), each R8is independently C1-C6 alkyl. In some embodiments of Formula (I) or (I*), each R8is hydrogen. In some embodiments of Formula (I) or (I*), t is 1-8. In some embodiments of Formula (I) or (I*), t is 1-6. In some embodiments of Formula (I) or (I*), t is 1-5. In some embodiments of Formula (I) or (I*), t is 1-4. In some embodiments of Formula (I) or (I*), t is 1-3. In some embodiments of Formula (I) or (I*), t is 1 or 2. In some embodiments of Formula (I) or (I*), t is 1. In some embodiments of Formula (I) or (I*), t is 2. In some embodiments of Formula (I) or (I*), t is 3. In some embodiments of Formula (I) or (I*), R5is:wherein, t1is 0-3; t2is 6-20; and RQis -CO2H, -P(=O)(OH)2, phenyl, 5-membered heteroaryl, or 2-amino-5-methyl-5,6,7,8- tetrahydropteridin-4(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen. In some embodiments of Formula (I) or (I*), R5is:wherein, t2 is 6-20; t3 is 2-10; and RQis -CO2H, -P(=O)(OH)2, phenyl, 5-membered heteroaryl, or 2-amino-5-methyl-5,6,7,8- tetrahydropteridin-4(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen. In some embodiments of Formula (I) or (I*), R5is:In some embodiments of Formula (I) or (I*), RQis -CH3. In some embodiments of Formula (I) or (I*), RQis -C(=O)OH. In some embodiments of Formula (I) or (I*), RQis -P(=O)(OH)3. In some embodiments of Formula (I) or (I*), RQis phenyl, which is optionally substituted with one, two, or three halogen. In some embodiments of Formula (I) or (I*), RQis phenyl para substituted with Br, Cl, F, or I.In some embodiments of Formula (I) or (I*), RQis a 5-membered heteroaryl. In some embodiments of Formula (I) or (I*), RQis tetrahydro-1H-thieno[3,4-d]- 27 -midazole-2(3H)-one. In some embodiments of Formula (I) or (I*), t1 is 0. In some embodiments of Formula (I) or (I*), t1 is 1 or 2. In some embodiments of Formula (I) or (I*), t1 is 3. In some embodiments of Formula (I) or (I*), t1 is 2. In some embodiments of Formula (I) or (I*), t1 is 1. In some embodiments of Formula (I) or (I*), t1 is 0. In some embodiments of Formula (I) or (I*), t2 is 6-20. In some embodiments of Formula (I) or (I*), t2 is 10-20. In some embodiments of Formula (I) or (I*), t2 is 10-15. In some embodiments of Formula (I) or (I*), t3 is 2-5. In some embodiments of Formula (I) or (I*), t3 is 2 or 3. In some embodiments of Formula (I) or (I*), t3 is 2. In some embodiments of Formula (I) or (I*) t3is 3. In some embodiments of Formula (I) or (I*), R5is:In some embodiments of Formula (I) or (I*), R5is:,. In some embodiments, the prodrug is of Formula (III):Formula (III) wherein: each Lbis independently -C(=O)NR13-alkylene- or -C(=O)NR13-polyethylene glycol-; Lcis absent or -C(=O)NR11-alkylene-; t4is 0-3; t5is 6-20; and R12is hydrogen, -OH, -CO2H, or C1-C3alkyl optionally substituted with -OH or -CO2H. In some embodiments of Formula (III), each Lbis independently -C(=O)NR13-C2-C10alkylene- or -C(=O)NR13-(polyethylene glycol)2-4. In some embodiments of Formula (III), each Lbis independently -C(=O)NH-(CH2CH2O)3-. In some embodiments of Formula (III), each Lbis independently -C(=O)NH- (CH2CH2O)2-. In some embodiments of Formula (III), each R13is independently hydrogen or methyl. In some embodiments of Formula (III), Lcis -C(=O)NR13-C1-C10alkylene. In some embodiments of Formula (III), Lcis -C(=O)NR13-C1-C4alkylene-. In some embodiments of Formula (III), Lcis -C(=O)NR13-CH2CH2-. In some embodiments of Formula (III), Lcis -C(=O)NR13-CH2-. In some embodiments of Formula (III), Lcis absent. In some embodiments of Formula (III), R12is -CO2H. In some embodiments of Formula (III), R12is -CH2CO2H. In some embodiments of Formula (III), t4is 1 or 2. In some embodiments of Formula (III), t4is 1. In some embodiments of Formula (III), t4is 2.In some embodiments of Formula (III), t5 is 6-20. In some embodiments of Formula (III), t5 is 10-20. In some embodiments of Formula (III), t5 is 10-15. In some embodiments, the prodrug moiety of Formula (III) is selected from:In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to the prodrug at an amino containing side chain residue. In some embodiments, the first amino acid is selected from lysine, ornithine, diaminobutyric acid, diaminopropionic acid, and homolysine. In some embodiments, the first amino acid is lysine. In some embodiments, the first amino acid is homolysine. In some embodiments, the first amino acid is ornithine. In some embodiments, the first amino acid is diaminobutyric acid. In some embodiments, the first amino acid is diaminopropionic acid. In some embodiments, the prodrug moiety of Formula (I) is attached to the prodrug at the N-terminal amine of the protein. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to the protein at a lysine at position X15, X16, X17, X24, X27, X28, X31, X32, X33, X34, X35, X36, X37, X38, X39, or X40. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to the protein at a lysine at position X15. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to the protein at a lysine at position X16. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to the protein at a lysine at position X17. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to the protein at a lysine at position X24. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to the protein at a lysine at position X28. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to the protein at a lysine at position X31. In some embodiments, the prodrug moiety is attached to the protein at a lysine at position X32. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to the protein at a lysine at position X33. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to the protein at a lysine at position X34. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to the protein at a lysine at position X35. In some embodiments, the prodrug moiety is attached to the protein at a lysine at position X36. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to the protein at a lysine at position X37. In some embodiments, the prodrug moiety of Formula (I) is attached to the protein at a lysine at position X38. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to theprotein at a lysine at position X39. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached to the protein at a lysine at position X40. In some embodiments, the prodrug moiety of Formula (I) or (I*) is attached at a diaminobutyric acid at X40. In some embodiments, the prodrug moiety is attached at a D or L-diaminobutyric acid at X40. In some embodiments, the prodrug moiety of Formula (III) is attached to the prodrug at a hydroxy containing side chain residue. In some embodiments, the first amino acid is selected from serine and threonine. In some embodiments, the first amino acid is a serine. In some embodiments, the first amino acid is a threonine. In some embodiments, the prodrug moiety of Formula (III) is attached to the protein at a serine at position X8, X11, X32, X33, X39, or X40. In some embodiments, the prodrug moiety of Formula (III) is attached to the protein at a serine at position X8. In some embodiments, the prodrug moiety of Formula (III) is attached to the protein at a serine at position X11. In some embodiments, the prodrug moiety of Formula (III) is attached to the protein at a serine at position X32. In some embodiments, the prodrug moiety of Formula (III) is attached to the protein at a serine at position, X33. In some embodiments, the prodrug moiety of Formula (III) is attached to the protein at a serine at position X39. In some embodiments, the prodrug moiety of Formula (III) is attached to the protein at a serine at position X40. In some embodiments, the prodrug moiety of Formula (III) is attached to the protein at a threonine at position X7, X39, or X40. In some embodiments, the prodrug moiety of Formula (III) is attached to the protein at a threonine at position X7. In some embodiments, the prodrug moiety of Formula (III) is attached to the protein at a threonine at position X39. In some embodiments, the prodrug moiety of Formula (III) is attached to the protein at a threonine at position X40. Staple In some embodiments, the peptide conjugate comprises a staple. In some embodiments, the stable attached to the peptide at a second amino acid and a third amino acid. In some embodiments, the staple attached to the peptide is of Formula (II):Formula (II) wherein; A is -N-; XAand XBare a bond, -C(=O)-, -alkylene-C(=O)-, -C(=O)-alkylene-, -alkylene-C(=O)NR3-, -alkylene- NR3C(=O)-, -C(=O)NR3-alkylene-, -NR3C(=O)-alkylene-, -alkylene-C(=O)NR3-alkylene-, or - alkylene-NR3C(=O)-alkylene-; wherein XAis attached to the second amino acid of the peptide, XBis attached to the third amino acid of the peptide, and XAand XBare identical; R is hydrogen or -(L)s-Y;each L is independently -(CR1R2)v-, -alkylene-O-, -O-alkylene-, -C(=O)-alkylene-, - alkylene-C(=O)-, - NR3-alkylene-, - alkylene-NR3-, -S-alkylene-, -alkylene-S-, -S(=O)-alkylene-, - alkylene-S(=O)-, - S(=O)2-alkylene, - alkylene-S(=O)2-, -C(=O)-, -C(=O)NR3-, -NR3C(=O)-, -NR3C(=O)NR3-, - NR3C(=O)NR3-alkylene-, -NR3C(=O)-alkylene-NR3-, -alkylene-C(=O)NR3-, -C(=O)NR3-alkylene-, - alkylene-NR3C(=O)-, or -NR3C(=O)-alkylene-; v is 2-20; each R1or R2is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, -P(=O)(ORa)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6alkyl, C1-C6haloalkyl, -ORa, or - NRcRd; or R1and R2are taken together to form a C1-C6cycloalkyl or C1-C6heterocycloalkyl; each R3is independently hydrogen, -S(=O)Rb, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, - C(=O)NRcRd, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6alkyl, C1-C6haloalkyl, -ORa, or -NRcRd; Y is hydrogen, C1-C6alkyl, -CO2H, -P(=O)(OH)2, -CO2(C1-C6alkyl), -CO2NH2, -CO2N(alkyl)2, - CO2NH(alkyl), or 5-membered heteroaryl; s is 0-20; Rais hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1- C6alkyl, C1-C6haloalkyl, -OH, -OMe, or -NH2; Rbis C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1- C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2; and each Rcand Rdis independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and thecycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2; or Rcand Rd, together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. In some embodiments, the staple attached to the peptide is of Formula (II):Formula (II) wherein: A is -N-; X1and X2are a bond, -C(=O)-, -alkylene-C(=O)-, -C(=O)-alkylene-, -alkylene-C(=O)NR3-, -alkylene- NR3C(=O)-, -C(=O)NR3-alkylene-, -NR3C(=O)-alkylene-, -alkylene-C(=O)NR3-alkylene-, or - alkylene-NR3C(=O)-alkylene-; wherein X1is attached to a first amino acid of the peptide, X2is attached to a second amino acid of the peptide, and X1and X2are identical; R is hydrogen or -(L)s-Y; each L is independently -(CR1R2)v-, -alkylene-O-, -O-alkylene-, -C(=O)-alkylene-, - alkylene-C(=O)-, - NR3-alkylene-, - alkylene-NR3-, -S-alkylene-, -alkylene-S-, -S(=O)-alkylene-, - alkylene-S(=O)-, - S(=O)2-alkylene, - alkylene-S(=O)2-, -C(=O)-, -C(=O)NR3-, -NR3C(=O)-, -NR3C(=O)NR3-, - NR3C(=O)NR3-alkylene-, -NR3C(=O)-alkylene-NR3-, -alkylene-C(=O)NR3-, -C(=O)NR3-alkylene-, - alkylene-NR3C(=O)-, or -NR3C(=O)-alkylene-; v is 2-20; each R1or R2is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, - ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORa, or -NRcRd; or R1and R2are taken together to form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl; each R3is independently hydrogen, -S(=O)Rb, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORa, or -NRcRd; Y is hydrogen, C1-C6 alkyl, -CO2H, -CO2(C1-C6 alkyl), -CO2NH2, -CO2N(alkyl)2, or -CO2NH(alkyl);s is 0-20; Rais hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1- C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2; Rbis C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1- C6alkyl, C1-C6haloalkyl, -OH, -OMe, or -NH2; and each Rcand Rdis independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6alkyl, C1-C6haloalkyl, -OH, -OMe, or -NH2; or Rcand Rd, together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6alkyl, C1-C6haloalkyl, -OH, -OMe, or -NH2. In some embodiments, A is optionally substituted alkylene. In some embodiments, A is - (CH2)t-, wherein t is 1-12. In some embodiments, A is -(CH2)t-, wherein t is 1-10. In some embodiments, A is -(CH2)t-, wherein t is 1-8. In some embodiments, A is -(CH2)t-, wherein t is 1-6. In some embodiments, A is -(CH2)t-, wherein t is 1-4. In some embodiments, A is optionally substituted arylene. In some embodiments, A is arylene optionally substituted with halogen, alkyl, or haloalkyl. In some embodiments, A is unsubstituted arylene. In some embodiments, A is -NR3-alkylene-NR3-. In some embodiments, A is -N-. In some embodiments, XAand XBare identical. In some embodiments, XAand XBare different. In some embodiments, XAand XBare -C(=O)-. In some embodiments, XAand XBare independently -alkylene-C(=O)- or -C(=O)alkylene-. In some embodiments, XAand XBare independently -CH2-C(=O)- or -C(=O)-CH2-. In some embodiments, XAand XBare independently - alkylene-C(=O)NR3- or -C(=O)NR3-alkylene-. In some embodiments, XAand XBare independently - CH2-C(=O)NR3- or -C(=O)NR3-CH2-. In some embodiments, XAand XBare independently -alkylene- C(=O)NR3-alkylene- or -alkylene-NR3C(=O)-alkylene-. In some embodiments, XAand XBare independently -CH2-C(=O)NR3-CH2CH2- or -CH2-NR3C(=O)-CH2CH2-. In some embodiments, XAand XBare independently -CH2-C(=O)NH-CH2CH2- or -CH2-NHC(=O)-CH2CH2-.In some embodiments, each R3is independently hydrogen or C1-C6 alkyl. In some embodiments, each R3is hydrogen. In some embodiments, >A-R has the following structure: , wherein r1 and r2 are each independently 0-4. In some embodiments, r1 and r2 are each independently 0-2. In some embodiments, r1 and r2 are each 0. In some embodiments, r1 and r2 are each 1. In some embodiments, r1 and r2 are each 3. In some embodiments, r1 and r2 are each 2. In some embodiments, >A-R has the following structure:. In some embodiments, >A-R has the following structure:1-5. In some embodiments, p1 is 1-3. In some embodiments, p1 is 1-2. In some embodiments, p1 is 1. In some embodiments, p1 is 2. In some embodiments, p1 is 3. In some embodiments, p1 is 4. In some embodiments, p1 is 5. In some embodiments, >A-R has the following structure:. In some embodiments, >A-R has the following structure:. In some embodiments, s is 1-15. In some embodiments, s is 1-10. In some embodiments, s is 5- 15. In some embodiments, s is 5-10. In some embodiments, s is 5-20. In some embodiments, Y is hydrogen or -CO2H. In some embodiments, Y is hydrogen. In some embodiments, Y is -CO2H. In some embodiments, each L is independently -(CR1R2)v-, -alkylene-O-, -C(=O)-, - C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; and v is 2-20. In some embodiments, each L is independently -(CR1R2)v-, -alkylene-O-, -C(=O)-, - C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; and v is 2-16. In some embodiments, v is 2-16. In some embodiments, v is 2-5. In some embodiments, v is 5- 16. In some embodiments, v is 5 or 16. In some embodiments, v is 2 or 16. In some embodiments, each R1or R2is independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, or C1-C6 alkyl.In some embodiments, each R1or R2is independently hydrogen, halogen, -CO2Ra, - C(=O)NRcRd, or C1-C6 alkyl. In some embodiments, each R1or R2is independently hydrogen, -CO2Ra, or -C(=O)NRcRd. In some embodiments, each R1or R2is independently hydrogen or -CO2Ra. In some embodiments, the staple is:. In some embodiments, the staple attached to the peptide is:wherein each L1is independently -(CR1R2)v-, -alkylene-O-, -O-alkylene-, -C(=O)NR3-, -NR3C(=O)-, - alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s1 is 1-15. In some embodiments, the staple attached to the peptide is:wherein each L2is independently -(CR1R2)v-, -alkylene-O-, - O-alkylene-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s2 is 1-15. In some embodiments, the staple attached to the peptide is:wherein each L3is independently -(CR1R2)v- , -alkylene-O-, -O-alkylene-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s3 is 1-15. In some embodiments, the staple attached to the peptide is:wherein each L4isindependently -(CR1R2)v-, -alkylene-O-, -O-alkylene-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s4 is 1-15. In some embodiments, the staple attached to the peptide is:wherein each L5is independently -(CR1R2)v-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene- NR3C(=O)-; v is 2-20; and s5 is 1-10. In some embodiments, the staple attached to the peptide is:independently -(CR1R2)v-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s6 is 1-5. In some embodiments, the staple attached to the peptide is:wherein each L7is independently -(CR1R2)v-, -C(=O)NR3-, or -NR3C(=O)-; v is 2-20; and s7 is 1-5. In some embodiments, the staple attached to the peptide is:-(CR1R2)v- and v is 10-20.In some embodiments, the staple attached to the peptide is:wherein each L9is independently - (CR1R2)v-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s9 is 1-5. In some embodiments, the staple attached to the peptide is:wherein L10is -(CR1R2)v- and v is 10- 20. In some embodiments, the staple attached to the peptideIn some embodiments, the staple attached to the peptidewherein each L11is independently -(CR1R2)v-, -alkylene-O-, -O-alkylene-, -C(=O)NR3-, -NR3C(=O)-, -alkylene- C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s11 is 1-15. In some embodiments, the staple attached to the peptide is:wherein each L12is independently -(CR1R2)v-, -alkylene-O-, -O- alkylene-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s12 is 1-15.In some embodiments, the staple attached to the peptide is:wherein each L13is independently -(CR1R2)v-, - alkylene-O-, -O-alkylene-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s13 is 1-15. In some embodiments, the staple attached to the peptide is:. wherein each L14is independently - (CR1R2)v-, -alkylene-O-, -O-alkylene-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene- NR3C(=O)-; v is 2-20; and s14 is 1-15. In some embodiments, the staple attached to the peptide is:independently -(CR1R2)v-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s15 is 1-10. In some embodiments, the staple attached to the peptide is:(CR1R2)v-, -C(=O)NR3-, or -NR3C(=O)-; v is 2-20; and s16 is 1-5. In some embodiments, the staple attached to the peptide is:independently -(CR1R2)v-, -C(=O)NR3-, or -NR3C(=O)-; v is 2-20; and s17 is 1-5.In some embodiments, the staple attached to the peptide is:wherein L18is - (CR1R2)v- and v is 10-20. In some embodiments, the staple attached to the peptide is:wherein each L19is independently -(CR1R2)v-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s19 is 1-5. In some embodiments, the staple attached to the peptide is:wherein L20is -(CR1R2)v- and v is 10-20. In some embodiments, the staple attached to the peptide comprises Formula (IIa):Formula (IIa) wherein: ZAis a 5-membered heteroaryl, -CO2H, or -P(=O)(OH)2; each R3is independently hydrogen or methyl; R10is -OH or -NH2; R11is hydrogen, -OH, or -P(=O)(OH)2; n0is 0 or 1; n1and n2are each independently 1-4; and m is 6-20. In some embodiments, the staple attached to the peptide comprises Formula (IIb):Formula (IIb) wherein: each R3is independently hydrogen or methyl; R10is -OH or -NH2; R11is hydrogen, -OH, or -P(=O)(OH)2; n0 is 0 or 1; n1 and n2 are each independently 1-4; and m is 6-20. In some embodiments, ZAis -CO2H. In some embodiments, ZAis -P(=O)(OH)2. In some embodiments, ZAis a 5-membered heteroaryl. In some embodiments, ZAis tetrazole. In some embodiments, R10is -OH. In some embodiments, R10is -NH2. In some embodiments, R11is -OH. In some embodiments, R11is -P(=O)(OH)2. In some embodiments, R11is hydrogen. In some embodiments, the staple attached to the peptide comprises:1-4; n2is 1-4; and m is 6-20. In some embodiments, the staple attached to the peptide comprises:wherein n1 is 1-4; n2 is 1- 4; and m is 6-20. In some embodiments, the staple attached to the peptide comprises4; and m is 6-20. In some embodiments, the staple attached to the peptide comprises:, wherein n1is 1-4; n2is 1-4; and m is 6-20. In some embodiments, n1is: 1-3. In some embodiments, n1is 4. In some embodiments, n1is 3. In some embodiments, n1 is 2. In some embodiments, n1 is 1. In some embodiments, n2 is 1-3. In some embodiments, n2 is 3. In some embodiments, n2 is 2. In some embodiments, n2 is 1. In some embodiments, m is 6-20. In some embodiments, m is 10-20. In some embodiments, m is 15-20. In some embodiments, m is 15-18. In some embodiments, m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13. In some embodiments, m is 13. In some embodiments, m is 14. In some embodiments, m is 15. In some embodiments, m is 16. In some embodiments, m is 17. In some embodiments, m is 18. In some embodiments, m is 19. In some embodiments, m is 20. In some embodiments, the staple attached to the peptide is:the “⌇-S” being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6- mercaptohexanoic acid residue and the “⌇-NH” being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue. In some embodiments, the staple attached to the peptide is:. In some embodiments, the staple attached to the peptide is:In some embodiments, the staple attached to the peptide is:In some embodiments, the staple attached to the peptide is:In some embodiments, the staple attached to the peptide is:In some embodiments, the staple attached to the peptide is:In some embodiments, the staple attached to the peptide comprises Linker L1, Linker L2, or Linker L3:. In some embodiments, X independently comprises C14, C14 diacid, C16, C16 diacid, C18, C18 diacid, C20 or C20 diacid. In some embodiments, X comprises Propionic acid (CH3CH2COOH, C3:0). In some embodiments, X comprises Butyric acid (Butanoic acid, CH3(CH2)2COOH, C4:0). In some embodiments, X is Valeric acid (Pentanoic acid, CH3(CH2)3COOH, C5:0). In some embodiments, X comprises Caproic acid (Hexanoic acid, CH3(CH2)4COOH, C6:0). In some embodiments, X comprises Enanthic acid (Heptanoic acid, CH3(CH2)5COOH, C7:00. In some embodiments, X comprises Caprylic acid (Octanoic acid, CH3(CH2)6COOH, C8:0). In some embodiments, X comprises Pelargonic acid(Nonanoic acid, CH3(CH2)7COOH, C9:0). In some embodiments, X comprises Capric acid (Decanoic acid, CH3(CH2)8COOH, C10:0). In some embodiments, X comprises Undecylic acid (Undecanoic acid, CH3(CH2)9COOH, C11:0). In some embodiments, X comprises Lauric acid (Dodecanoic acid, CH3(CH2)10COOH, C12:0). In some embodiments, X comprises Tridecylic acid (Tridecanoic acid, CH3(CH2)11COOH, C13:0). In some embodiments, X comprises Myristic acid (Tetradecanoic acid, CH3(CH2)12COOH, C14:0). In some embodiments, X comprises Pentadecylic acid (Pentadecanoic acid, CH3(CH2)13COOH, C15:0). In some embodiments, X comprises Palmitic acid (Hexadecanoic acid, CH3(CH2)14COOH, C16:0). In some embodiments, X comprises Margaric acid (Heptadecanoic acid, CH3(CH2)15COOH, C17:0). In some embodiments, X comprises Stearic acid (Octadecanoic acid, CH3(CH2)16COOH, C18:0). In some embodiments, X comprises Nonadecylic acid (Nonadecanoic acid, CH3(CH2)17COOH, C19:0). In some embodiments, X comprises Arachidic acid (Eicosanoic acid, CH3(CH2)18COOH, C20:0). In some embodiments, X comprises Heneicosylic acid (Heneicosanoic acid, CH3(CH2)19COOH, C21:0). In some embodiments, X comprises Behenic acid (Docosanoic acid, CH3(CH2)20COOH, C22:0). In some embodiments, X comprises Tricosylic acid (Tricosanoic acid, CH3(CH2)21COOH, C23:0). In some embodiments, X comprises Lignoceric acid (Tetracosanoic acid, CH3(CH2)22COOH, C24:0). In some embodiments, X comprises Pentacosylic acid (Pentacosanoic acid, CH3(CH2)23COOH, C25:0). In one aspect, disclosed herein are peptide conjugates comprising: a peptide and a staple attached to the peptide at a second amino acid and a third amino acid. Non-limiting examples of amino acids for use in conjugation include cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, homolysine, other sulfhydryl containing amino acids, or other amine containing amino acids. In some embodiments, the two amino acids connected by a staple are about or at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more amino acids apart. For example, the second amino acid has position i, and the third amino acid has position i + 7, i + 11, i + 13, i + 15, or i + 16. For example, the second amino acid has a position i in the peptide and the third amino acid has a position i + n in the peptide, wherein n is 4-16. In some embodiments, the second amino acid is at the 14 position and the third amino acid is at the 21 position in the peptide. In some embodiments, the second amino acid is at the 17 position and the third amino acid is at the 24 position in the peptide. For example, the second amino acid has a position i in the peptide and the third amino acid has a position i + 4 in the peptide. For example, the second amino acid has a position i in the peptide and the third amino acid has a position i + 5 in the peptide. For example, the second amino acid has a position i in the peptide and the third amino acid has a position i + 6 in the peptide. For example, the second amino acid has a position i in the peptide and the third amino acid has a position i + 7 in the peptide. For example, the second amino acid has a position i in the peptide and the third amino acid has a position i + 8 in the peptide. For example, the second amino acid has a position i in the peptide and the third amino acid has a position i + 9 in the peptide. For example, the second amino acid has a position i in the peptide and the third amino acid has a position i + 10 in the peptide. For example, the second amino acid has aposition i in the peptide and the third amino acid has a position i + 11 in the peptide. For example, the second amino acid has a position i in the peptide and the third amino acid has a position i + 12 in the peptide. For example, the second amino acid has a position i in the peptide and the third amino acid has a position i + 13 in the peptide. For example, the second amino acid has a position i in the peptide and the third amino acid has a position i + 14 in the peptide. For example, the second amino acid has a position i in the peptide and the third amino acid has a position i + 15 in the peptide. For example, the second amino acid has a position i in the peptide and the third amino acid has a position i + 16 in the peptide. In some embodiments, the second amino acid and the third amino acid are independently selected from the group consisting of an amine-containing amino acid and a sulfhydryl-containing amino acid. In some embodiments, the second amino acid and third amino acid is independently selected from cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, and 2-amino-6-mercaptohexanoic acid. In some embodiments, the second amino acid and third amino acid are cysteines. In some embodiments, the second amino acid and third amino acid is independently selected from lysine, ornithine, diaminobutyric acid, diaminopropionic acid and homolysine. In some embodiments, the second amino acid and third amino acid are lysines. In some embodiments, the second amino acid and third amino acid are ornithines. Compound Intermediates In another aspect, provided herein is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof:Formula (V) wherein: each R3is independently hydrogen or methyl; R10is -OH or -NH2; R11is hydrogen, -OH, or -P(=O)(OH)2; n0is 0 or 1; n1and n2are each independently 1-4; and m is 6-20. In some embodiments of Formula (V), n0is 0. In some embodiments of Formula (V), n0is 1. In some embodiments of Formula (V), each R3is methyl. In some embodiments of Formula (V), each R3is hydrogen.In some embodiments of Formula (V), R10is -OH. In some embodiments of Formula (V), R10is -NH2. In some embodiments of Formula (V), R11is hydrogen. In some embodiments, the compound is of Formula:wherein n1is 1-4; n2is 1-4; and m is 6-20. In some embodiments, the compound is of Formula:wherein n1 is 1-4; n2 is 1-4; and m is 6-20. In some embodiments of Formula (V), n1 is 1, 2, or 3. In some embodiments of Formula (V), n1 is 1. In some embodiments, n1 is 2. In some embodiments, nis 3. In some embodiments of Formula (V), n2 is 1, 2, or 3. In some embodiments of Formula (V), n2 is 1. In some embodiments, n2 is 2. In some embodiments, n2 is 3. In some embodiments of Formula (V), m is 10-20. In some embodiments of Formula (V), m is 10-20. In some embodiments of Formula (V), m is 15-20. In some embodiments of Formula (V), m is 15- 18. In some embodiments of Formula (V), m is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In some embodiments, the compound is:pharmaceutically acceptable salt or solvate thereof.Peptide Conjugates In some embodiments, a peptide conjugate described herein is as shown in Table 2. Table 2: Exemplary Peptide Conjugates

[0202] In some embodiments, a peptide conjugate described herein is as shown in Table 3.Table 3: Exemplary Peptide ConjugatesPharmcokinetics

[0203] Mechanisms by which peptides and peptide conjugates positively influence pharmacokinetic or pharmacodynamic behavior include, but are not limited to, (i) preventing or mitigating in vivo proteolytic degradation or other activity-diminishing chemical modification of the therapeutic agent; (ii) improving half-life or other pharmacokinetic properties by reducing renal filtration, decreasing receptor-mediated clearance or increasing bioavailability; (iii) reducing toxicity; (iv) improving solubility; and / or (v) increasing biological activity and / or target selectivity of the unconjugated therapeutic agent. The therapeutic agent may comprise a peptide that modulates and / or binds to: a GLP-1 receptor, a GIP receptor, or a GLP-1 receptor and GIP receptor. The therapeutic agent may comprise a peptide comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOS: 1-86.

[0204] Peptide conjugates may enhance one or more pharmacokinetic properties of a therapeutic agent when attached to the therapeutic agent. Peptide conjugates disclosed herein may enhance the one or more pharmacokinetic properties of the therapeutic agent by at least about 200% as measured by pharmacodynamics when compared to the therapeutic agent or unmodified therapeutic peptide alone. Peptide conjugates disclosed herein may enhance the one or more pharmacokinetic properties of the therapeutic agent by at least about 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% as measured by pharmacodynamics when compared to the therapeutic agent or unmodified therapeutic peptide alone.

[0205] The pharmacokinetic properties may comprise a half-life. The half-life of the peptide conjugate may be at least about two-fold longer compared to the half-life of the unmodified peptide alone. The half- life of the peptide conjugate disclosed herein may be at least about 3-fold, 4-fold, 5-fold, or 10-fold longer compared to the half-life of the therapeutic agent or unmodified therapeutic peptide alone. The half-life of a peptide conjugate disclosed herein may be at least about 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, or 50-fold longer compared to the half-life of the unmodified peptide alone.

[0206] In some embodiments, the half-life of the peptide conjugate is at least about 2-fold greater than the half-life of an unmodified form of the peptide. In some embodiments, the half-life of the peptide conjugate is at least about 5-fold greater than the half-life of an unmodified form of the peptide. In some embodiments, the half-life of the peptide conjugate is at least about 10-fold greater than the half-life of an unmodified form of the peptide.

[0207] In addition, a peptide conjugate as described herein may have a positive effect on terms of increasing manufacturability, and / or reducing immunogenicity of the peptide, compared to an unconjugated form of the unmodified therapeutic peptide. Therapeutic Use

[0208] In one aspect, peptides and peptide conjugates disclosed herein are useful for treating, alleviating, inhibiting and / or preventing one or more diseases and / or conditions. The disease and / or condition may be a chronic disease or condition. Alternatively, the disease and / or condition is an acute disease or condition. The disease or condition may be recurrent, refractory, accelerated, or in remission. The disease or condition may affect one or more cell types. The one or more diseases and / or conditions may be an autoimmune disease, inflammatory disease, or metabolic disease.

[0209] Disclosed herein are methods for treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a peptide conjugate described herein. The disease or condition may be diabetes or obesity, or a medical condition associated with diabetes or obesity. The diabetes may be type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes, neonatal diabetes, maturity onset diabetes of the young, or latent autoimmune diabetes in adults, or any combination thereof. The disease or condition may be non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF), or cardiovascular disease. The disease or condition may be non-alcoholic fatty liver disease (NAFLD). The disease or condition may be nonalcoholic steatohepatitis (NASH). The disease or condition may be idiopathic pulmonary fibrosis (IPF). The disease or condition may be cardiovascular disease. The disease or condition may be an autoimmune disorder. The disease or condition may be Crohn’s disease or ulcerative colitis. The disease or condition may be short bowel syndrome (SBS). The disease or condition may be inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), or psoriasis. The disease or condition may be inflammatory bowel disease (IBD). The disease or condition may be inflammatory bowel syndrome (IBS). The disease or condition may be psoriasis. The disease or condition may be Alzheimer’s disease, Parkinson’s disease or Huntington’s disease. The disease or condition may be Alzheimer’s disease. The disease or condition may be Parkinson’s disease. The disease or condition may be Huntington’s disease. The peptide conjugate may be administered with one or more additional therapeutic agents. Disclosed herein are methods of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a composition disclosed herein comprising one or more peptide conjugates.

[0210] Provided herein is a method of preventing or treating a metabolic disease or condition in a subject in need thereof, the method comprising administering to the subject a peptide conjugate described herein. The metabolic disease or condition may be diabetes. The metabolic disease or condition may beobesity. The metabolic disease or condition may be glycogen storage disease, phenylketonuria, maple syrup urine disease, glutaric acidemia type 1, Carbamoyl phosphate synthetase I deficiency, alcaptonuria, Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD), acute intermittent porphyria, Lesch-Nyhan syndrome, lipoid congenital adrenal hyperplasia, congenital adrenal hyperplasia, POMPC deficiency, LEPR deficiency, Bardet Biedl syndrome, Alstrome syndrome, Prader-Willi Syndrome, Kearns-Sayre syndrome, Zellweger syndrome, Gaucher's disease, or Niemann Pick disease.

[0211] Provided herein is a method of preventing or treating NAFLD, NASH, IPF, or cardiovascular disease in a subject in need thereof, the method comprising administering to the subject a peptide conjugate described herein.

[0212] Provided herein is a method of preventing or treating short bowel syndrome (SBS) in a subject in need thereof, the method comprising administering to the subject a peptide conjugate described herein.

[0213] Provided herein is a method of preventing or treating inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), or psoriasis in a subject in need thereof, the method comprising administering to the subject a peptide conjugate described herein.

[0214] Provided herein is a method of preventing or treating Crohn’s disease or ulcerative colitis in a subject in need thereof, the method comprising administering to the subject a peptide conjugate described herein.

[0215] Provided herein is a method of preventing or treating chronic kidney disease (for example complication of diabetes). Provided herein is a method of preventing or treating diabetic heart disease. Provided herein is a method of preventing or treating cardiovascular events. Provided herein is a method of preventing or treating Alzheimer’s disease, Parkinson’s disease or Huntington’s disease in a subject in need thereof, the method comprising administering to the subject a peptide conjugate described herein.

[0216] Provided herein is a method of preventing or treating stomach and bowel-related disorders, such as the treatment of neonatals with compromised intestine function, osteoporosis, and DPP-IV (dipeptidylpeptidase-IV) mediated conditions. By way of example, the stomach and bowel-related disorders include ulcers, gastritis, digestion disorders, malabsorption syndromes, short-gut syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue (for example arising from gluten induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemia sprue, enteritis, regional enteritis (Crohn's disease), ulcerative colitis, irritable bowel syndrome associated with diarrhea, Small intestine damage and short bowel syndrome.

[0217] Provided herein is a method of preventing or treating radiation enteritis, infectious or post- infectious enteritis, and small intestinal damage due to toxic or other chemotherapeutic agents. This may require administration of the peptide conjugate prior to, concurrently with or following a course of chemotherapy or radiation therapy in order to reduce side effects of chemotherapy such as diarrhea, abdominal cramping and vomiting, and reduce the consequent structural and functional damage of the intestinal epithelium resulting from the chemotherapy or radiation therapy.

[0218] Provided herein is a method of preventing or treating malnutrition, for example conditions such as the wasting syndrome cachexia and anorexia.

[0219] Provided herein is a method of preventing or treating a disease or condition which benefits from a modulator and / or binder of a GLP-1 receptor in a subject in need thereof comprising administering to the subject a peptide conjugate described herein.

[0220] Provided herein is a method of preventing or treating a disease or condition which benefits from a modulator and / or binder of a GLP-1 / GIP receptor in a subject in need thereof comprising administering to the subject a peptide conjugate described herein.

[0221] Provided herein is a method of preventing or treating a disease or condition which benefits from a modulator and / or binder of a GIP receptor in a subject in need thereof comprising administering to the subject a peptide conjugate described herein. Combinations

[0222] Disclosed herein are pharmaceutical compositions comprising a peptide or peptide conjugate described herein and one or more additional therapeutic agents.

[0223] The additional therapeutic agents may comprise one or more other diabetes drugs, DPP4 inhibitors, SGLT2 inhibitors, hypoglycemic drugs and biguanidine drugs, insulin secretogogues and sulfonyl urea drugs, TZD drugs, insulin and insulin analogs, FGF21 and analogs, leptin or leptin analogs, amylin and amylin analogs, an anti-inflammatory drug, cyclosporine A or FK506, 5-ASA, or a statin, or any combination thereof. The additional therapeutic agent may be aspirin.

[0224] The additional therapeutic agents may comprise a therapeutic incretin or derivative thereof. Non-limiting examples of incretins or derivatives thereof include GLP-1, glucagon, oxyntomodulin, exendin-4, GLP-2, GIP, and combinations thereof.

[0225] In some embodiments, combination treatment demonstrates superior glucose control, food intake reduction, and weight loss than administration of a single agent. In some embodiments, combination treatment mimics the beneficial effects of bariatric surgery in an obese patient. Definitions

[0226] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition,method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

[0227] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0228] “Alkyl” refers to a straight or branched chain hydrocarbon monoradical, which may be fully saturated or unsaturated, having from one to about ten carbon atoms, or from one to six carbon atoms, wherein a sp3-hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples of saturated hydrocarbon monoradical include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl- 3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2- pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1- butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C1-C6alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10alkyl, a C1-C9alkyl, a C1-C8alkyl, a C1-C7alkyl, a C1-C6alkyl, a C1-C5alkyl, a C1-C4alkyl, a C1-C3alkyl, a C1-C2alkyl, or a C1alkyl. When the alkyl refers to an unsaturated straight or branched chain hydrocarbon monoradical it is known as an “alkenyl” or an “alkynyl”. The alkenyl may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples of alkenyls include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-C10alkenyl, a C2-C9alkenyl, a C2-C8alkenyl, a C2-C7alkenyl, a C2-C6alkenyl, a C2-C5alkenyl, a C2-C4alkenyl, a C2-C3alkenyl, or a C2alkenyl. Examples of alkynyl include, but are not limited to ethynyl, 2-propynyl, 2- and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10 alkynyl, a C2-C9 alkynyl, a C2-C8 alkynyl, a C2-C7 alkynyl, a C2-C6 alkynyl, a C2-C5 alkynyl, a C2-C4 alkynyl, a C2-C3 alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with oxo,halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0229] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Whenever it appears herein, a numerical range such as “C1-C6 alkylene” means that the alkylene consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkylene” where no numerical range is designated. In some embodiments, the alkylene is a C1-C10 alkylene, a C1-C9 alkylene, a C1-C8 alkylene, a C1-C7 alkylene, a C1-C6 alkylene, a C1-C5 alkylene, a C1-C4 alkylene, a C1-C3 alkylene, a C1-C2 alkylene, or a C1 alkylene. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0230] “Alkoxy” refers to a radical of the formula -ORawhere Rais an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0231] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as- indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. In some embodiments, the aryl is phenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0232] “Cycloalkyl” refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl isbonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0233] “Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0234] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0235] “Heterocycloalkyl” refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C2-C15heterocycloalkyl), from two to ten carbon atoms (C2-C10heterocycloalkyl), from two to eight carbon atoms (C2-C8heterocycloalkyl), from two to six carbon atoms (C2-C6heterocycloalkyl), from two to five carbon atoms (C2-C5heterocycloalkyl), or two to four carbon atoms (C2-C4heterocycloalkyl). In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3- oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Partially saturated heterocycloalkyls include, for example dihydropyrrolyl or tetrahydropyridine. Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0236] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)- ), sulfur, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0237] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In someembodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or - OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0238] 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.

[0239] Percent (%) sequence identity with respect to a reference polypeptide sequence is the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are known for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Appropriate parameters for aligning sequences are able to be determined, including algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer programALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0240] “Pharmaceutically acceptable” refers to approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans.

[0241] “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.

[0242] “Pharmaceutically acceptable excipient, carrier or adjuvant” refers to an excipient, carrier or adjuvant that may be administered to a subject, together with at least one antibody of the present disclosure, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

[0243] “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient, or carrier with which at least one antibody of the present disclosure is administered.

[0244] Terms such as “treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” may refer to: 1) therapeutic measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic condition or disorder; and / or 2) prophylactic or preventative measures that prevent and / or slow the development of a targeted pathologic condition or disorder. “Treatment” refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, and diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improvedprognosis. Thus, those in need of treatment may include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented.

[0245] “Amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function similarly to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, gamma-carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, e.g., an alpha carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs can have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions similarly to a naturally occurring amino acid.

[0246] “Disorder” or “disease” refers to a condition that would benefit from treatment with a substance / molecule (e.g., a peptide conjugate disclosed herein) or method disclosed herein. This includes chronic and acute disorders or diseases including those pathological conditions which predispose the mammal to the disorder in question.

[0247] “Incretin” refers to a metabolic hormone that stimulates a decrease blood glucose levels. Examples of incretins include but are not limited to GLP-1 and GIP.

[0248] “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, rodents (e.g., mice and rats), and monkeys; domestic and farm animals; and zoo, sports, laboratory, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. In some embodiments, the mammal is selected from a human, dog, rodent, or monkey. In some embodiments, the subject having a disease or condition in need of treating is a human. In some embodiments, the subject having a disease or condition in need of treating is a companion animal. In some embodiments, the subject having a disease or condition in need of treating is a dog. In some embodiments, the subject having a disease or condition in need of treating is a cat.

[0249] “Modulate” refers to the ability of a peptide to bind to a protein receptor. In some embodiments, the modulator is a ligand of the receptor. In some embodiments, the modulator is an agonist. In some embodiments, the modulator is an antagonist. For instance, a peptide that modulates the GLP-1 receptor binds to a GLP-1 receptor (GLP-1R). For instance, a peptide that modulates the GCG receptor binds to a GCG receptor (GCGR). For instance, a peptide that modulates the GIP receptor binds to a GIP receptor (GIPR). For instance, a peptide that modulates the PYY receptor binds to a PYY receptor (PYYR). As non-limiting examples, the peptide that modulates the GLP-1 receptor is a GLP-1R agonist. As non-limiting examples, the peptide that modulates both the GLP-1 receptor and the GCG receptor is a dual GLP-1R / GCGR agonist. As non-limiting examples, the peptide that modulates both the GLP-1 receptor and the GIP receptor is a dual GLP-1R / GIPR agonist. As non-limiting examples, the peptide that modulates the PYY receptor is a PYYR agonist.

[0250] “Unmodified peptide” refers to either an unmodified sequence (wild type peptide) or a modified sequence without a staple. EXAMPLES

[0251] Peptides were synthesized by standard solid-phase peptide synthesis (SPPS) techniques and purified via HPLC.

[0252] Unless otherwise noted, all reagents were purchased from commercial suppliers and used without further purification. All reactions involving air or moisture sensitive reagents or intermediates were performed under an inert atmosphere of nitrogen or argon. All solvents used were of HPLC grade. Reactions were monitored by LC-MS or by thin-layer chromatography (TLC) on Merck 50 × 100 mm silica gel 60 aluminum sheets stained using an aqueous solution of KMnO4.

[0253] Flash chromatography purifications were performed on silica gel prepacked columns (40 μm, RediSep®Rf from Teledyne Isco) on a CombiFlash®Rf (Teledyne Isco). Purified final compounds were eluted as single and symmetrical peaks (thereby confirming a purity of ≥95%).

[0254] Semi-preparative chromatography were performed on a Shimadzu HPLC with a Phenomenex Luna column (C18, 100 Å pore size, 10 µm particle size, 250 × 10.0 mm, flow: 4 mL / min) or on an Agilent 1200 HPLC with a Phenomenex Luna column (C18, 100 Å pore size, 5 µm particle size, 150 × 21.2 mm, flow: 20 mL / min).

[0255] 1H and13C NMR spectra were recorded on a Bruker 400 system in d6-DMSO, CDCl3or CD3OD. Chemical shifts are given in parts per million (ppm) with tetramethylsilane as an internal standard. Abbreviations are used as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, dd = doublet of doublets, br = broad. Coupling constants (J values) are given in hertz (Hz).

[0256] Low resolution mass spectra were recorded on a Waters Acquity UPLC with a Phemomenex Luna Omega C18 column (C18, 100 Å pore size, 1.6 µm particle size, 50 × 2.1 mm, flow: 0.4 mL / min). Solvents: A - H2O + 0.1% formic acid, B - MeCN + 0.1% formic acid, gradient: 0-1 min 10-90% B, 1- 1.6 min 90% B, 1.6-1.7 min 90-10% B, 1.7-2 min 10% B.

[0257] High resolution mass spectra (HRMS) were recorded on an Agilent 1200 Series Accurate Mass Time-of-Flight (TOF) with an Aeris Widepore column (XB-C8, 3.6 µm particle size, 150 × 2.1 mm, flow: 0.5mL / min). Solvents: A - H2O + 0.1% formic acid, B - MeCN + 0.1% formic acid, gradient: 0-2 min 5% B, 2-12 min 5-60% B, 12-13 min 60-80% B, 13-14 min 80-20% B, 14-15 min 20-80% B, 15-16 min 80-20% B, 16-17 min 20-95% B, 17-20 min 95% B, 20-21 min 95-5% B. General protocol A for loading of chlorotrityl chloride resin

[0258] Fmoc-Lys(ivDde)-OH (60 mg, 100 µmol) was coupled to 2-chlorotrityl chloride resin (Novabiochem) (100 mg, 80 µmol) by mixing the amino acid, resin, and DIEA (70 µL, 400 µmol) in 5 mL of DMF and stirring for 30 min. The resin was then washed with DMF (3x), DCM (3x) and treated with CH3OH / DCM / DIEA (8:1:1) for 10 min to cap the unreacted trityl chloride sites, dried under vacuum and stored in a desiccator.General protocol B for deprotection of Fmoc protecting group

[0259] To the resin was added piperidine in DMF (20%). The mixture was shaken for 5 min and drained. Fresh 20% piperidine was added and this time the mixture was shaken for 15 min. Positive ninhydrin and / or TNBS test was observed. The resin was then washed with DMF (3x), DCM (3x). General protocol C for deprotection of ivDde protecting group

[0260] After washing with DMF and DCM, the resin was treated with 2% hydrazine in DMF (5 mL, 2 × 15 min). Positive ninhydrin and / or TNBS test was observed. The resin was then washed with DMF (3x), DCM (3x). General protocol D for peptide coupling

[0261] The resin was treated with the carboxylic acid derivative specified (3 eq) using coupling reagent HATU (3.3 eq), and DIEA (3.3 eq) in DMF (5 mL) for 2 h or repeated until a negative ninhydrin and / or TNBS test was observed. The resin was then washed with DMF (3x), DCM (3x). General protocol E for on-resin bromoacetylation

[0262] The resin was then treated with bromoacetic anhydride (2.4 eq), and DIEA (2.6 eq) in 200 mL of DCM for 30 min. General protocol F for cleavage of peptides from chlorotrityl resin

[0263] The resin was washed with DCM (3x), the product was cleaved from the resin using 5 mL of 10% TFA in DCM containing 10% H2O and 10% triisopropylsilane for 1 h. Example 1: Synthesis of Staple L5A

[0264] The peptide was synthesized using standard Fmoc chemistry.

[0265] 1. Resin preparation: To a solution of 2-CTC Resin (2.0 mmol, 1.00 eq, Sub 0.50 mmol / g) and Fmoc-Lys(Dde)-OH (1.00 eq) in DCM (50.0 mL) was added DIEA (4.00 eq) and the mixture was agitated under N2 at 25 °C for 2.5 h. Then MeOH (4.00 mL) was added to the resin and the mixture was agitated under N2 at 25 °C for 0.5 h. Next the mixture was filtered and the resin which was washed with DMF (50.0 mL * 5).

[0266] 2. Deprotection: 20% piperidine in DMF (50.0 mL) was added to the mixture and the resin was agitated under N2 at 25 °C for 15 min. Then the resin was washed with DMF (50.0 mL * 5) and filtered to obtain the modified and deprotected resin.

[0267] 3. Coupling: A solution of HBTU (2.85 eq) and C18Diacid(tBu) (3.00 eq) in DMF (50.0 mL) was added to the resin followed by DIEA (6.00 eq). The mixture was agitated under N2 at 25 ℃ for 30 min. Then the resin was washed with DMF (50.0 mL * 5).

[0268] After the coupling of C18Diacid(tBu), 3% H2N·NH2 / DMF (50.0 mL) was added and the mixture was reacted from 30 min. Then the mixture was drained and washed with DMF (50.0 mL) 5 times.

[0269] 4. Steps 2 and 3 were repeated for the coupling of following amino acids: (Nos 3-5).

[0270] 5. Deprotection: 20% piperidine in DMF (50.0 mL) was added and the resin was agitated under N2 at 25 °C for 15 min. Then the resin was washed with DMF (50.0 mL * 5) and filtered.

[0271] 6. Coupling: A solution of 2-bromoacetic acid (6.00 eq) in DMF (50.0 mL) was added to the resin. Then DIC (6.00 eq) was added and the mixture was agitated under N2 at 25 ℃ for 30 min. Next the resin was washed with DMF (50.0 mL * 5) and filtered to obtain the resin linked staple (7.1g).

[0272] Cleavage and Purification:

[0273] Cleavage solution (75.0 mL, 92.5% TFA / 2.50% TIS / 2.50% H2O / 2.50% 3-Mercaptopropionic acid) was added to the flask containing the resin at room temperature and the mixture was stirred for 2 h.

[0274] The staple was precipitated with cold isopropyl ether (750 mL) and filtered. The filter cake was washed with isopropyl ether (750 mL * 2) and dried under vacuum for 2 h to obtain the crude staple (2.51 g).

[0275] The crude staple was purified by prep-HPLC (TFA condition: A: 0.075 % TFA in H2O, B: CAN) to give Staple L5A (1.3 g, 846.93 μmol, 42.35% yield, 84.83% purity, TFA) as a white solid. Staple L5A was confirmed via LCMS (Rt= 1.628 min) and HPLC (Rt= 15.601min).

[0276] Purification conditions:Example 2: General procedure for the preparation of Staple P1CBR-221

[0277] General procedure for the preparation of compound 2

[0278] To a solution of compound 1 (50.0 g, 132 mmol, 1.00 eq) in MeOH (500 mL) was added H2SO4(12.9 g, 132 mmol, 7.06 mL, 1.00 eq). The mixture was stirred at 80 °C for 8 h. TLC (petroleum ether: ethyl acetate = 3: 1) showed that compound 1 was consumed. The reaction mixture was concentrated under vacuum. The crude product was diluted with H2O (400 mL) and ethyl acetate (500 mL * 3) and the aqueous phase was adjusted to pH 7 with saturated NaHCO3(80 mL). The combined organic layers were washed with brine (200 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 2 (55.0 g, crude) as a white solid.

[0279] 1H NMR: 400 MHz, CDCl3δ: 3.66 (s, 3H), 3.40 (t, J = 6.8 Hz, 2H), 2.29 (t, J = 7.6 Hz, 2H), 1.81 – 1.88 (m, 2H), 1.54 – 1.65 (m, 2H), 1.22 – 1.43 (m, 28H).

[0280] General procedure for the preparation of compound 4

[0281] To a solution of Cs2CO3(33.2 g, 102 mmol, 2.00 eq) and tetraethylammoniumiodide (13.1 g, 51.0 mmol, 1.00 eq) in DMF (200 mL) was compound 3 (14.7 g, 56.2 mmol, 1.10 eq) was addeddropwise at 20 °C. Then compound 2 (20.0 g, 51.0 mmol, 1.00 eq) was added and the reaction was stirred at 35 °C for 8 h. The reaction mixture was filtered and the filtrate was quenched with H2O (500 mL) and extracted with ethyl acetate (500 mL * 2). The combined organic layers were washed with brine (500 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 4 (30.0 g, 50.1 mmol, 98.2% yield, 95.8% purity) as a white solid.

[0282] LCMS: MS cal.: 572.3, MS observed: [M+H]+= 573.3

[0283] 1H NMR:400 MHz, CDCl3 δ:7.29 – 7.36 (m, 10H), 4.89 – 5.11 (m, 4H), 3.65 (s, 3H), 2.29 (t, J = 7.6 Hz, 2H), 1.68 – 1.87 (m, 2H), 1.49 – 1.62 (m, 4H), 1.21 – 1.27 (m, 28H).

[0284] General procedure for the preparation of Intermediate A

[0285] To a solution of compound 4 (15.0 g, 25.0 mmol, 1.00 eq) in THF (140 mL) was added LiOH.H2O (3.15 g, 75.2 mmol, 3.00 eq) and H2O (140 mL). The mixture was stirred at 35 °C for 8 h. The reaction mixture was quenched with the addition of 1 N HCl (100.0 mL), and was extracted with ethyl acetate (400 mL * 2). The combined organic layers were washed with brine (400 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give Intermediate A (22.0 g, 39.3 mmol, 78.4% yield, 100% purity) as a white solid.

[0286] LCMS: MS cal.: 558.7, MS observed: [M+H]+= 559.3

[0287] 1H NMR: 400 MHz, DMSO-d6δ: 11.9 (s, 1H), 7.30 – 7.39 (m, 10H), 4.91 – 5.03 (m, 4H), 2.17 (t, J = 7.6 Hz, 2H), 1.72 – 1.80 (m, 2H), 1.34 – 1.48 (m, 4H), 1.18 – 1.30 (m, 28H).

[0288] General procedure for the preparation of compound 6

[0289] To a solution of compound 5 (25.0 g, 82.4 mmol, 1.00 eq) in DCM (50.0 mL) was added dihydrofuran-2,5-dione (8.24 g, 82.4 mmol, 1.00 eq) and the mixture was stirred at 20 °C for 12 h. Then reaction was concentrated. The residue was purified by column chromatography (SiO2, DCM: MeOH = 10: 1 to 1: 1, dichloromethane: methanol = 10: 1, Rf= 0.65) to obtain compound 6 (25.0 g, 61.9 mmol, 75.1% yield) as a yellow oil.

[0291] 1. Resin preparation: To 2-CTC Resin (20.0 mmol, 1.00 eq, Sub: 1.10 mmol / g) was added Alloc- Lys(Fmoc)-OH (20.0 mmol, 1.00 eq) and DIEA (20.0 mmol, 4.00 eq) in DCM (200 mL). The mixture was agitated under N2 for 2 h at 20 °C. Then MeOH (19.0 mL) was added and the mixture was agitated under N2 for 30 min. The resin was then washed with DMF (200 mL * 5).

[0292] 2. Deprotection: 20% piperidine in DMF (200 mL) was added and the resin was agitated under N2 for 15 min. The resin was then washed with DMF (200 mL * 5) and filtered.

[0293] 3. Coupling: To a solution of Fmoc-NH-PEG2-Propionic Acid (20.0 mmol, 2.00 eq) and HBTU (20.0 mmol, 2.85 eq) in DMF (2000 mL) was added DIEA (20 mmol, 6.00 eq) and the resin was agitated under N2for 60 min. at 20 °C. The resin was then washed with DMF (200 mL * 5).

[0294] Steps 2 and 3 were repeated for the coupling of following amino acids (1-4).

[0295] Cleavage and Purification:

[0296] The resin was washed with MeOH (200 mL * 3) and dried under vacuum to obtain 50.0 g of resin bound product. Then 500 mL of cleavage solution (20% HIFP / 80% DCM) was at 20 °C and the mixture was stirred for 45 min. The crude product was concentrated under vacuum and was monitored via LCMS.

[0297] The crude product was purified by prep-HPLC (A: 0.075% TFA in H2O, B: CAN) to obtain compound 7 (10.1 g, 6.37 mmol, 31.8% yield, 82.2% purity, TFA) as a white solid.

[0298] LCMS (MS cal.: 1190.0, MS observed: [M+H]+= 1191.0).

[0299] HPLC (82.2% purity).

[0300] General procedure for the preparation of compound 8

[0301] To a solution of compound 7 (8.00 g, 6.72 mmol, 1.00 eq) in THF (10.0 mL) and H2O (10.0 mL) was added Pd / C (0.80 g, 10% purity). The resulting mixture was stirred in H2 (50 psi) atmosphere at 20 °C for 1 h. The LCMS showed compound 7 was consumed and the product mass was detected (MS cal.: 1010.2 MS observed: [M / 2+H]+= 506.0). The residue was filtered and concentrated under reduced pressure to obtain compound 8 (5.00 g, 4.94 mmol, 73.6% yield) as a white solid.

[0302] General procedure for the preparation of Staple P1CBR-221

[0303] To a solution of compound 8 (1.00 g, 989 μmol, 1.00 eq) in THF (10.0 mL) was added saturated NaHCO3 solution (3.00 mL) and (2,5-dioxopyrrolidin-1-yl) 2-bromoacetate (584 mg, 2.47 mmol, 2.50 eq). The mixture was stirred at 20 °C for 1 h. LCMS showed compound 8 was consumed completely and the desired product mass was detected (MS cal.: 1252, MS observed: [M / 2+H]+= 626.8). Next, 2 mL of citric acid solution was added to adjust the pH to 5. The residue was purified by prep-HPLC (TFA condition) to obtain staple P1CBR-221 (3.00 g, 2.39 mmol, 60.5% yield) as a white solid.

[0304] HPLC: Rt = 3.08 min, 99.2% purity

[0305] 1H NMR: 400 MHz, DMSO-d6: 8.45 (t, J = 4.0 Hz, 1H), 8.29 (t, J = 4.2 Hz, 1H), 7.81 – 8.00 (m, 4H), 4.08 – 4.15 (m, 1H), 3.81 – 3.86 (m, 4H), 3.56 – 3.60 (m, 4H), 3.81 – 3.86 (m, 4H), 3.47 (s, 8H), 3.36 – 3.39 (m, 6H), 3.23 – 3.31 (m, 4H), 3.17 – 3.21 (m, 6H), 2.98 – 3.03 (m, 2H), 1.29 – 1.67 (m, 12H), 1.23 (s, 30H). Example 4. General procedure for the Linear Peptide of Compound 91-B

[0306] Peptide Synthesis:

[0307] The peptide was synthesized using standard Fmoc chemistry.

[0308] 1. Resin preparation: Rink Amine MBHA resin (0.3 mmol, 1.00 eq, Sub 0.52mmol / g) in DMF (50.0 mL) was agitated under N2at 25 °C for 0.5 h. Then the mixture was filtered.

[0309] 2. Deprotection: 20% piperidine in DMF (30.0 mL) was added and the resin was agitated under N2at 25 °C for 15 min. The resin was then washed with DMF (30.0 mL * 5) and filtered.

[0310] 3. Coupling: A solution of HBTU (2.85 eq) and Fmoc-Ser(tBu)-OH (3.00 eq) in DMF (10.0 mL) was added to the resin followed by DIEA (6.00 eq). The resulting mixture was agitated under N2at 25 ℃ for 30 min. The resin was then washed with DMF (30.0 mL * 5).

[0311] 4. Steps 2 and 3 were repeated for the coupling of the following amino acids: (Nos.2-38).

[0312] 5. The resin was drained and washed with DMF (30.0 mL) for 5 times to obtain the peptide bound resin (2.16g).

[0313] Peptide Cleavage and Purification:

[0314] 1. The cleavage solution (20.0 mL, 92.5% TFA / 2.50% TIS / 2.50% H2O / 2.50% 3- Mercaptopropionic acid) was added to the flask containing the resin at room temperature and the mixture was stirred for 2 h.

[0315] 2. The peptide was precipitated with cold isopropyl ether (200 mL), filtered, and collected. The filter cake was washed with isopropyl ether (200 mL * 2) and dried under vacuum for 2 h to obtain the crude peptide (1.20 g).

[0316] 3. The crude peptide was purified by prep-HPLC (TFA condition: A: 0.075 % TFA in H2O, B: CAN) to give the appropriate Linear Peptide as a white solid.

[0317] Purification conditions:

[0318] General procedure for the preparation of Compound 91-B

[0319] To a mixture of Linear Peptide from the above steps (0.017 mmol, 80.47% purity, TFA, 1.00 eq) in CAN (4 mL) and H2O (6 mL) was added NH4HCO3(1M, 60.95μl, 1.00 eq) until the pH 8~9. Then the Staple P1CBR-221 (0.017mmol, 95.21% purity, TFA, 1.00 eq) in CAN (2 mL) and H2O (3 mL) was added drop-wise. The reaction mixture was stirred at 25 °C for 0.5 hr. After completion, the reaction mixture was adjusted to pH 5~6 with 1M HCl. Then the reaction mixture was lyophilized. The crude product was purified by prep-HPLC (TFA condition: A: 0.075 % TFA in H2O, B: CAN) to give compound 91-B. Compound 91-B was verified by LCMS and HPLC (see Table 3).

[0320] Purification conditions:Example 5. General procedure for Peptidyl Resin to for Compounds 24-A and 25-A

[0321] Peptide Synthesis:

[0322] The peptide was synthesized using standard Fmoc chemistry. The procedures are similar to the procedures for the linear peptide solid phase synthesis described in Example 4.

[0323] 1. Resin preparation: Rink Amide MBHA resin (0.3 mmol, 1.00 eq, Sub 0.52mmol / g) in DMF (50.0 mL) was agitated with N2 at 25 °C for 0.5 h. Then the mixture was filtered.

[0324] 2. Deprotection: 20% piperidine in DMF (30.0 mL) was added and the mixture was agitated under N2 at 25 °C for 15 min. The resin was washed with DMF (30.0 mL * 5) and filtered.

[0325] 3. Coupling: A solution of HBTU (2.85 eq) and Fmoc-Ser(tBu)-OH (3.00 eq) in DMF (10.0 mL) was added to the resin. Then DIEA (6.00 eq) was added and the mixture was agitated under N2 at 25 ℃ for 30 min. Next, the resin was washed with DMF (30.0 mL * 5).

[0326] 4. Steps 2 and 3 were repeated for the following amino acids: (Nos.2-38).

[0327] 5. The resulting resin bound peptide was drained and washed with DMF (30.0 mL) 5 times and then filtered to afford the peptidyl resin (2.16g) precursor for compounds 24-A and 25-A.Example 6: General Procedure for Synthesis of Compound 24-A

[0328] Following synthesis of the linear peptide of Example 5, the following steps were performed on resin using solid state chemistry.

[0329] 1. Dde removal: To peptidyl resin (0.1 mmol) was added a solution of 4% hydrazine in DMF (5.0 mL). The resin was agitated under N2 at 25 °C for three times for 12 min each. The mixture was drained and washed with DMF (5.0 mL) 5 times for 30 seconds.

[0330] 2. Coupling Fmoc-Pro(4-NH-Alloc)-OH (2S,4S): To a solution of Fmoc-Pro(4-NH-Alloc)-OH (2S,4S) (4 equiv.) and HCTU (3.9 equiv.) in DMF (5.0 mL) was added DIPEA (8 equiv.). The mixture was added to the peptidyl resin and agitated under N2at 25 °C for 2 h. The resin was drained and washed with DMF (5.0 mL) five times for 30 seconds.

[0331] 3. Fmoc removal: The peptidyl resin was treated with a solution of 20% piperidine in DMF (5 mL). The resin was agitated under N2at 25 °C twice for 10 min. The resin was drained and washed with DMF (5.0 mL) five times for 30 seconds.

[0332] 4. Coupling Boc-DVal-OH: To a mixture of Boc-DVal-OH (4 equiv.) and HCTU (3.9 equiv.) in DMF (5.0 mL) was added DIPEA (8 equiv.). The mixture was added to the peptidyl resin and agitated under N2at 25 °C for 2 h. The resin was subsequently drained and washed with DMF (5.0 mL) five times for 30 seconds, followed washing with CH2Cl2(5.0 mL) five times for 30 seconds.

[0333] 5. Alloc protecting group removal: The peptidyl resin was treated with a mixture of Pd(Ph3)4(0.1 equiv.) and PhSiH3(10 equiv.) in CH2Cl2(10.0 mL). The resin was agitated under N2at 25 °C for 3 h. The resin was subsequently drained and washed with CH2Cl2(5.0 mL) for 5 × 30 seconds, DMF (5.0 mL) for 5 × 30 seconds, a solution of sodium diethyl dithiocarbamate in DMF (0.5% w / v) for 3 × 20 min, and then again with DMF (5.0 mL) for 5 × 30 seconds.

[0334] 6. Coupling succinic acid: To a mixture of succinic acid (1 equiv.) and HCTU (0.9 equiv.) in DMF (5.0 mL) was added DIPEA (2 equiv.). The mixture was added to the peptidyl resin and agitated under N2at 25 °C for 2 h. The resin was drained and washed with DMF (5.0 mL) five times for 30 seconds.

[0335] 7. Coupling H-Lys(Fmoc)-OtBu.HCl: To a mixture of H-Lys(Fmoc)-OtBu.HCl (2 equiv.) and HCTU (1.9 equiv.) in DMF (5.0 mL) was added DIPEA (4 equiv.). The mixture was added to the peptidyl resin and agitated under N2 at 25 °C for 2 h. The resin was drained and washed with DMF (5.0 mL) five times for 30 seconds.

[0336] 8. Fmoc removal: Step 3 was repeated to remove the Fmoc protecting group.

[0337] 9. Coupling p-iodophenyl butyric acid: To a mixture of p-iodophenyl butyric acid (2 equiv.) and HCTU (1.9 equiv.) in DMF (5.0 mL) was added DIPEA (4 equiv.). The mixture was added to the peptidyl resin and agitated under N2 at 25 °C for 2 h. The resin was drained and washed with DMF (5.0 mL) for 5 × 30 seconds, CH2Cl2 (5.0 mL) for 5 × 30 seconds, and then dried under vacuum for 3 h.

[0338] 10. Resin cleavage and global side-chain protecting group removal:

[0339] To the peptidyl resin was added a cleavage cocktail solution of TFA:TIPS: 3-mercaptopropionic acid:H2O (92.5:2.5:2.5:2.5, v / v / v / v, 10 mL). The mixture was agitated at 25 °C for 4 h.

[0340] The resin was drained and the yellow filtrate was collected. Residual TFA was removed under a light stream of N2.

[0341] The peptide was then precipitated from cold diethyl ether (40 mL), isolated (centrifugation), dissolved in a mixture of MeCN / H2O (1:1, v / v, 10 mL) containing 0.1% TFA, and lyophilized.

[0342] The crude peptide was purified by semi-preparative RP-HPLC (Solvent A: 0.075% TFA in H2O, Solvent B: MeCN) to afford the Linear Peptide as a white solid.

[0343] Procedure for stapling:

[0344] To a mixture of linear peptide from the preceding step (1 equiv.) in MeCN (4 mL) and H2O (6 mL) was added NH4HCO3 (1 M), until a pH 8-9 was obtained. Staple P1CBR-221 (1.2 equiv.) in MeCN (2 mL) and H2O (3 mL) were added dropwise to the peptide mixture and the pH was adjusted to pH 8-9 using NH4HCO3 (1 M). The mixture was stirred at 25 °C for 3 h. Following the reaction completion, the reaction mixture was quenched with HCl (1 M) to pH 5-6 and then the mixture was then lyophilized. The crude peptide was purified by semi-preparative RP-HPLC (Solvent A: 0.075% TFA in H2O, Solvent B: MeCN) to obtain compound 24-A as a white powder (15.8 mg). Compound 24-A was verified by LCMS and HPLC (see Table 2).

[0345] Purification conditions:Example 6: Procedure for Synthesis of Compound 25-A

[0346] Following synthesis of the linear peptide of Example 4, the following steps were performed on resin.

[0347] 1. Dde removal: To peptidyl resin obtained in Example 4 (0.1 mmol) was added a solution of 4% hydrazine in DMF (5.0 mL). The resin was agitated under N2at 25 °C for 3 × 12 min. The mixture was drained and washed with DMF (5.0 mL) for 5 × 30 seconds.

[0348] 2. Coupling Fmoc-Pro(4-NH-Alloc)-OH (2S,4S): To a solution of Fmoc-Pro(4-NH-Alloc)-OH (2S,4S) (4 equiv.) and HCTU (3.9 equiv.) in DMF (5.0 mL) was added DIPEA (8 equiv.). The mixture was added to the peptidyl resin and agitated under N2at 25 °C for 2 h. The resin was drained and washed with DMF (5.0 mL) for 5 × 30 seconds.

[0349] 3. Fmoc removal: The peptidyl resin was treated with a solution of 20% piperidine in DMF (5 mL). The resin was agitated under N2at 25 °C for 2 × 10 min. Then the resin was drained and washed with DMF (5.0 mL) for 5 × 30 seconds.

[0350] 4. Coupling Boc-DVal-OH: To a mixture of Boc-DVal-OH (4 equiv.) and HCTU (3.9 equiv.) in DMF (5.0 mL) was added DIPEA (8 equiv.). The mixture was added to the peptidyl resin and agitated under N2 at 25 °C for 2 h. The resin was subsequently drained and washed with DMF (5.0 mL) for 5 × 30 seconds, followed by CH2Cl2 (5.0 mL) for 5 × 30 seconds.

[0351] 5. Alloc protecting group removal: The peptidyl resin was treated with a mixture of Pd(Ph3)4 (0.1 equiv.) and PhSiH3 (10 equiv.) in CH2Cl2 (10.0 mL). The resin was agitated under N2 at 25 °C for 3 h. The resin was subsequently drained and washed with CH2Cl2 (5.0 mL) for 5 × 30 seconds, DMF (5.0mL) for 5 × 30 seconds, a solution of sodium diethyl dithiocarbamate in DMF (0.5% w / v) for 3 × 20 minutes, and then again with DMF (5.0 mL) for 5 × 30 seconds.

[0352] 4. Coupling bis-PEG2-acid: To a mixture of bis-PEG2-acid (1 equiv.) and HCTU (0.9 equiv.) in DMF (5.0 mL) was added DIPEA (2 equiv.). The mixture was added to the peptidyl resin and agitated under N2 at 25 °C for 2 h. The resin was drained and washed with DMF (5.0 mL) for 5 × 30 seconds.

[0353] 5. Coupling H-Lys(Fmoc)-OtBu.HCl: To a mixture of H-Lys(Fmoc)-OtBu.HCl (2 equiv.) and HCTU (1.9 equiv.) in DMF (5.0 mL) was added DIPEA (4 equiv.). The mixture was added to the peptidyl resin and agitated under N2 at 25 °C for 2 h. The resin was drained and washed with DMF (5.0 mL) for 5 × 30 seconds.

[0354] 6. Fmoc removal: Step 3 was repeated to remove the Fmoc protecting group.

[0355] 7. Coupling p-iodophenyl butyric acid: To a mixture of p-iodophenyl butyric acid (2 equiv.) and HCTU (1.9 equiv.) in DMF (5.0 mL) was added DIPEA (4 equiv.). The mixture was added to the peptidyl resin and agitated under N2at 25 °C for 2 h. The resin was drained and washed with DMF (5.0 mL) for 5 × 30 seconds, CH2Cl2(5.0 mL) for 5 × 30 seconds, and then dried under vacuum for 3 h.

[0356] 8. Resin cleavage and global side-chain protecting group removal:

[0357] To the peptidyl resin was added a cleavage cocktail solution of TFA:TIPS: 3-mercaptopropionic acid:H2O (92.5:2.5:2.5:2.5, v / v / v / v, 10 mL). The mixture was agitated at 25 °C for 4 h.

[0358] The resin was drained and the yellow filtrate was collected. Residual TFA was removed under a light stream of N2.

[0359] The peptide was then precipitated from cold diethyl ether (40 mL), isolated (centrifugation), dissolved in a mixture of MeCN / H2O (1:1, v / v, 10 mL) containing 0.1% TFA, and lyophilized.

[0360] The crude peptide was purified by semi-preparative RP-HPLC (Solvent A: 0.075% TFA in H2O, Solvent B: MeCN) to afford the Linear Peptide as a white solid.

[0361] Purification conditions:

[0362] Procedure for stapling:

[0363] To a mixture of linear peptide from the preceding step (1 equiv.) in MeCN (4 mL) and H2O (6 mL) was added NH4HCO3 (1 M), until pH 8-9 was obtained. Staple P1CBR-221 (1.2 equiv.) in MeCN (2 mL) and H2O (3 mL) was added dropwise to the peptide mixture and pH was adjusted to pH 8-9 using NH4HCO3 (1 M). The mixture was stirred at 25 °C for 3 h. Following reaction completion, the reaction mixture was quenched with HCl (1 M) to pH 5-6. The reaction mixture was lyophilized and the crude peptide was purified by semi-preparative RP-HPLC (Solvent A: 0.075% TFA in H2O, Solvent B: MeCN) to afford compound 25-A (confirmed by LC-MS and HPLC) as a white powder (18.1 mg). Compound 25-A was confirmed by LCMS and HPLC (see Table 2).

[0364] Purification conditions:Example 7: Preparation of Compound 2-A

[0365] General procedure for Linear Peptide Synthesis for 2-A

[0366] The peptide was synthesized using standard Fmoc chemistry.

[0367] 1. Resin preparation: Sieber resin (0.4 mmol, 1.00 eq, Sub 0.52mmol / g) in DMF (20.0 mL) was agitated with N2 at 25 °C for 0.5 h. The mixture was filtered to get the resin.

[0368] 2. Deprotection: 20% piperidine in DMF (20.0 mL) was added and agitated the resin with N2 at 25 °C for 15 min. The resin was washed with DMF (20.0 mL * 5) and filtered to get the resin.

[0369] 3. Coupling: A solution of HBTU (2.85 eq) and Fmoc-Lys(Dde)-OH (3.00 eq) in DMF (20.0 mL) was added to the resin, then the DIEA (6.00 eq) was added, the mixture was agitated with N2 at 25 ℃ for 30 min. The resin was washed with DMF (20.0 mL * 5).

[0370] 4. Steps 2 and 3 were repeated for the following amino acids: (Nos.2-40).

[0371] 5. Boc-Tyr(tBu)-OH, add 3% H2N·NH2 / DMF (20.0 mL) was reacted with the solution mixture for 30. The mixture was drained and washed DMF (20.0 mL * 5).

[0372] 6. Steps 2 to 3 were repeated for the coupling of following amino acids: (Nos.41-44).

[0373] Peptide Cleavage and Purification:

[0374] Add cleavage solution (25.0 mL, 92.5% TFA / 2.50% TIS / 2.50% H2O / 2.50% 3- Mercaptopropionic acid) to the flask containing resin at room temperature and stirred for 2 h.

[0375] Precipitated the peptide with cold isopropyl ether (250 mL). Filter and collect the filter cake. The filter cake was washed with isopropyl ether (250 mL * 2). Dry the crude peptide under vacuum 2 h to get the crude peptide (2.17 g), the crude peptide was confirmed via LCMS (Rt =1.629 min).

[0376] The crude peptide was purified by prep-HPLC (TFA condition: A: 0.075 % TFA in H2O, B: ACN) to give the final product (220 mg, 29.68 μmol,7.42% yield, 66.78% purity, TFA) as a white solid. The purified linear peptide was confirmed via LC-MS (Rt= 1.649 min, MS cal.: 4835.57, MS observed: [M+3H]3+ = 1613.0) with a purity of 90.35.

[0377] Purification conditions:

[0378] Synthsis of Compound 2-A

[0379] To a mixture Linear peptide (220 mg, 29.68 μmol, TFA, 1.00 equiv) in ACN (5ml) and H2O (10ml) was added NH4HCO3(1M, 23.82μl, 1.00 equiv) until the PH=8~9, then was added drop-wise Staple L5A in ACN (5ml) and H2O (10ml) . The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was monitored by LC-MS. The reaction mixture was adjusted to PH=5~6 with 1M HCl aq. Then the reaction mixture was lyophilized. The crude was purified by prep-HPLC (TFA condition: A: 0.075 % TFA in H2O, B: ACN) and (Na condition:5% ACN-25 min (0.1M NaHCO3),5% ACN-10 min (H2O),30-90-50 min (H2O) to give the final product (41.6 mg, 6.95 μmol,23.41% yield, 98.29% purity, Na) as a white solid. The identity of Compound 2-A was confirmed via LC-MS (Rt= 1.329 min, MS cal.: 5861.85, MS observed: [M+H]+= 5862.03) with a purity of 98.29%.

[0380] Purification conditions:Example B-1: Experimental Procedures

[0381] Peptide cross-linking. The dicysteine-containing peptide (2 mM, >85% pure) (Shanghai Apeptide Co., Shanghai, China) and the cross-linker (1.5 eq) were dissolved in CH3CN / 30 mM NH4HCO3buffer (v / v; 1:3) pH 8.5), and the reaction was stirred at room temperature for 2-4 h. Under ice cooling, acetic acid was then added dropwise to reduce the pH of the mixture to around 5 and the crude cross-linked peptide was then purified by semi-preparative chromatography on Agilent 1200 with a Phenomenex Luna column (C18, 100 Å pore size, 5 µm particle size, 150 x 21.2 mm). A linear gradient from 30% to 60% CH3CN / H2O containing 0.05% trifluoroacetic acid was applied for 60 min at a flow rate of 20 mL min-1. The fractions containing the products were collected and lyophilized to afford the products as a powder with >90% purity.

[0382] The identity and purity of the peptide were determined using an Agilent 6520 accurate-mass quadrupole-time-of-light (QTOF) instrument equipped with reversed-phase liquid chromatography and an electrospray ionization (ESI). Aeris Widepore column (XB-C18, 3.6 µm particle size, 150 x 2.1 mm) was used with a flow rate of 0.5 mL min-1and peptides were detected using a UV-Vis detection wavelength of 214 nm.

[0383] Generation of CRE-Luc stable cell line overexpressing GLP-1R or GIP. HEK293 cells were infected with lentivirus encoding firefly luciferase gene under the control of cAMP responsive element (CRE) promoter (Qiagen, The Netherlands) and then were selected using 1 μg mL-1puromycin (Life Technologies, Carlsbad) for 1 week. The surviving cells (referred to as CRE-HEK293) were expanded and then transfected with a G418 selective mammalian expression plasmid encoding human GLP-1R or GIPR. In brief, GLP-1R or GIPR plasmid was transfected into CRE-HEK293 cells using Lipofectamine 2000 and selected with 400 μg mL-1Geneticin (Life Technologies, Carlsbad, CA). Single colony stable cell line overexpressing CRE-luciferase and GLP-1R or GIPR (HEK293-GLP-1R-CRE or HEK293- GIPR-CRE) was then established for in vitro activity assay.

[0384] In vitro receptor activation reporter assay (receptor-mediated cAMP synthesis) HEK293- GLP-1R-CRE or HEK293-GIPR-CRE cells were seeded in 384-well plates at a density of 5000 cells per well and cultured for 18 h in DMEM with 10% FBS at 37 °C and 5% CO2. Cells were treated with peptides in a dose-dependent manner for 24 h, and receptor activation was reported by luminescence intensities, using One-Glo (Promega, WI) luciferase reagent following manufacturer’s instruction. The EC50 of each peptide was determined using GraphPad Prism 6 software (GraphPad, San Diego, CA).

[0385] cAMP assay

[0386] CHOK1 cells stably overexpressed human GLP-1R or GIPR (20 μL of 5000 cells per well) were seeded in a white solid 384 well plate covered with metal lid and incubated overnight. On day 2, the culture medium was replaced by fresh medium containing no FBS (for 0% FBS group). Cells were treated with 5 μL peptide in 12-point dose response, in culture medium with 0.5 mM IBMX in triplicate for 30 min at 37 ^C, 5% CO2. cAMP dynamic 2 kit from Cisbio was used to detect cAMP level. Briefly, 25 µL of cAMP detection reagent (1:1:38 of cAMP-d2, Cryptate conjugate, lysis buffer) per well was added and incubated at room temperature for 1 h. For cell negative control wells, cAMP detection reagent without d2 was added. Plates were then read at Ex320 nm, Em-1665 nm and, EM-2620 nm. Graphs were plotted with Ratio or ΔF using Prism software and EC50 values were then obtained: Ratio= A665 nm / B620 nm x 104% ΔF= (standard or sample ratio - rationeg) / rationeg x 100.

[0387] Animals Animal care and experimental procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Calibr at the Scripps Research Institute, strictly following the NIH guidelines for humane treatment of animals.

[0388] Pharmacokinetics of peptides in mice Female CD-1 mice (n = 4 per group) from Charles River Laboratory were fasted overnight and administered 100 µL of each peptide in phosphate buffered saline by intravenous (i.v.) or subcutaneous (s.c.) route. Food was provided to mice after blood collection at 3 h time point. Blood was collected into heparin tubes and centrifuged at 3,000x g for 15 min. The resulting plasma were then stored at -80 °C for peptide concentration determination. The concentrations of peptides in plasma at each time point were determined by in vitro cell based activity assay. Briefly, HEK293-GLP-1R-CRE cells were treated with plasma samples at different time points (5-point dose response, starting from 1:10 to 1:100 dilution of each plasma sample) and incubated for 16 h in DMEM with 10% FBS at 37 °C with 5% CO2, and the firefly luciferase activity was then measured. Simultaneously, the same peptides were used to obtain standard curves and parameters for Bottom, Top, EC50, and Hill Slope. Relative luciferase unit (RLU) for each plasma sample was used to calculate the peptide concentrations in plasma (nmol / L), using parameters derived from the standard curve: (RLU = Bottom + (Top - Bottom) / (1 + 10((LogEC50 - Conc.) x Hill Slope)) Peptide concentrations in plasma were obtained and plotted against time points to obtain in vivo half-life of each peptide, using WinNonLin Phoenix software (Pharsight Corp, St. Louis, MO).Example B-2: In vitro receptor activation reporter assay (receptor-mediated cAMP synthesis) HEK293

[0389] Generation of CRE-Luc stable cell line overexpressing GLP-1R

[0390] HEK293 cells were infected with lentivirus encoding firefly luciferase gene under the control of cAMP responsive element (CRE) promoter (Qiagen, The Netherlands) and then were selected using 1 μg / mL puromycin (Life Technologies, Carlsbad) for 1 week. The surviving cells (referred to as CRE- HEK293) were expanded and then transfected with a G418 selective mammalian expression plasmid encoding human GLP-1R. In brief, GLP-1R plasmid was transfected into CRE-HEK293 cells using Lipofectamine 2000 and selected with 400 μg / mL Geneticin (Life Technologies, Carlsbad, CA). Single colony stable cell line overexpressing CRE-luciferase and GLP1R was then established for in vitro activity assay.

[0391] GLP-1R-CRE or HEK293-GIPR-CRE cells were seeded in 384-well plates at a density of 5000 cells per well and cultured for 18 h in DMEM with 10% FBS at 37 °C and 5% CO2. Cells were treated with peptides in a dose dependent manner for 24 h, and receptor activation was reported by luminescence intensities, using One-Glo (Promega, WI) luciferase reagent following manufacturer’s instruction. The EC50of each peptide was determined using GraphPad Prism 6 software (GraphPad, San Diego, CA).

[0392] Measurements indicate distinct and separable in vitro activation potencies of a number of peptide conjugates described herein. In some instances, novel peptide conjugates were tested against known GLP1R or dual GLP1R / GIPR agonists under the same assay conditions. Results are shown in Tables 4 and 5. Table 4.Table 5.Example B-3: Dog Pharmacokinetics

[0393] Beagle Dogs (male, 7-10 kg) were dosed (IV) with the test compounds at a variety of dosages. The results are shown in Table 6.Table 6.Example B-4: Monkey Pharmacokinetics

[0394] Cynomolgus Monkeys (male, 2-5 kg) were dosed (IV / SC) with the test compounds at 0.1 mg / kg in PBS. The blood sample was taken at 0, 0.5, 1, 3, 7, 10, 24, 48, 72, 96, 120, 168, 240, 336 and 504 hr (up to 21 days) post dose and analyzed by LC-MS / MS method to generate the PK parameters. The results are shown in Table 7. Table 7.Example B-5: Minipig Pharmacokinetics

[0395] Bama Miniature Swine (three males, 9-11 kg) was dosed IV with the test compound (0.1 – 0.2 mg / kg) in PBS. The blood sample was taken at 0, 0.5, 1, 2, 3, 7, 24, 48, 72, 96, 120, 168, 336 and 504 hr (up to 21 days) post dose and analyzed by LC-MS / MS method to generate the PK parameters. The results are shown in Table 8. Table 8.

[0396] Example B-6: Simulated Intestinal and Gastric Fluid Table 9.Example B-9: Methods of measuring conversion half-life

[0397] The assay was performed to investigate the conversion half-life of a prodrug to the parent of the prodrug peptide compounds described herein. The conversion half-life was investigated in vitro at pH 7.4 upon incubation at 37 °C with shaking at 250 rpm.

[0398] 20 mM DMSO working solution (1 μL) was added to 1X PBS, pH 7.4 (999 μL). The peptide compound solution was vortexed and then incubated at 37 °C on an orbital shaker at 250 rpm. Aliquot (100 μL) was sampled at 0, 2, 6, 24, 48, 96 and 168 hr and quenched with MeCN containing internal standard (300 μL). The solution was then vortexed, solvent spun down, and then kept in -80 °C until analysis. At the end of the incubation, all the time point samples were brought to room temperature, centrifuged at 4000 rpm for 10 minutes and the supernatants transferred into 96 well plate for LC- MS / MS analysis.

[0399] The results are shown in Table 10. Table 10.EMBODIMENTS

[0400] 1. A peptide conjugate comprising: a) a peptide comprising a sequence: Tyr-X2-Glu-Gly-Thr-X6-Thr-Ser-X9-X10-X11-Ile-X13-X14-Asp-Lys-X17-Ala-Ala-Aib-Glu-Phe- Val-X24-X25-X26-X27-X28-Gly-Gly-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-NH2wherein; X2is Aib, D-Pro, Gly, or D-Ala; X6is Phe, αMe-Phe, or αMe-Phe2F; X9is Asp or αMe-Asp; X10is Tyr, Val, Leu, Ile, Ala, Val(3-OH), or 4Pal; X11is Ser, αMe-Ser, or Val(3-OH); X13is Tyr, αMe-Leu, Cha, or Nle; X14is Leu or αMe-Leu; X17is Cys or Lys; X24is Cys or Lys; X25is Trp, Tyr, αMe-Trp, or αMe-Tyr; X26is Leu, Val, or αMe-Leu; X27is Ile, Leu, αMe-Leu, Tle, cpA, or Lys; X28is Ala, Glu, Hgl, or Lys; X31is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X32is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X33is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X34is Gly, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X35is Ala, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X36is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X37is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X38is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X39is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; and X40is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; and b) a prodrug moiety attached to the peptide at a first amino acid; wherein the prodrug moiety is of Formula (I):wherein, each R4is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, or C3-C10 heterocycloalkyl, each of which is optionally substituted with one, two, or three R6; or two R4together with the carbon to which they are attached to form a C3-C7 cycloalkyl or heterocycloalkyl which is optionally substituted with one, two, or three R6;R5is –(CHR5a-NHC(=O))0-2-(La)t-RQ; each R6is independently halogen, -ORa, -SRa, -NO2, -NRcRd, -CO2Ra, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one, two, or three halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORa, or -NRcRd; RQis -CH3, -C(=O)OH, -P(=O)(OH)2, phenyl, 5-membered heteroaryl, 2-amino-5-methyl-5,6,7,8- tetrahydropteridin-4(3H)-one, or tetrahydro-1H-thieno[3,4-d]imidazol-2(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen; R5ais hydrogen or C1-C6 alkyl, which is optionally substituted with one, two, or three R6a; each R6ais independently -ORa, -SRa, -NRcRd, -CO2Ra, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one, two, or three halogen, C1-C6alkyl, C1-C6haloalkyl, -ORa, or -NRcRd; each Lais independently -(CR7R7)w-, -alkylene-O-, -O-alkylene-, -C(=O)-alkylene-, - alkylene-C(=O)-, - NR8-alkylene-, - alkylene-NR8-, -S-alkylene-, -alkylene-S-, -S(=O)-alkylene-, - alkylene-S(=O)-, - S(=O)2-alkylene, - alkylene-S(=O)2-, -C(=O)-, -C(=O)NR8-, -NR8C(=O)-, -NR8C(=O)NR8-, - NR8C(=O)NR8-alkylene-, -NR8C(=O)-alkylene-NR8-, -alkylene-C(=O)NR8-, -C(=O)NR8-alkylene-, - alkylene-NR8C(=O)-, -NR8C(=O)-alkylene-, or phenylene; f is 0 or 1; p is 0 or 1; q is 0 or 1; t is 1-10; each R7is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, - NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, - ORa, -NRcRd, or -C(=O)NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6alkyl, C1-C6haloalkyl, -ORa, or - NRcRd; each R8is independently hydrogen, -S(=O)Rb, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORa, or -NRcRd; R9is hydrogen, C1-C6 alkyl, or C3-C10 cycloalkyl; w is 1-20;Rais hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1- C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2; Rbis C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1- C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2; and each Rcand Rdis independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, three, or more of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, three, or more of halogen, C1-C6alkyl, C1-C6haloalkyl, -OH, -OMe, or -NH2; or Rcand Rd, together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6alkyl, C1-C6haloalkyl, -OH, -OMe, or -NH2.

[0401] The peptide conjugate of embodiment 1, wherein the protein comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO.1 (Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG- PSSGA-PPPSX40), wherein X40is absent, L or D-lysine, L- or D-ornithine, or L- or D-diaminobutyric acid.

[0402] The peptide conjugate of embodiment 2, wherein X40is L or D-lysine.

[0403] The peptide conjugate of embodiment 2, wherein X40is L- or D-ornithine.

[0404] The peptide conjugate of embodiment, wherein X40is L- or D-diaminobutyric acid.

[0405] The peptide conjugate of embodiment 2, wherein X40is absent.

[0406] The peptide conjugate of any one of embodiments 1-6 wherein the peptide comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO.2-90: Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.2); Y(Aib)EGT-(amF)TS(amD)Y-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 3); Y(Aib)EGT-(amF)TSDY-S(amI)YLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 4); Y(Aib)EGT-(amF)TSDY-SI(amY)LD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 5);Y(Aib)EGT-(amF)TSDY-SIY(amL)D-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 6); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 7); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVCW-(amL)IAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 8); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSK-NH2 (SEQ ID NO.9); Y(Aib)EGT-(amF)TSDY-S(amI)Y(amL)D-KCAA(Aib)-EFVC(amW)-(amL)IAGG-PSSGA-PPPS-NH2 (SEQ ID NO.10); Y(Aib)EGT-(amF)TSDY-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.11); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-(Nle)IEGG-PSSGA-PPPS-NH2(SEQ ID NO.12); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.13); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.14); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.15); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.16); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Cha)(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.17); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Nle)(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.18); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(1Nal)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.19); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(Aib)-L(amL)AGG-PSSGA-PPPS-NH2(SEQ ID NO.20); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)E-(Hgn)CAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.21); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.22); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-NH2 (SEQ ID NO.23); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(W1Me)-(Nle)IEGG-PSSGA-PPPS-NH2 (SEQ ID NO.24); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LD-KCAA(Aib)-EFVC(amW)-L(amL)AGG-PSSGA-PPPS-NH2 (SEQ ID NO.25);Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-L(amL)AGG-PSSGA-PPPS-NH2 (SEQ ID NO.26); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGG-NH2 (SEQ ID NO. 27); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(Tle)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.28); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Ac6c)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.29); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGGK-NH2 (SEQ ID NO. 30); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)EKCAA(Aib)EFVC(Tic)L(Tle)EGGPSSGAPPPS-NH2(SEQ ID NO.31); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)L(cpA)EGGPSSGAPPPS-NH2(SEQ ID NO.32); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)(cpA)LEGGPSSGAPPPS-NH2(SEQ ID NO.33); Y(Aib)EGS(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)(cpA)LEGGPSSGAPPPS-NH2(SEQ ID NO.34); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA-PPPS-NH2(SEQ ID NO.35); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Nle)(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA-PPPS- NH2(SEQ ID NO.36); Y(Aib)EGS-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.37); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LI(Nle)GG-PSSGA-PPPS-NH2(SEQ ID NO.38); Y(Aib)EGT-(amF)TSDV-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.39); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)E-(Dab)CAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.40); Y(Aib)EGT-(amF)TSD(Nle)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.41); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGG-PSSGA-PPPS-NH2 (SEQ ID NO.42); Y(Aib)EGT(amF)TSDVSI(amL)(Tle)EKCAA(Aib)EFVC(amY)L(Tle)EGGPSSGAPPPS-NH2 (SEQ ID NO.43); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)E(Orn)CAA(Aib)EFVC(amY)(Tle)IEGGPSSGAPPPS-NH2 (SEQ ID NO.44);Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(amY)L(cpA)EGGPSSGAPPPS-NH2 (SEQ ID NO.45); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Tle)(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA-PPPS-NH2 (SEQ ID NO.46); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)EKCAA(Aib)EFVC(amY)(Tle)IEGGPSSGAPPPS-NH2 (SEQ ID NO.47); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)EKCAA(Aib)EFVC(amY)L(Tle)EGGPSSGAPPPS-NH2 (SEQ ID NO.48); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LI(Hgl)GG-PSSGA-PPPS-NH2 (SEQ ID NO.49); Y(Aib)EGT-(amF)TSD(Bip)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.50); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(26DiMeY))-(amL)IAGG-PSSGA-PPPS- NH2(SEQ ID NO.51); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(Y(Me))-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.52); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS-NH2(SEQ ID NO.53); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(7Cl))-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.54); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(2Me))-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.55); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.56); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPSK-NH2(SEQ ID NO. 57); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCY-LIEGG-PSSGA-PPPSK-NH2(SEQ ID NO. 58); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS-NH2(SEQ ID NO.59); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.60); Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO. 61); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 62); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.63);Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 64); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.65); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)I(amL)LD-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS-NH2 (SEQ ID NO.66); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.67); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPSK-NH2 (SEQ ID NO.68); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS-NH2(SEQ ID NO.69); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(amL)AGG-PSSGA-PPPS-NH2(SEQ ID NO.70); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(amL)AGG-PSSGA-PPPS-NH2(SEQ ID NO.71); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.72); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LE-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.73); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(26DiMeY)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.74); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(Me))-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.75); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.76); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.77); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(Tle)EGG-PSSGA-PPPS-NH2(SEQ ID NO.78); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA-PPPS-NH2(SEQ ID NO.79); Y(Aib)EGT-FTSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.80); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPT-NH2 (SEQ ID NO.81); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPT-NH2 (SEQ ID NO.82); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSK-NH2 (SEQ ID NO.83);Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS(dk)-NH2 (SEQ ID NO.84); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPK-NH2 (SEQ ID NO.85); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSKGA-PPPS-NH2 (SEQ ID NO.86); Y(Aib)EGT-(amF)TSDV-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.87); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.88); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.89); or Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS-NH2(SEQ ID NO.90).

[0407] The peptide conjugate of any one of embodiments 1-6, wherein the protein comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to: Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.2); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.56); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPT-NH2(SEQ ID NO.81); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPT-NH2(SEQ ID NO.82); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSK-NH2(SEQ ID NO.83); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS(dk)-NH2(SEQ ID NO.84); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPK-NH2(SEQ ID NO.85); or Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSKGA-PPPS-NH2(SEQ ID NO.86).

[0408] The peptide conjugate of any one of embodiments 1-6, wherein the peptide comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO.2 (Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)- EFVCW-LIAGG-PSSGA-PPPS).

[0409] The peptide conjugate of any one of embodiments 1-9, wherein the peptide modulates a GLP-1 receptor.

[0410] The peptide conjugate of any one of embodiments 1-9, wherein the peptide binds to a GLP-1 receptor.

[0411] The peptide conjugate of any one of embodiments, 1-9, wherein the peptide modulates a GIP receptor.

[0412] The peptide conjugate of any one of embodiments1-9, wherein the peptide binds to a GIP receptor.

[0413] The peptide conjugate of any one of embodiments 1-13, wherein the peptide is a GLP-1 receptor agonist.

[0414] The peptide conjugate of any one of embodiments 1-14, wherein the peptide is a GIP receptor agonist.

[0415] The peptide conjugate of any one of embodiments 1-15, wherein the peptide is a dual GLP-1 receptor and GIP receptor agonist.

[0416] The peptide conjugate of any one of embodiments 1-16, wherein the peptide is resistant to proteolysis by a gastrointestinal protease.

[0417] The peptide conjugate of embodiment 1, wherein the prodrug moiety is attached to the peptide at first amino acid comprising an amine containing side chain residue or the N-terminal amine of the peptide.

[0418] The peptide conjugate of embodiment18, wherein the first amino acid is selected from lysine, ornithine, diaminobutyric acid, diaminopropionic acid, and homolysine.

[0419] The peptide conjugate of embodiment 1 or 18, wherein the prodrug moiety is attached at a lysine at position X16, X31, X32, X33, X34, X35, X36, X37, X38, X39, or X40.

[0420] The peptide conjugate of embodiment 20, wherein the prodrug moiety is attached at a lysine at position X11.

[0421] The peptide conjugate of embodiment 20, wherein the prodrug moiety is attached at a lysine at position X17.

[0422] The peptide conjugate of embodiment 20, wherein the prodrug moiety is attached at a lysine at position X24.

[0423] The peptide conjugate of embodiment 20, wherein the prodrug moiety is attached at a lysine at position X27.

[0424] The peptide conjugate of embodiment 20, wherein the prodrug moiety is attached at a lysine at position X28.

[0425] The peptide conjugate of embodiment 20, wherein the prodrug moiety is attached at a lysine at position X31.

[0426] The peptide conjugate of embodiment 20, wherein the prodrug moiety is attached at a lysine at position X31.

[0427] The peptide conjugate of embodiment 20, wherein the prodrug moiety is attached at a lysine at position X33.

[0428] The peptide conjugate of embodiment 20, wherein the prodrug moiety is attached at a lysine at position X40.

[0429] The peptide conjugate of embodiment 1, wherein p is 1 and q is 1.

[0430] The peptide conjugate of embodiment 1, wherein the prodrug moiety of Formula (I) has the structure of Formula (Ia), (Ib), (Ic), or (Id):

[0431] The peptide conjugate of any one of embodiments 1 or 30-34, wherein each R4is independently hydrogen, C1-C6alkyl, or C1-C6heteroalkyl, each of which is optionally substituted with one, two, or three R6.

[0432] The peptide conjugate of embodiment 35, wherein each R4is independently C1-C6alkyl.

[0433] The peptide conjugate of any one of embodiments 1 or 30-36, wherein each R6is independently halogen, -ORa, -NRcRd, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl.

[0434] The peptide conjugate of embodiment 37, wherein each R6is independently halogen, -ORa, - NRcRd, or 5-membered heteroaryl.

[0435] The peptide conjugate of any one of embodiments 1 or 30-36, wherein each R6is independently selected from -NH2 or imidazole.

[0436] The peptide conjugate of embodiment 35, wherein each R4is hydrogen.

[0437] The peptide conjugate of any one of embodiments 1 or 30-34, wherein each R4is independently.

[0438] The peptide conjugate of any one of embodiments 1 or 30-41, wherein the prodrug moiety comprises:

[0439] The peptide conjugate of any one of embodiments 1 or 30-42, wherein –(CR5aH-NHC(=O))0-2– (La)t-1-(CR7R7)w-RQ, wherein w is 1-20.

[0440] The peptide conjugate of embodiment 43, wherein R5ais -CH2CH2CO2H.

[0441] The peptide conjugate of any one of embodiments 1 or 30-44, wherein each Lais independently - (CR7R7)w-, -alkylene-O-, -O-alkylene-, -NR8-alkylene-, - alkylene-NR8-, -C(=O)NR8-, -NR8C(=O)-, - alkylene-C(=O)NR8-, -C(=O)NR8-alkylene-, -alkylene-NR8C(=O)-, or -NR8C(=O)-alkylene-.

[0442] The peptide conjugate of claim 45, wherein each Lais independently -(CR7R7)w-, -alkylene-O-, - O-alkylene-, -C(=O)NR8-, or -NR8C(=O)-.

[0443] The peptide conjugate of any one of embodiments 1 or 30-46, wherein t is 1-5.

[0444] The peptide conjugate of any one of embodiments1 or 30-46, wherein t is 1-3.

[0445] The peptide conjugate of any one of embodiments 1 or 30-48, wherein each R7is independently hydrogen, -ORa, -NRcRd, or -CO2Ra.

[0446] The peptide conjugate of embodiment 49, wherein each R7is independently hydrogen or -CO2H.

[0447] The peptide conjugate of any one of embodiments 1 or 30-50, wherein R5is

[0448] The peptide conjugate of embodiment 51, wherein t1 is 1 or 2.

[0449] The peptide conjugate of embodiment 51, wherein t1 is 0.

[0450] The peptide conjugate of any one of embodiments 51-53, wherein t2 is 10-20.

[0451] The peptide conjugate of any one of embodiments 51-53, wherein t2 is 10-15.

[0452] The peptide conjugate of any one of embodiments 1 or 30-55, wherein R5is: , ,,,.

[0453] The peptide conjugate of any one of embodiments 1-56, wherein the conjugate further comprises a staple attached to the peptide at a second amino acid and a third amino acid; wherein the staple is of Formula (II):Formula (II) wherein; A is -N-; XAand XBare a bond, -C(=O)-, -alkylene-C(=O)-, -C(=O)-alkylene-, -alkylene-C(=O)NR3-, -alkylene- NR3C(=O)-, -C(=O)NR3-alkylene-, -NR3C(=O)-alkylene-, -alkylene-C(=O)NR3-alkylene-, or - alkylene-NR3C(=O)-alkylene-; wherein XAis attached to the second amino acid of the peptide, XBis attached to the third amino acid of the peptide, and XAand XBare identical; R is hydrogen or -(L)s-Y; each L is independently -(CR1R2)v-, -alkylene-O-, -O-alkylene-, -C(=O)-alkylene-, - alkylene-C(=O)-, - NR3-alkylene-, - alkylene-NR3-, -S-alkylene-, -alkylene-S-, -S(=O)-alkylene-, - alkylene-S(=O)-, - S(=O)2-alkylene, - alkylene-S(=O)2-, -C(=O)-, -C(=O)NR3-, -NR3C(=O)-, -NR3C(=O)NR3-, - NR3C(=O)NR3-alkylene-, -NR3C(=O)-alkylene-NR3-, -alkylene-C(=O)NR3-, -C(=O)NR3-alkylene-, - alkylene-NR3C(=O)-, or -NR3C(=O)-alkylene-; v is 2-20;each R1or R2is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, -P(=O)(ORa)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORa, or - NRcRd; or R1and R2are taken together to form a C1-C6 cycloalkyl or C1-C6 heterocycloalkyl; each R3is independently hydrogen, -S(=O)Rb, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, - C(=O)NRcRd, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6alkyl, C1-C6haloalkyl, -ORa, or -NRcRd; Y is hydrogen, C1-C6alkyl, -CO2H, -P(=O)(OH)2, -CO2(C1-C6alkyl), -CO2NH2, -CO2N(alkyl)2, - CO2NH(alkyl), or 5-membered heteroaryl; s is 0-20; Rais hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1- C6alkyl, C1-C6haloalkyl, -OH, -OMe, or -NH2; Rbis C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1- C6alkyl, C1-C6haloalkyl, -OH, -OMe, or -NH2; and each Rcand Rdis independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2; or Rcand Rd, together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2.

[0454] The peptide conjugate of embodiment 57, wherein the second amino acid and the third amino acid are independently a sulfydryl containing amino acid.

[0455] The peptide conjugate of embodiment 57, wherein the second amino acid and the third amino acid are independently selected from cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, and 2- amino-6-mercaptohexanoic acid.

[0456] The peptide conjugate of embodiment 57, wherein the second amino acid and third amino acids are cysteines.

[0457] The peptide conjugate of embodiment 57, wherein the second amino acid and the third amino acid are independently an amine-containing amino acid.

[0458] The peptide conjugate of embodiment 61, wherein the amine-containing amino acid is selected from lysine, ornithine, diaminobutyric acid, diaminopropionic acid and homolysine.

[0459] The peptide conjugate of embodiment 62, wherein the second amino acid and the third amino acids are lysines.

[0460] The peptide conjugate of any one of embodiments 57-63, wherein the second amino acid has a position i in the peptide and the third amino acid has a position i + n in the peptide, wherein n is 4-16.

[0461] The peptide conjugate of any one of embodiments 57-63, wherein the second amino acid has a position i in the peptide and the third amino acid has a position i + 4 in the peptide.

[0462] The peptide conjugate of any one of embodiments 57-63, wherein the second amino acid has a position i in the peptide and the third amino acid has a position i + 7 in the peptide.

[0463] The peptide conjugate of any one of embodiments 57-66, wherein XAand XBare -C(=O)-.

[0464] The peptide conjugate of any one of embodiments 57-66, wherein XAand XBare -alkylene- C(=O)- or -C(=O)alkylene-.

[0465] The peptide conjugate of any one of embodiments 57-66, wherein XAand XBare -CH2-C(=O)- or -C(=O)-CH2-.

[0466] The peptide conjugate of any one of embodiments 57-66, wherein XAand XBare -alkylene- C(=O)NR3- or -C(=O)NR3-alkylene-.

[0467] The peptide conjugate of any one of embodiments 57-66, wherein XAand XBare -CH2- C(=O)NR3- or -C(=O)NR3-CH2-.

[0468] The peptide conjugate of any one of embodiments 57-66, wherein XAand XBare -alkylene- C(=O)NR3-alkylene- or -alkylene-NR3C(=O)-alkylene-.

[0469] The peptide conjugate of any one of embodiments 57-66, wherein XAand XBare -CH2- C(=O)NR3-CH2CH2- or -CH2-NR3C(=O)-CH2CH2-.

[0470] The peptide conjugate of any one of embodiments 57-66, wherein XAand XBare -CH2- C(=O)NH-CH2CH2- or -CH2-NHC(=O)-CH2CH2-.

[0471] The peptide conjugate of any one of embodiments 57-74, wherein >A-R has the following structure:.

[0472] The peptide conjugate of embodiment 75, wherein s is 1-15.

[0473] The peptide conjugate of embodiment 75, wherein s is 1-10.

[0474] The peptide conjugate of embodiment 75, wherein s is 1-5.

[0475] The peptide conjugate of any one of embodiments 57-78, wherein Y is hydrogen or -CO2H.

[0476] The peptide conjugate of any one of embodiments 57-79, wherein each L is independently - (CR1R2)v-, -alkylene-O-, -C(=O)-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene- NR3C(=O)-; and v is 2-20.

[0477] The peptide conjugate of embodiment 80, wherein each R1and R2is independently hydrogen or - CO2H.

[0478] The peptide conjugate of embodiment 80 or 81, wherein R3is hydrogen.

[0479] The peptide conjugate of any one of embodiments 57-82, wherein the peptide conjugate comprises:wherein n1 is 1-4; n2 is 1-4; and m is 6-20.

[0480] The peptide conjugate of any one of embodiments, 57-82, wherein the peptide conjugate comprises:wherein n1is 1-4; n2is 1-4; and m is 6-20.

[0481] The peptide conjugate of embodiments 83 or 84, wherein n1is 1 or 2.

[0482] The peptide conjugate of any one of embodiments 83-85 wherein n2is 1 or 2.

[0483] The peptide conjugate of any one of embodiments 83-86, wherein m is 10-20.

[0484] The peptide conjugate of any one of embodiments 83-86, wherein m is 15-20.

[0485] The peptide conjugate of any one of embodiments 57-82, wherein the peptide conjugate comprises:,

[0486] A peptide conjugate comprising: a) a peptide comprising a sequence: Tyr-X2-Glu-Gly-Thr-X6-Thr-Ser-X9-X10-X11-Ile-X13-X14-Asp-Lys-X17-Ala-Ala-Aib-Glu-Phe- Val-X24-X25-X26-X27-X28-Gly-Gly-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-NH2 wherein; X2is Aib, D-Pro, Gly, or D-Ala; X6is Phe, αMe-Phe, or αMe-Phe2F; X9is Asp or αMe-Asp; X10is Tyr, Val, Leu, Ile, Ala, Val(3-OH), or 4Pal; X11is Ser, αMe-Ser, or Val(3-OH); X13is Tyr, αMe-Leu, Cha, or Nle; X14is Leu or αMe-Leu; X17is Cys or Lys; X24is Cys or Lys; X25is Trp, Tyr, αMe-Trp, or αMe-Tyr; X26is Leu, Val, or αMe-Leu; X27is Ile, Leu, αMe-Leu, Tle, cpA, or Lys; X28is Ala, Glu, Hgl, or Lys; X31is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent;X32is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X33is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X34is Gly, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X35is Ala, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X36is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X37is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X38is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X39is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; and X40is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; and b) a staple attached to the peptide at a second amino acid and a third amino acid; wherein the staple is of Formula (II):Formula (II) wherein; A is -N-; XAand XBare a bond, -C(=O)-, -alkylene-C(=O)-, -C(=O)-alkylene-, -alkylene-C(=O)NR3-, -alkylene- NR3C(=O)-, -C(=O)NR3-alkylene-, -NR3C(=O)-alkylene-, -alkylene-C(=O)NR3-alkylene-, or - alkylene-NR3C(=O)-alkylene-; wherein XAis attached to the second amino acid of the peptide, XBis attached to the third amino acid of the peptide, and XAand XBare identical; R is hydrogen or -(L)s-Y; each L is independently -(CR1R2)v-, -alkylene-O-, -O-alkylene-, -C(=O)-alkylene-, - alkylene-C(=O)-, - NR3-alkylene-, - alkylene-NR3-, -S-alkylene-, -alkylene-S-, -S(=O)-alkylene-, - alkylene-S(=O)-, - S(=O)2-alkylene, - alkylene-S(=O)2-, -C(=O)-, -C(=O)NR3-, -NR3C(=O)-, -NR3C(=O)NR3-, - NR3C(=O)NR3-alkylene-, -NR3C(=O)-alkylene-NR3-, -alkylene-C(=O)NR3-, -C(=O)NR3-alkylene-, - alkylene-NR3C(=O)-, or -NR3C(=O)-alkylene-; v is 2-20; each R1or R2is independently hydrogen, halogen, -CN, -ORa, -SRa, -S(=O)Rb, -NO2, -NRcRd, -S(=O)2Rd, -NRaS(=O)2Rd, -S(=O)2NRcRd, -C(=O)Rb, -OC(=O)Rb, -CO2Ra, -OCO2Ra, -C(=O)NRcRd, - OC(=O)NRcRd, -NRaC(=O)NRcRd, -NRaC(=O)Rb, -NRaC(=O)ORa, -P(=O)(ORa)2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6alkyl, C1-C6haloalkyl, -ORa, or - NRcRd; or R1and R2are taken together to form a C1-C6cycloalkyl or C1-C6heterocycloalkyl;each R3is independently hydrogen, -S(=O)Rb, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, - C(=O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -ORa, or -NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -ORa, or -NRcRd; Y is hydrogen, C1-C6 alkyl, -CO2H, -P(=O)(OH)2, -CO2(C1-C6 alkyl), -CO2NH2, -CO2N(alkyl)2, - CO2NH(alkyl), or 5-membered heteroaryl; s is 0-20; Rais hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1- C6alkyl, C1-C6haloalkyl, -OH, -OMe, or -NH2; Rbis C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1- C6alkyl, C1-C6haloalkyl, -OH, -OMe, or -NH2; and each Rcand Rdis independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6alkyl, C1-C6haloalkyl, -OH, -OMe, or -NH2; or Rcand Rd, together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6alkyl, C1-C6haloalkyl, -OH, -OMe, or -NH2.

[0487] The peptide conjugate of embodiment 99, wherein the peptide comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO.1 (Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW- LIAGG-PSSGA-PPPSX40), wherein X40is absent, L or D-lysine, L- or D-ornithine, or L- or D- diaminobutyric acid.

[0488] The peptide conjugate of embodiment 99 or 100, wherein X40is L or D-lysine.

[0489] The peptide conjugate of embodiment 99 or 100, wherein X40is L- or D-ornithine.

[0490] The peptide conjugate of embodiment 99 or 100, wherein X40is L- or D-diaminobutyric acid.

[0491] The peptide conjugate of embodiment 54, wherein X40is absent.

[0492] The peptide conjugate of embodiment 99, wherein the peptide comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO.2-90: Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.2); Y(Aib)EGT-(amF)TS(amD)Y-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 3); Y(Aib)EGT-(amF)TSDY-S(amI)YLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 4); Y(Aib)EGT-(amF)TSDY-SI(amY)LD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 5); Y(Aib)EGT-(amF)TSDY-SIY(amL)D-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO. 6); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO. 7); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVCW-(amL)IAGG-PSSGA-PPPS-NH2(SEQ ID NO. 8); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSK-NH2(SEQ ID NO.9); Y(Aib)EGT-(amF)TSDY-S(amI)Y(amL)D-KCAA(Aib)-EFVC(amW)-(amL)IAGG-PSSGA-PPPS-NH2(SEQ ID NO.10); Y(Aib)EGT-(amF)TSDY-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.11); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-(Nle)IEGG-PSSGA-PPPS-NH2(SEQ ID NO.12); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.13); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.14); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.15); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.16); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Cha)(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.17); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Nle)(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.18); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(1Nal)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.19);Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(Aib)-L(amL)AGG-PSSGA-PPPS-NH2 (SEQ ID NO.20); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)E-(Hgn)CAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.21); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.22); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-NH2 (SEQ ID NO.23); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(W1Me)-(Nle)IEGG-PSSGA-PPPS-NH2 (SEQ ID NO.24); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LD-KCAA(Aib)-EFVC(amW)-L(amL)AGG-PSSGA-PPPS-NH2 (SEQ ID NO.25); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-L(amL)AGG-PSSGA-PPPS-NH2(SEQ ID NO.26); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGG-NH2(SEQ ID NO. 27); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(Tle)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.28); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Ac6c)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.29); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGGK-NH2(SEQ ID NO. 30); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)EKCAA(Aib)EFVC(Tic)L(Tle)EGGPSSGAPPPS-NH2(SEQ ID NO.31); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)L(cpA)EGGPSSGAPPPS-NH2(SEQ ID NO.32); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)(cpA)LEGGPSSGAPPPS-NH2(SEQ ID NO.33); Y(Aib)EGS(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)(cpA)LEGGPSSGAPPPS-NH2(SEQ ID NO.34); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA-PPPS-NH2(SEQ ID NO.35); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Nle)(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA-PPPS- NH2 (SEQ ID NO.36); Y(Aib)EGS-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.37); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LI(Nle)GG-PSSGA-PPPS-NH2 (SEQ ID NO.38);Y(Aib)EGT-(amF)TSDV-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.39); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)E-(Dab)CAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.40); Y(Aib)EGT-(amF)TSD(Nle)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.41); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGG-PSSGA-PPPS-NH2 (SEQ ID NO.42); Y(Aib)EGT(amF)TSDVSI(amL)(Tle)EKCAA(Aib)EFVC(amY)L(Tle)EGGPSSGAPPPS-NH2 (SEQ ID NO.43); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)E(Orn)CAA(Aib)EFVC(amY)(Tle)IEGGPSSGAPPPS-NH2(SEQ ID NO.44); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(amY)L(cpA)EGGPSSGAPPPS-NH2(SEQ ID NO.45); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Tle)(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA-PPPS-NH2(SEQ ID NO.46); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)EKCAA(Aib)EFVC(amY)(Tle)IEGGPSSGAPPPS-NH2(SEQ ID NO.47); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)EKCAA(Aib)EFVC(amY)L(Tle)EGGPSSGAPPPS-NH2(SEQ ID NO.48); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LI(Hgl)GG-PSSGA-PPPS-NH2(SEQ ID NO.49); Y(Aib)EGT-(amF)TSD(Bip)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.50); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(26DiMeY))-(amL)IAGG-PSSGA-PPPS- NH2(SEQ ID NO.51); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(Y(Me))-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.52); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS-NH2(SEQ ID NO.53); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(7Cl))-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.54); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(2Me))-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.55); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.56); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPSK-NH2 (SEQ ID NO. 57);Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCY-LIEGG-PSSGA-PPPSK-NH2 (SEQ ID NO. 58); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS-NH2 (SEQ ID NO.59); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.60); Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO. 61); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 62); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.63); Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO. 64); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.65); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)I(amL)LD-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS-NH2(SEQ ID NO.66); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.67); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPSK-NH2(SEQ ID NO.68); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS-NH2(SEQ ID NO.69); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(amL)AGG-PSSGA-PPPS-NH2(SEQ ID NO.70); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(amL)AGG-PSSGA-PPPS-NH2(SEQ ID NO.71); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.72); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LE-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.73); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(26DiMeY)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.74); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(Me))-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.75); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.76);Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.77); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(Tle)EGG-PSSGA-PPPS-NH2 (SEQ ID NO.78); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA-PPPS-NH2 (SEQ ID NO.79); Y(Aib)EGT-FTSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.80); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPT-NH2 (SEQ ID NO.81); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPT-NH2 (SEQ ID NO.82); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSK-NH2(SEQ ID NO.83); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS(dk)-NH2(SEQ ID NO.84); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPK-NH2(SEQ ID NO.85); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSKGA-PPPS-NH2(SEQ ID NO.86); Y(Aib)EGT-(amF)TSDV-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.87); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS-NH2(SEQ ID NO.88); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.89); or Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS-NH2(SEQ ID NO.90);

[0493] The peptide conjugate of any one of embodiments 99-105, wherein the peptide modulates a GLP-1 receptor.

[0494] The peptide conjugate of any one of embodiments 99-105, wherein the peptide binds to a GLP-1 receptor.

[0495] The peptide conjugate of any one of embodiments 99-105, wherein the peptide modulates a GIP receptor.

[0496] The peptide conjugate of any one of embodiments 99-105, wherein the peptide binds to a GIP receptor.

[0497] The peptide conjugate of any one of embodiments 99-105, wherein the peptide is a GLP-1 receptor agonist.

[0498] The peptide conjugate of any one of embodiments 99-105, wherein the peptide is a GIP receptor agonist.

[0499] The peptide conjugate of any one of embodiments 99-105, wherein the peptide is a dual GLP-1 receptor and GIP receptor agonist.

[0500] The peptide conjugate of any one of embodiments 99-112, wherein the peptide is resistant to proteolysis by a gastrointestinal protease.

[0501] The peptide conjugate of any one of embodiments 99-113, wherein the second amino acid and the third amino acid are independently a sulfydryl containing amino acid.

[0502] The peptide conjugate of any one of embodiments 99-114, wherein the second amino acid and the third amino acid are independently selected from cysteine, homocysteine, 2-amino-5- mercaptopentanoic acid, and 2-amino-6-mercaptohexanoic acid.

[0503] The peptide conjugate of any one of embodiments 99-114, wherein the second amino acid and third amino acids are cysteines.

[0504] The peptide conjugate of embodiment 116, wherein the second amino acid and the third amino acid are independently an amine-containing amino acid.

[0505] The peptide conjugate of embodiment 117, wherein the amine-containing amino acid is selected from lysine, ornithine, diaminobutyric acid, diaminopropionic acid and homolysine.

[0506] The peptide conjugate of claim 118, wherein the second amino acid and the third amino acids are lysines.

[0507] The peptide conjugate of any one of embodiments 99-119, wherein the second amino acid has a position i in the peptide and the third amino acid has a position i + n in the peptide, wherein n is 4-16.

[0508] The peptide conjugate of any one of embodiments 99-119, wherein the second amino acid has a position i in the peptide and the third amino acid has a position i + 4 in the peptide.

[0509] The peptide conjugate of any one of embodiments 99-119, wherein the second amino acid has a position i in the peptide and the third amino acid has a position i + 7 in the peptide.

[0510] The peptide conjugate of any one of embodiments 99-122, wherein XAand XBare -C(=O)-.

[0511] The peptide conjugate of any one of embodiments 99-122, wherein XAand XBare -alkylene- C(=O)- or -C(=O)alkylene-.

[0512] The peptide conjugate of any one of embodiments 99-122, wherein XAand XBare -CH2-C(=O)- or -C(=O)-CH2-.

[0513] The peptide conjugate of any one of embodiments 99-122, wherein XAand XBare -alkylene- C(=O)NR3- or -C(=O)NR3-alkylene-.

[0514] The peptide conjugate of any one of embodiments 99-122, wherein XAand XBare -CH2- C(=O)NR3- or -C(=O)NR3-CH2-.

[0515] The peptide conjugate of any one of embodiments 99-122, wherein XAand XBare -alkylene- C(=O)NR3-alkylene- or -alkylene-NR3C(=O)-alkylene-.

[0516] The peptide conjugate of any one of embodiments 99-122, wherein XAand XBare -CH2- C(=O)NR3-CH2CH2- or -CH2-NR3C(=O)-CH2CH2-.

[0517] The peptide conjugate of any one of embodiments 99-122, wherein XAand XBare -CH2- C(=O)NH-CH2CH2- or -CH2-NHC(=O)-CH2CH2-.

[0518] The peptide conjugate of any one of embodiments 99-130, wherein >A-R has the following structure:.

[0519] The peptide conjugate of embodiment 131, wherein s is 1-15.

[0520] The peptide conjugate of embodiment 131, wherein s is 1-10.

[0521] The peptide conjugate of embodiment 131, wherein s is 1-5.

[0522] The peptide conjugate of any one of embodiments 99-134, wherein Y is hydrogen or -CO2H.

[0523] The peptide conjugate of any one of embodiments 52-91, wherein each L is independently - (CR1R2)v-, -alkylene-O-, -C(=O)-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene- NR3C(=O)-; and v is 2-20.

[0524] The peptide conjugate of embodiment 136, wherein each R1and R2is independently hydrogen or -CO2H.

[0525] The peptide conjugate of embodiment 136 or 137, wherein R3is hydrogen.

[0526] The peptide conjugate of any one of embodiments 98-137, wherein the peptide conjugate comprises:wherein: ZAis a 5-membered heteroaryl, -CO2H, or -P(=O)(OH)2; each R3is independently hydrogen or methyl; R10is -OH or -NH2; R11is hydrogen, -OH, or -P(=O)(OH)2; n0 is 0 or 1; n1 and n2 are each independently 1-4; and m is 6-20.

[0527] The peptide conjugate of embodiment 138, wherein the peptide conjugate comprises:,wherein n1is 1-4; n2is 1-4; and m is 6-20.

[0528] The peptide conjugate of any one of embodiments 138-142, wherein n1is 1 or 2.

[0529] The peptide conjugate of any one of embodiments 138-143, wherein n2is 1 or 2.

[0530] The peptide conjugate of any one of embodiments 138-144, wherein m is 10-20.

[0531] The peptide conjugate of any one of embodiments 138-145, wherein m is 15-20.

[0532] The peptide conjugate of any one of embodiments 98-146, wherein the peptide conjugate comprises: , ,,

[0533] A peptide comprising a sequence: NH2-Tyr-X2-Glu-Gly-Thr-X6-Thr-Ser-X9-X10-X11-Ile-X13-X14-Asp-Lys-X17-Ala-Ala-Aib-Glu- Phe-Val-X24-X25-X26-X27-X28-Gly-Gly-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-NH2 wherein; X2is Aib, D-Pro, Gly, or D-Ala; X6is Phe, αMe-Phe, or αMe-Phe2F; X9is Asp or αMe-Asp; X10is Tyr, Val, Leu, Ile, Ala, Val(3-OH), or 4Pal; X11is Ser, αMe-Ser, or Val(3-OH); X13is Tyr, αMe-Leu, Cha, or Nle; X14is Leu or αMe-Leu; X17is Cys or Lys; X24is Cys or Lys; X25is Trp, Tyr, αMe-Trp, or αMe-Tyr; X26is Leu, Val, or αMe-Leu; X27is Ile, Leu, αMe-Leu, Tle, cpA, or Lys; X28is Ala, Glu, Hgl, or Lys; X31is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X32is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X33is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X34is Gly, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X35is Ala, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X36is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X37is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X38is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X39is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; and X40is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent;wherein the protein sequence is not Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG- PSSGA-PPPS (SEQ ID NO: 2).

[0534] The peptide of embodiment 153, wherein the sequence has at least 95% identical to a sequence selected from (SEQ ID NOS: 3-90): Y(Aib)EGT-(amF)TS(amD)Y-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 3); Y(Aib)EGT-(amF)TSDY-S(amI)YLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 4); Y(Aib)EGT-(amF)TSDY-SI(amY)LD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 5); Y(Aib)EGT-(amF)TSDY-SIY(amL)D-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO. 6); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO. 7); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVCW-(amL)IAGG-PSSGA-PPPS-NH2(SEQ ID NO. 8); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSK-NH2(SEQ ID NO.9); Y(Aib)EGT-(amF)TSDY-S(amI)Y(amL)D-KCAA(Aib)-EFVC(amW)-(amL)IAGG-PSSGA-PPPS-NH2(SEQ ID NO.10); Y(Aib)EGT-(amF)TSDY-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.11); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-(Nle)IEGG-PSSGA-PPPS-NH2(SEQ ID NO.12); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.13); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.14); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.15); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.16); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Cha)(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.17); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Nle)(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.18); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(1Nal)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.19);Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(Aib)-L(amL)AGG-PSSGA-PPPS-NH2 (SEQ ID NO.20); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)E-(Hgn)CAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.21); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.22); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-NH2 (SEQ ID NO.23); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(W1Me)-(Nle)IEGG-PSSGA-PPPS-NH2 (SEQ ID NO.24); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LD-KCAA(Aib)-EFVC(amW)-L(amL)AGG-PSSGA-PPPS-NH2 (SEQ ID NO.25); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-L(amL)AGG-PSSGA-PPPS-NH2(SEQ ID NO.26); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGG-NH2(SEQ ID NO. 27); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(Tle)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.28); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Ac6c)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.29); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGGK-NH2(SEQ ID NO. 30); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)EKCAA(Aib)EFVC(Tic)L(Tle)EGGPSSGAPPPS-NH2(SEQ ID NO.31); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)L(cpA)EGGPSSGAPPPS-NH2(SEQ ID NO.32); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)(cpA)LEGGPSSGAPPPS-NH2(SEQ ID NO.33); Y(Aib)EGS(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)(cpA)LEGGPSSGAPPPS-NH2(SEQ ID NO.34); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA-PPPS-NH2(SEQ ID NO.35); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Nle)(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA-PPPS- NH2 (SEQ ID NO.36); Y(Aib)EGS-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.37); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LI(Nle)GG-PSSGA-PPPS-NH2 (SEQ ID NO.38);Y(Aib)EGT-(amF)TSDV-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.39); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)E-(Dab)CAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.40); Y(Aib)EGT-(amF)TSD(Nle)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.41); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGG-PSSGA-PPPS-NH2 (SEQ ID NO.42); Y(Aib)EGT(amF)TSDVSI(amL)(Tle)EKCAA(Aib)EFVC(amY)L(Tle)EGGPSSGAPPPS-NH2 (SEQ ID NO.43); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)E(Orn)CAA(Aib)EFVC(amY)(Tle)IEGGPSSGAPPPS-NH2(SEQ ID NO.44); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(amY)L(cpA)EGGPSSGAPPPS-NH2(SEQ ID NO.45); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Tle)(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA-PPPS-NH2(SEQ ID NO.46); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)EKCAA(Aib)EFVC(amY)(Tle)IEGGPSSGAPPPS-NH2(SEQ ID NO.47); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)EKCAA(Aib)EFVC(amY)L(Tle)EGGPSSGAPPPS-NH2(SEQ ID NO.48); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LI(Hgl)GG-PSSGA-PPPS-NH2(SEQ ID NO.49); Y(Aib)EGT-(amF)TSD(Bip)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.50); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(26DiMeY))-(amL)IAGG-PSSGA-PPPS- NH2(SEQ ID NO.51); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(Y(Me))-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.52); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS-NH2(SEQ ID NO.53); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(7Cl))-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.54); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(2Me))-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.55); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.56); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPSK-NH2 (SEQ ID NO. 57);Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCY-LIEGG-PSSGA-PPPSK-NH2 (SEQ ID NO. 58); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS-NH2 (SEQ ID NO.59); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.60); Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO. 61); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 62); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.63); Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO. 64); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.65); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)I(amL)LD-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS-NH2(SEQ ID NO.66); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.67); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPSK-NH2(SEQ ID NO.68); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS-NH2(SEQ ID NO.69); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(amL)AGG-PSSGA-PPPS-NH2(SEQ ID NO.70); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(amL)AGG-PSSGA-PPPS-NH2(SEQ ID NO.71); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.72); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LE-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.73); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(26DiMeY)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.74); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(Me))-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.75); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.76);Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.77); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(Tle)EGG-PSSGA-PPPS-NH2 (SEQ ID NO.78); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA-PPPS-NH2 (SEQ ID NO.79); Y(Aib)EGT-FTSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.80); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPT-NH2 (SEQ ID NO.81); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPT-NH2 (SEQ ID NO.82); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSK-NH2(SEQ ID NO.83); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS(dk)-NH2(SEQ ID NO.84); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPK-NH2(SEQ ID NO.85); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSKGA-PPPS-NH2(SEQ ID NO.86); Y(Aib)EGT-(amF)TSDV-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.87); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS-NH2(SEQ ID NO.88); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.89); or Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS-NH2(SEQ ID NO.90).

[0535] A pharmaceutical composition comprising the peptide conjugate of any one of embodiments 1- 154 or the peptide of claim embodiment 155 or 156; and a pharmaceutically acceptable excipient.

[0536] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS What is claimed is:

1. A compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof:Formula (V) wherein: each R3is independently hydrogen or methyl; R10is -OH or -NH2; R11is hydrogen, -OH, or -P(=O)(OH)2; n0 is 0 or 1; n1 and n2 are each independently 1-4; and m is 6-20.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is hydrogen.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R10is -OH and R11is hydrogen.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is of Formula:wherein n1is 1-4; n2is 1-4; and m is 6-20.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is of Formula:wherein n1 is 1-4; n2 is 1-4; and m is 6-20.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein n1 is 1 or 2.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein n2 is 1, 2, or 3.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 10-20.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 15-20.

10. The compound of any one of claims 1-9, wherein the compound is:, or a pharmaceutically acceptable salt or solvate thereof.

11. A peptide conjugate comprising: a) a peptide; and b) a staple attached to the peptide at a second amino acid and a third amino acid, wherein the second and third amino acid are each a cysteine and wherein the staple is of Formula (IIb):Formula (IIb) wherein: each R3is independently hydrogen or methyl; R10is -OH or -NH2; R11is hydrogen, -OH, or -P(=O)(OH)2; n0 is 0 or 1; n1 and n2 are each independently 1-4;m is 6-20; and each * denotes the attachment point to a sulfur atom of the second and third amino acid.

12. The peptide conjugate of claim 11, wherein each R3is independently hydrogen.

13. The peptide conjugate of claim 11 or 12, wherein R10is -OH and R11is hydrogen.

14. The peptide conjugate of claim 11, wherein the staple is of Formula:wherein n1 is 1-4; n2 is 1-4; and m is 6-20.

15. The peptide conjugate of claim 11, wherein the staple is of Formula:wherein n1is 1-4; n2is 1-4; and m is 6-20.

16. The peptide conjugate of any one of claims 11-15, wherein n1is 1 or 2.

17. The peptide conjugate of any one of claims 11-16, wherein n2is 1, 2, or 3.

18. The peptide conjugate of any one of claims 11-17, wherein m is 10-20.

19. The peptide conjugate of any one of claims 11-18 wherein m is 15-20 20. The peptide conjugate of any one of claims 11-19, wherein the staple is:.

21. The peptide conjugate of any one of claims 11-20, wherein the peptide is an incretin.

22. The peptide conjugate of any one of claims 11-21, wherein the peptide binds to a GIP receptor.

23. The peptide conjugate of any one of claims 11-21, wherein the peptide binds to a GLP-1 receptor.

24. The peptide conjugate of claim 22 or 23, wherein the peptide binds to both a GLP-1 receptor and a GIP receptor.

25. The peptide conjugate of any one of claims 11-24, wherein the peptide comprises a sequence: Tyr-X2-Glu-Gly-Thr-X6-Thr-Ser-X9-X10-X11-Ile-X13-X14-Asp-Lys-X17-Ala-Ala-Aib-Glu-Phe-Val- X24-X25-X26-X27-X28-Gly-Gly-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-NH2, wherein: X2is Aib, D-Pro, Gly, or D-Ala; X6is Phe, αMe-Phe, or αMe-Phe2F; X9is Asp or αMe-Asp; X10is Tyr, Val, Leu, Ile, Ala, Val(3-OH), or 4Pal; X11is Ser, αMe-Ser, or Val(3-OH); X13is Tyr, αMe-Leu, Cha, or Nle; X14is Leu or αMe-Leu; X17is Cys or Lys; X24is Cys or Lys; X25is Trp, Tyr, αMe-Trp, or αMe-Tyr; X26is Leu, Val, or αMe-Leu; X27is Ile, Leu, αMe-Leu, Tle, cpA, or Lys; X28is Ala, Glu, Hgl, or Lys; X31is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X32is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X33is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X34is Gly, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X35is Ala, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X36is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X37is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X38is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X39is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; and X40is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent.

26. The peptide conjugate of claim 25, wherein the peptide comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO.2-115: Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO. 2); Y(Aib)EGT-(amF)TS(amD)Y-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.3);Y(Aib)EGT-(amF)TSDY-S(amI)YLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.4); Y(Aib)EGT-(amF)TSDY-SI(amY)LD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.5); Y(Aib)EGT-(amF)TSDY-SIY(amL)D-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.6); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.7); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVCW-(amL)IAGG-PSSGA-PPPS-NH2 (SEQ ID NO.8); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSK-NH2(SEQ ID NO.9); Y(Aib)EGT-(amF)TSDY-S(amI)Y(amL)D-KCAA(Aib)-EFVC(amW)-(amL)IAGG-PSSGA- PPPS-NH2(SEQ ID NO.10); Y(Aib)EGT-(amF)TSDY-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.11); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-(Nle)IEGG-PSSGA- PPPS-NH2(SEQ ID NO.12); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.13); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.14); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.15); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.16); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Cha)(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA- PPPS-NH2(SEQ ID NO.17); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Nle)(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA- PPPS-NH2(SEQ ID NO.18); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(1Nal)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.19); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(Aib)-L(amL)AGG-PSSGA- PPPS-NH2 (SEQ ID NO.20); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)E-(Hgn)CAA(Aib)-EFVC(amW)-LIEGG-PSSGA- PPPS-NH2 (SEQ ID NO.21); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.22);Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-NH2 (SEQ ID NO.23); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(W1Me)-(Nle)IEGG-PSSGA- PPPS-NH2 (SEQ ID NO.24); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LD-KCAA(Aib)-EFVC(amW)-L(amL)AGG-PSSGA- PPPS-NH2 (SEQ ID NO.25); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-L(amL)AGG-PSSGA- PPPS-NH2 (SEQ ID NO.26); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGG-NH2 (SEQ ID NO.27); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(Tle)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.28); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Ac6c)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.29); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGGK-NH2(SEQ ID NO.30); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)EKCAA(Aib)EFVC(Tic)L(Tle)EGGPSSGAPPPS- NH2(SEQ ID NO.31); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)L(cpA)EGGPSSGAPPP S-NH2(SEQ ID NO.32); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)(cpA)LEGGPSSGAPPP S-NH2(SEQ ID NO.33); Y(Aib)EGS(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)(cpA)LEGGPSSGAPPP S-NH2(SEQ ID NO.34); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA- PPPS-NH2(SEQ ID NO.35); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Nle)(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA- PPPS-NH2(SEQ ID NO.36); Y(Aib)EGS-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.37); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LI(Nle)GG-PSSGA- PPPS-NH2 (SEQ ID NO.38); Y(Aib)EGT-(amF)TSDV-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.39); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)E-(Dab)CAA(Aib)-EFVC(amW)-LIEGG-PSSGA- PPPS-NH2 (SEQ ID NO.40); Y(Aib)EGT-(amF)TSD(Nle)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.41);Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGG-PSSGA- PPPS-NH2 (SEQ ID NO.42); Y(Aib)EGT(amF)TSDVSI(amL)(Tle)EKCAA(Aib)EFVC(amY)L(Tle)EGGPSSGAPPPS-NH2 (SEQ ID NO.43); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)E(Orn)CAA(Aib)EFVC(amY)(Tle)IEGGPSSGAPPP S-NH2 (SEQ ID NO.44); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(amY)L(cpA)EGGPSSGAPP PS-NH2 (SEQ ID NO.45); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Tle)(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA- PPPS-NH2 (SEQ ID NO.46); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)EKCAA(Aib)EFVC(amY)(Tle)IEGGPSSGAPPPS- NH2(SEQ ID NO.47); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)EKCAA(Aib)EFVC(amY)L(Tle)EGGPSSGAPPPS- NH2(SEQ ID NO.48); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LI(Hgl)GG-PSSGA- PPPS-NH2(SEQ ID NO.49); Y(Aib)EGT-(amF)TSD(Bip)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.50); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(26DiMeY))-(amL)IAGG- PSSGA-PPPS-NH2(SEQ ID NO.51); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(Y(Me))-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.52); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS- NH2(SEQ ID NO.53); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(7Cl))-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.54); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(2Me))-LIEGG-PSSGA- PPPS-NH2(SEQ ID NO.55); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.56); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPSK-NH2(SEQ ID NO.57); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCY-LIEGG-PSSGA-PPPSK-NH2 (SEQ ID NO.58); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS- NH2 (SEQ ID NO.59); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.60);Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.61); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.62); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.63); Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.64); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.65); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)I(amL)LD-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA- PPPS-NH2(SEQ ID NO.66); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.67); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPSK- NH2(SEQ ID NO.68); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS- NH2(SEQ ID NO.69); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(amL)AGG-PSSGA-PPPS- NH2(SEQ ID NO.70); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(amL)AGG-PSSGA- PPPS-NH2(SEQ ID NO.71); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.72); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LE-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.73); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(26DiMeY)-LIEGG-PSSGA- PPPS-NH2(SEQ ID NO.74); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(Me))-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.75); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.76); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.77); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(Tle)EGG-PSSGA-PPPS- NH2 (SEQ ID NO.78); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA- PPPS-NH2 (SEQ ID NO.79);Y(Aib)EGT-FTSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.80); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPT-NH2 (SEQ ID NO. 81); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPT- NH2 (SEQ ID NO.82); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSK-NH2 (SEQ ID NO. 83); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS(dk)-NH2 (SEQ ID NO.84); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPK- NH2(SEQ ID NO.85); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSKGA-PPPS- NH2(SEQ ID NO.86); Y(Aib)EGT-(amF)TSDV-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.87); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS- NH2(SEQ ID NO.88); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.89); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS- NH2(SEQ ID NO.90); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPSK- NH2(SEQ ID NO.91); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA- PPPS(dk)-NH2(SEQ ID NO.92); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA- PPPS(Orn)-NH2(SEQ ID NO.93); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA- PPPS(Dab)-NH2(SEQ ID NO.94); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA- PPPS(Dap)-NH2 (SEQ ID NO.95); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS(D- Dab)-NH2 (SEQ ID NO.96); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIKGG-PSSGA-PPPS- NH2 (SEQ ID NO.97); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LKAGG-PSSGA-PPPS- NH2 (SEQ ID NO.98);Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVCW-(amL)IAGG-PSSGA-PPPS- NH2 (SEQ ID NO.99); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.100); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.101); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-(amL)IEGG-K-NH2 (SEQ ID NO.102); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.103); Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS-NH2(SEQ ID NO.104); Y(Aib)EGT-(amF)TSDY-(amS)IVLD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS-NH2(SEQ ID NO.105); Y(Aib)EGT-(amF)TSDV-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS- NH2(SEQ ID NO.106); Y(Aib)EGT-(amF)TSDY-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS- NH2(SEQ ID NO.107); Y(Aib)EGT-(amF)TSDY-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS- NH2(SEQ ID NO.108); Y(Aib)EGT-(amF)TSDY-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.109); Y(Aib)EGT-(amF)TSDV-(Aib)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.110); Y(Aib)EGT-(amF)TSDV-(amS)I(Aib)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.111); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.112); Y(Aib)EGT-(amF)TSDL-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.113); Y(Aib)EGT-(amF)TSDL-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.114); or Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-VIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.115).

27. The peptide conjugate of any one of claims 11-26, wherein the second amino acid has a position i in the peptide and the third amino acid has a position i + n in the peptide, wherein n is 4-16.

28. The peptide conjugate of claim 27, wherein the second amino acid has a position i in the peptide and the third amino acid has a position i + 4 in the peptide.

29. The peptide conjugate of claim 27, wherein the second amino acid has a position i in the peptide and the third amino acid has a position i + 7 in the peptide.

30. The peptide conjugate of claim 11, wherein the peptide conjugate is:

31. A composition comprising a compound of Formula (I*), or a pharmaceutically acceptable salt or solvate thereof:Formula (I*) wherein: each R4is independently hydrogen, -CH3, -CH2CH3,,R5is –(CHR5a-NHC(=O))0-2-(La)t-RQ; wherein; each R5ais hydrogen, -C(=O)OH, or -CH2CH2C(=O)OH; each Lais independently -(CR7R7)w-, -alkylene-O-, -O-alkylene-, -NR8-alkylene-, - alkylene-NR8-, -C(=O)NR8-, -NR8C(=O)-, -alkylene-C(=O)NR8-, -C(=O)NR8- alkylene-, -alkylene-NR8C(=O)-, or -NR8C(=O)-alkylene, wherein each R7is independently hydrogen or -CH(=O)OH; each R8is independently hydrogen; and w is 1-10; RQis -CH3, -C(=O)OH, -P(=O)(OH)2, phenyl, 5-membered heteroaryl, 2-amino-5- methyl-5,6,7,8-tetrahydropteridin-4(3H)-one, or tetrahydro-1H-thieno[3,4- d]imidazol-2(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen; t is 1-10; and f is 0 or 1; R9is hydrogen or methyl; RXis a nitrogen of an amine containing amino acid.

32. The composition of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4is independently hydrogen, -CH3, or.

33. The composition of claim 31 or 32, or a pharmaceutically acceptable salt or solvate thereof, wherein f is 1.

34. The composition of any one of claims 31-33, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is:wherein: t1 is 0, 1, or 2; t2is 6-20; and RQis -CO2H, phenyl, 5-membered heteroaryl, or 2-amino-5-methyl-5,6,7,8-tetrahydropteridin- 4(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen.

35. The composition of any one of claims 31-33, or a pharmaceutically acceptable salt or solvate thereof, wherein R5is:wherein: t2 is 6-20; t3 is 2-10; and RQis -CO2H, phenyl, 5-membered heteroaryl, or 2-amino-5-methyl-5,6,7,8-tetrahydropteridin- 4(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen.

36. The composition of claim 34 and 35, or a pharmaceutically acceptable salt or solvate thereof, wherein RQis -C(=O)OH.

37. The composition of claim 35 or 36, or a pharmaceutically acceptable salt or solvate thereof, wherein RQis phenyl optionally substituted with one, two, or thee halogen.

38. The composition of any one of claim 31-37, wherein R5is: ,,39. The composition of any one of claims 31-38, wherein the composition further comprises a peptide comprising the amine containing amino acid.

40. The composition of claim 39, wherein the peptide sequence comprises: Tyr-X2-Glu-Gly-Thr-X6-Thr-Ser-X9-X10-X11-Ile-X13-X14-Asp-Lys-X17-Ala-Ala-Aib-Glu-Phe-Val- X24-X25-X26-X27-X28-Gly-Gly-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-NH2, wherein: X2is Aib, D-Pro, Gly, or D-Ala; X6is Phe, αMe-Phe, or αMe-Phe2F; X9is Asp or αMe-Asp; X10is Tyr, Val, Leu, Ile, Ala, Val(3-OH), or 4Pal; X11is Ser, αMe-Ser, or Val(3-OH);X13is Tyr, αMe-Leu, Cha, or Nle; X14is Leu or αMe-Leu; X17is Cys or Lys; X24is Cys or Lys; X25is Trp, Tyr, αMe-Trp, or αMe-Tyr; X26is Leu, Val, or αMe-Leu; X27is Ile, Leu, αMe-Leu, Tle, cpA, or Lys; X28is Ala, Glu, Hgl, or Lys; X31is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X32is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X33is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X34is Gly, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X35is Ala, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X36is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X37is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X38is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X39is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; and X40is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent.

41. The composition of claim 40, wherein the peptide comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO.2-115: Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO. 2); Y(Aib)EGT-(amF)TS(amD)Y-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.3); Y(Aib)EGT-(amF)TSDY-S(amI)YLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.4); Y(Aib)EGT-(amF)TSDY-SI(amY)LD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.5); Y(Aib)EGT-(amF)TSDY-SIY(amL)D-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.6); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.7); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVCW-(amL)IAGG-PSSGA-PPPS-NH2 (SEQ ID NO.8); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSK-NH2 (SEQ ID NO.9);Y(Aib)EGT-(amF)TSDY-S(amI)Y(amL)D-KCAA(Aib)-EFVC(amW)-(amL)IAGG-PSSGA- PPPS-NH2 (SEQ ID NO.10); Y(Aib)EGT-(amF)TSDY-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.11); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-(Nle)IEGG-PSSGA- PPPS-NH2 (SEQ ID NO.12); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.13); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.14); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.15); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.16); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Cha)(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA- PPPS-NH2(SEQ ID NO.17); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Nle)(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA- PPPS-NH2(SEQ ID NO.18); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(1Nal)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.19); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(Aib)-L(amL)AGG-PSSGA- PPPS-NH2(SEQ ID NO.20); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)E-(Hgn)CAA(Aib)-EFVC(amW)-LIEGG-PSSGA- PPPS-NH2(SEQ ID NO.21); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.22); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-NH2(SEQ ID NO.23); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(W1Me)-(Nle)IEGG-PSSGA- PPPS-NH2(SEQ ID NO.24); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LD-KCAA(Aib)-EFVC(amW)-L(amL)AGG-PSSGA- PPPS-NH2 (SEQ ID NO.25); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-L(amL)AGG-PSSGA- PPPS-NH2 (SEQ ID NO.26); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGG-NH2 (SEQ ID NO.27); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(Tle)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.28);Y(Aib)EGT-(amF)TSD(4Pal)-SI(Ac6c)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.29); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGGK-NH2 (SEQ ID NO.30); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)EKCAA(Aib)EFVC(Tic)L(Tle)EGGPSSGAPPPS- NH2 (SEQ ID NO.31); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)L(cpA)EGGPSSGAPPP S-NH2 (SEQ ID NO.32); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)(cpA)LEGGPSSGAPPP S-NH2 (SEQ ID NO.33); Y(Aib)EGS(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)(cpA)LEGGPSSGAPPP S-NH2(SEQ ID NO.34); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA- PPPS-NH2(SEQ ID NO.35); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Nle)(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA- PPPS-NH2(SEQ ID NO.36); Y(Aib)EGS-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.37); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LI(Nle)GG-PSSGA- PPPS-NH2(SEQ ID NO.38); Y(Aib)EGT-(amF)TSDV-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.39); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)E-(Dab)CAA(Aib)-EFVC(amW)-LIEGG-PSSGA- PPPS-NH2(SEQ ID NO.40); Y(Aib)EGT-(amF)TSD(Nle)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.41); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGG-PSSGA- PPPS-NH2(SEQ ID NO.42); Y(Aib)EGT(amF)TSDVSI(amL)(Tle)EKCAA(Aib)EFVC(amY)L(Tle)EGGPSSGAPPPS-NH2(SEQ ID NO.43); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)E(Orn)CAA(Aib)EFVC(amY)(Tle)IEGGPSSGAPPP S-NH2 (SEQ ID NO.44); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(amY)L(cpA)EGGPSSGAPP PS-NH2 (SEQ ID NO.45); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Tle)(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA- PPPS-NH2 (SEQ ID NO.46); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)EKCAA(Aib)EFVC(amY)(Tle)IEGGPSSGAPPPS- NH2 (SEQ ID NO.47);Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)EKCAA(Aib)EFVC(amY)L(Tle)EGGPSSGAPPPS- NH2 (SEQ ID NO.48); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LI(Hgl)GG-PSSGA- PPPS-NH2 (SEQ ID NO.49); Y(Aib)EGT-(amF)TSD(Bip)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.50); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(26DiMeY))-(amL)IAGG- PSSGA-PPPS-NH2 (SEQ ID NO.51); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(Y(Me))-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.52); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS- NH2(SEQ ID NO.53); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(7Cl))-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.54); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(2Me))-LIEGG-PSSGA- PPPS-NH2(SEQ ID NO.55); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.56); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPSK-NH2(SEQ ID NO.57); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCY-LIEGG-PSSGA-PPPSK-NH2(SEQ ID NO.58); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS- NH2(SEQ ID NO.59); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.60); Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.61); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.62); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.63); Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.64); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.65); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)I(amL)LD-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA- PPPS-NH2 (SEQ ID NO.66);Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.67); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPSK- NH2 (SEQ ID NO.68); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS- NH2 (SEQ ID NO.69); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(amL)AGG-PSSGA-PPPS- NH2 (SEQ ID NO.70); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(amL)AGG-PSSGA- PPPS-NH2 (SEQ ID NO.71); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.72); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LE-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.73); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(26DiMeY)-LIEGG-PSSGA- PPPS-NH2(SEQ ID NO.74); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(Me))-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.75); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.76); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.77); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(Tle)EGG-PSSGA-PPPS- NH2(SEQ ID NO.78); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA- PPPS-NH2(SEQ ID NO.79); Y(Aib)EGT-FTSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.80); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPT-NH2(SEQ ID NO. 81); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPT- NH2 (SEQ ID NO.82); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSK-NH2 (SEQ ID NO. 83); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS(dk)-NH2 (SEQ ID NO.84); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPK- NH2 (SEQ ID NO.85);Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSKGA-PPPS- NH2 (SEQ ID NO.86); Y(Aib)EGT-(amF)TSDV-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.87); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.88); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.89); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.90); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPSK- NH2(SEQ ID NO.91); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA- PPPS(dk)-NH2(SEQ ID NO.92); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA- PPPS(Orn)-NH2(SEQ ID NO.93); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA- PPPS(Dab)-NH2(SEQ ID NO.94); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA- PPPS(Dap)-NH2(SEQ ID NO.95); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS(D- Dab)-NH2(SEQ ID NO.96); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIKGG-PSSGA-PPPS- NH2(SEQ ID NO.97); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LKAGG-PSSGA-PPPS- NH2(SEQ ID NO.98); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVCW-(amL)IAGG-PSSGA-PPPS- NH2(SEQ ID NO.99); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.100); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.101); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-(amL)IEGG-K-NH2 (SEQ ID NO.102); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.103); Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.104);Y(Aib)EGT-(amF)TSDY-(amS)IVLD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.105); Y(Aib)EGT-(amF)TSDV-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.106); Y(Aib)EGT-(amF)TSDY-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.107); Y(Aib)EGT-(amF)TSDY-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.108); Y(Aib)EGT-(amF)TSDY-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.109); Y(Aib)EGT-(amF)TSDV-(Aib)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.110); Y(Aib)EGT-(amF)TSDV-(amS)I(Aib)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.111); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.112); Y(Aib)EGT-(amF)TSDL-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.113); Y(Aib)EGT-(amF)TSDL-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.114); or Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-VIAGG-PSSGA-PPPS- NH2(SEQ ID NO.115).

42. The composition of any one of claims 31-41, wherein the amine containing amino acid is a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, and homolysine.

43. The composition of claim 42, wherein the amine containing amino acid is a lysine.

44. The composition of claim 43, wherein the amine containing amino acid is a lysine at position X16, X33, or X40.

45. The composition of any one of claim 31-44, wherein the compound of Formula (I*) modulates stability of the peptide.

46. The composition of any one of claims 31-44, wherein the compound of Formula (I*) increases metabolic stability of the peptide.

47. A peptide conjugate comprising: a) a peptide; and b) a prodrug moiety attached to the peptide at an amine containing side chain residue of a first amino acid; wherein the prodrug moiety is of Formula (I):Formula (I) wherein: each R4is independently hydrogen, -CH3, -CH2CH3,,R5is –(CHR5a-NHC(=O))0-2-(La)t-RQ; wherein each R5ais hydrogen, -CH(=O)OH, or -CH2CH2C(=O)OH; each Lais independently -(CR7R7)w-, -alkylene-O-, -O-alkylene-, -NR8-alkylene-, - alkylene-NR8-, -C(=O)NR8-, -NR8C(=O)-, -alkylene-C(=O)NR8-, -C(=O)NR8- alkylene-, -alkylene-NR8C(=O)-, or -NR8C(=O)-alkylene, wherein each R7is independently hydrogen or -CH(=O)OH; each R8is independently hydrogen; a w is 1-10; RQis -CH3, -C(=O)OH, -P(=O)(OH)2, phenyl, 5-membered heteroaryl, 2-amino-5- methyl-5,6,7,8-tetrahydropteridin-4(3H)-one, or tetrahydro-1H-thieno[3,4- d]imidazol-2(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen; t is 1-10; R9is hydrogen or methyl; f is 0 or 1; p and q are each 1; and denotes the attachment of the prodrug to the nitrogen atom of the peptide. . The peptide conjugate of claim 47, wherein the peptide conjugate further comprises a staple attached to the peptide at a second amino acid and a third amino acid, wherein the second and third amino acid are each cysteine, wherein the staple is of Formula (IIa):Formula (IIa) wherein: ZAis a 5-membered heteroaryl, -CO2H, or -P(=O)(OH)2; each R3is independently hydrogen or methyl; R10is -OH or -NH2; R11is hydrogen, -OH, or -P(=O)(OH)2; n0 is 0 or 1; n1 and n2 are each independently 1-4; m is 6-20; and each * denotes the attachment point to a sulfur atom of the second and third amino acid.

49. The peptide conjugate of claim 47, wherein each R4is independently hydrogen, -CH3, or, and f is 1.

50. The peptide conjugate of claim 47 or 49, wherein the prodrug is of formula:

51. The peptide conjugate of any one of claims 47, 49, or 50, wherein: each Lais independently -(CR7R7)w-, -alkylene-O-, -O-alkylene-, -C(=O)NR8-, -NR8C(=O)-, - alkylene-C(=O)NR8-, or -C(=O)NR8-alkylene-; and RQis -C(=O)OH, -P(=O)(OH)2, or phenyl which is optionally substituted with one, two, or three halogen.

52. The peptide conjugate of any one of claims 47 or 49-51, wherein R5is:wherein: t1 is 0, 1, or 2; t2 is 6-20; and RQis -CO2H, phenyl, 5-membered heteroaryl, or 2-amino-5-methyl-5,6,7,8-tetrahydropteridin- 4(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen.

53. The peptide conjugate of any one of claim 47 or 49-51, wherein R5is:wherein: t2is 6-20; t3is 2-10; andRQis -CO2H, phenyl, 5-membered heteroaryl, or 2-amino-5-methyl-5,6,7,8-tetrahydropteridin- 4(3H)-one, wherein the phenyl or heteroaryl is optionally substituted with one, two, or three halogen.

54. The peptide conjugate of claim 52 or 53, wherein RQis -C(=O)OH.

55. The peptide conjugate of claim 52 or 53, wherein RQis phenyl optionally substituted with one, two, or thee halogen.

56. The peptide conjugate of claim 46, wherein R5is,57. The peptide conjugate of any one of claims 47 or 49-56, wherein the prodrug is attached at the peptide at a lysine or homolysine side chain reside.

58. The peptide conjugate of claim 48, wherein each R3is independently hydrogen.

59. The peptide conjugate of claim 48 or 58, wherein R10is -OH and R11is hydrogen.

60. The peptide conjugate of any one of claims 48, 58, or 59, wherein n1 is 1 or 2.

61. The peptide conjugate of any one of claims 48 or 58-60, wherein n2 is 1 or 2.

62. The peptide conjugate of any one of claims 48 or 58-61, wherein m is 10-20.

63. The peptide conjugate of any one of claims 48 or 58-62, wherein m is 15-20.

64. The peptide conjugate of claim 48, wherein the staple is: ,,.

65. The peptide conjugate of any one of claims 47-64, wherein the peptide is an incretin.

66. The peptide conjugate of any one of claims 47-65, wherein the peptide binds to a GIP receptor.

67. The peptide conjugate of any one of claims 47-65, wherein the peptide binds to a GLP-1 receptor.

68. The peptide conjugate of claim 66 or 67, wherein the peptide binds to both a GLP-1 receptor and a GIP receptor.

69. The peptide conjugate of any one of claims 47-68, wherein the peptide comprising a sequence Tyr-X2-Glu-Gly-Thr-X6-Thr-Ser-X9-X10-X11-Ile-X13-X14-Asp-Lys-X17-Ala-Ala-Aib-Glu-Phe-Val- X24-X25-X26-X27-X28-Gly-Gly-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-NH2, wherein: X2is Aib, D-Pro, Gly, or D-Ala; X6is Phe, αMe-Phe, or αMe-Phe2F; X9is Asp or αMe-Asp; X10is Tyr, Val, Leu, Ile, Ala, Val(3-OH), or 4Pal; X11is Ser, αMe-Ser, or Val(3-OH); X13is Tyr, αMe-Leu, Cha, or Nle; X14is Leu or αMe-Leu; X17is Cys or Lys; X24is Cys or Lys; X25is Trp, Tyr, αMe-Trp, or αMe-Tyr; X26is Leu, Val, or αMe-Leu; X27is Ile, Leu, αMe-Leu, Tle, cpA, or Lys; X28is Ala, Glu, Hgl, or Lys; X31is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X32is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X33is Ser, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent;X34is Gly, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X35is Ala, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X36is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X37is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X38is Pro, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; X39is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent; and X40is Ser, Thr, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, or absent.

70. The peptide conjugate of claim 69, wherein the peptide comprises a sequence at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO.2-115: Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO. 2); Y(Aib)EGT-(amF)TS(amD)Y-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.3); Y(Aib)EGT-(amF)TSDY-S(amI)YLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.4); Y(Aib)EGT-(amF)TSDY-SI(amY)LD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.5); Y(Aib)EGT-(amF)TSDY-SIY(amL)D-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.6); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.7); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVCW-(amL)IAGG-PSSGA-PPPS-NH2(SEQ ID NO.8); Y(Aib)EGT-(amF)TSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSK-NH2(SEQ ID NO.9); Y(Aib)EGT-(amF)TSDY-S(amI)Y(amL)D-KCAA(Aib)-EFVC(amW)-(amL)IAGG-PSSGA- PPPS-NH2(SEQ ID NO.10); Y(Aib)EGT-(amF)TSDY-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.11); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-(Nle)IEGG-PSSGA- PPPS-NH2 (SEQ ID NO.12); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.13); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.14); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.15);Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.16); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Cha)(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA- PPPS-NH2 (SEQ ID NO.17); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Nle)(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA- PPPS-NH2 (SEQ ID NO.18); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(1Nal)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.19); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(Aib)-L(amL)AGG-PSSGA- PPPS-NH2 (SEQ ID NO.20); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)E-(Hgn)CAA(Aib)-EFVC(amW)-LIEGG-PSSGA- PPPS-NH2(SEQ ID NO.21); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.22); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-NH2(SEQ ID NO.23); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(W1Me)-(Nle)IEGG-PSSGA- PPPS-NH2(SEQ ID NO.24); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LD-KCAA(Aib)-EFVC(amW)-L(amL)AGG-PSSGA- PPPS-NH2(SEQ ID NO.25); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-L(amL)AGG-PSSGA- PPPS-NH2(SEQ ID NO.26); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGG-NH2(SEQ ID NO.27); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(Tle)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.28); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Ac6c)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.29); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGGK-NH2(SEQ ID NO.30); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)EKCAA(Aib)EFVC(Tic)L(Tle)EGGPSSGAPPPS- NH2 (SEQ ID NO.31); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)L(cpA)EGGPSSGAPPP S-NH2 (SEQ ID NO.32); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)(cpA)LEGGPSSGAPPP S-NH2 (SEQ ID NO.33); Y(Aib)EGS(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(Tic)(cpA)LEGGPSSGAPPP S-NH2 (SEQ ID NO.34);Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA- PPPS-NH2 (SEQ ID NO.35); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Nle)(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA- PPPS-NH2 (SEQ ID NO.36); Y(Aib)EGS-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.37); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LI(Nle)GG-PSSGA- PPPS-NH2 (SEQ ID NO.38); Y(Aib)EGT-(amF)TSDV-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.39); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)E-(Dab)CAA(Aib)-EFVC(amW)-LIEGG-PSSGA- PPPS-NH2(SEQ ID NO.40); Y(Aib)EGT-(amF)TSD(Nle)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2(SEQ ID NO.41); Y(Aib)EGT-(amF)TSD(4Pal)-SI(amL)LE-(Orn)CAA(Aib)-EFVC(amW)-LVEGG-PSSGA- PPPS-NH2(SEQ ID NO.42); Y(Aib)EGT(amF)TSDVSI(amL)(Tle)EKCAA(Aib)EFVC(amY)L(Tle)EGGPSSGAPPPS-NH2(SEQ ID NO.43); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)E(Orn)CAA(Aib)EFVC(amY)(Tle)IEGGPSSGAPPP S-NH2(SEQ ID NO.44); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)E(Orn)CAA(Aib)EFVC(amY)L(cpA)EGGPSSGAPP PS-NH2(SEQ ID NO.45); Y(Aib)EGT-(amF)TSD(4Pal)-SI(Tle)(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA- PPPS-NH2(SEQ ID NO.46); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(Nle)EKCAA(Aib)EFVC(amY)(Tle)IEGGPSSGAPPPS- NH2(SEQ ID NO.47); Y(Aib)EGT(amF)TSD(4Pal)SI(amL)(cpA)EKCAA(Aib)EFVC(amY)L(Tle)EGGPSSGAPPPS- NH2(SEQ ID NO.48); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LI(Hgl)GG-PSSGA- PPPS-NH2(SEQ ID NO.49); Y(Aib)EGT-(amF)TSD(Bip)-SIY(amL)D-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.50); Y(Aib)EGT-(amF)TSD(4Pal)-SIY(amL)D-KCAA(Aib)-EFVC(26DiMeY))-(amL)IAGG- PSSGA-PPPS-NH2 (SEQ ID NO.51); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(Y(Me))-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.52); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.53);Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(7Cl))-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.54); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(2Me))-LIEGG-PSSGA- PPPS-NH2 (SEQ ID NO.55); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.56); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPSK-NH2 (SEQ ID NO.57); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCY-LIEGG-PSSGA-PPPSK-NH2 (SEQ ID NO.58); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS- NH2(SEQ ID NO.59); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.60); Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.61); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.62); Y(Aib)EGT-(amF)TSDV-(amS)ILLD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.63); Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.64); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.65); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)I(amL)LD-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA- PPPS-NH2(SEQ ID NO.66); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.67); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPSK- NH2(SEQ ID NO.68); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-(amL)IEGG-PSSGA-PPPS- NH2 (SEQ ID NO.69); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(amL)AGG-PSSGA-PPPS- NH2 (SEQ ID NO.70); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(amL)AGG-PSSGA- PPPS-NH2 (SEQ ID NO.71); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.72);Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LE-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.73); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(26DiMeY)-LIEGG-PSSGA- PPPS-NH2 (SEQ ID NO.74); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(W(Me))-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.75); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2 (SEQ ID NO.76); Y(Aib)EGT-(amF)TSD(4Pal)-(amS)ILLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2 (SEQ ID NO.77); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-L(Tle)EGG-PSSGA-PPPS- NH2(SEQ ID NO.78); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-L(Tle)EGG-PSSGA- PPPS-NH2(SEQ ID NO.79); Y(Aib)EGT-FTSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.80); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPT-NH2(SEQ ID NO. 81); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPT- NH2(SEQ ID NO.82); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPSK-NH2(SEQ ID NO. 83); Y(Aib)EGT-FTSDY-SIYLD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS(dk)-NH2(SEQ ID NO.84); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPK- NH2(SEQ ID NO.85); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSKGA-PPPS- NH2(SEQ ID NO.86); Y(Aib)EGT-(amF)TSDV-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS- NH2(SEQ ID NO.87); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.88); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.89); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.90); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPSK- NH2 (SEQ ID NO.91);Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA- PPPS(dk)-NH2 (SEQ ID NO.92); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA- PPPS(Orn)-NH2 (SEQ ID NO.93); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA- PPPS(Dab)-NH2 (SEQ ID NO.94); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA- PPPS(Dap)-NH2 (SEQ ID NO.95); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS(D- Dab)-NH2 (SEQ ID NO.96); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIKGG-PSSGA-PPPS- NH2(SEQ ID NO.97); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LKAGG-PSSGA-PPPS- NH2(SEQ ID NO.98); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVCW-(amL)IAGG-PSSGA-PPPS- NH2(SEQ ID NO.99); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVCW-LIAGG-PSSGA-PPPS-NH2(SEQ ID NO.100); Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVCW-LIEGG-PSSGA-PPPS-NH2(SEQ ID NO.101); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVCW-(amL)IEGG-K-NH2(SEQ ID NO.102); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS- NH2(SEQ ID NO.103); Y(Aib)EGT-(amF)TSDY-(amS)ILLD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS-NH2(SEQ ID NO.104); Y(Aib)EGT-(amF)TSDY-(amS)IVLD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS-NH2(SEQ ID NO.105); Y(Aib)EGT-(amF)TSDV-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS- NH2(SEQ ID NO.106); Y(Aib)EGT-(amF)TSDY-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.107); Y(Aib)EGT-(amF)TSDY-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-VIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.108); Y(Aib)EGT-(amF)TSDY-(amS)I(amL)LD-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.109); Y(Aib)EGT-(amF)TSDV-(Aib)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.110);Y(Aib)EGT-(amF)TSDV-(amS)I(Aib)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.111); Y(Aib)EGT-(amF)TSDY-(amS)IY(amL)D-KCAA(Aib)-EFVC(amY)-LIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.112); Y(Aib)EGT-(amF)TSDL-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIEGG-PSSGA-PPPS- NH2 (SEQ ID NO.113); Y(Aib)EGT-(amF)TSDL-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-LIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.114); or Y(Aib)EGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFVC(amW)-VIAGG-PSSGA-PPPS- NH2 (SEQ ID NO.115).

71. The peptide conjugate of claim 69 or 70, wherein the second amino acid has a position i in the peptide and the third amino acid has a position i + n in the peptide, wherein n is 4-16.

72. The peptide conjugate of claim 69 or 70, wherein the second amino acid has a position i in the peptide and the third amino acid has a position i + 4 in the peptide.

73. The peptide conjugate of claim 69 or 70, wherein the second amino acid has a position i in the peptide and the third amino acid has a position i + 7 in the peptide.

74. The peptide conjugate of claim 69 or 70, wherein the second amino acid is cysteine 17 and the third amino acid is cysteine 24.

75. The peptide conjugate of claim 69 or 70, wherein the prodrug is attached to the peptide at a lysine at position X16, X33, or X40.

76. The peptide conjugate of claim 47, wherein the peptide conjugate is:

77. The peptide conjugate of claim 47, wherein the peptide conjugate is:

78. The peptide conjugate of claim 47, wherein the peptide conjugate is:

79. The peptide conjugate of claim 47, wherein the peptide conjugate is:

80. The peptide conjugate of claim 47, wherein the peptide conjugate is:

81. The peptide conjugate of claim 47, wherein the peptide conjugate is:

82. A pharmaceutical composition comprising a peptide conjugate of any one of claims 11-30 or 47- 79, and a pharmaceutically acceptable excipient.

83. A method for treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of the peptide conjugate of any one of claims 11-30 or 47-79.

84. The method of claim 81, wherein the disease or condition is diabetes or obesity.

85. The method of claim 82, wherein the diabetes is Type 1 diabetes mellitus, Type 2 diabetes mellitus, gestational diabetes, neonatal diabetes, maturity onset diabetes of the young, or latent autoimmune diabetes in adults, or any combination thereof.

86. The method of claim 81, wherein the disease or condition is non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF), or cardiovascular disease.

87. The method of claim 81, wherein the disease or condition is short bowel syndrome (SBS).

88. The method of claim 81, wherein the disease or condition is inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), or psoriasis.

89. The method of claim 81, wherein the disease or condition is Alzheimer’s disease, Parkinson’s disease or Huntington’s disease.

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