Triple GIP / GLP-1 / glucagon peptide conjugates and methods of use

Abstract

Provided herein are peptides and peptide conjugates having activity as triple agonists of the glucose-dependent insulinotropic polypeptide (GIP) receptor, the glucagon-like peptide 1 (GLP-1) receptor, and the glucagon (GCG) receptor. The peptide conjugates provided herein are cross-linked via a half-life extending staple. The peptides and peptide conjugates may be used for blood glucose management and treating conditions such as diabetes mellitus, obesity, dyslipidemia, metabolic syndrome, and metabolic dysfunction-associated steatohepatitis (MASH).

Description

WSGR Docket No. 36271-720.601TRIPLE GIP / GLP-l / GLUCAGON PEPTIDE CONJUGATES AND METHODS OF USECROSS-REFERENCE

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 701,445 filed September 30, 2024; U.S. Provisional Application No. 63 / 830,318, filed June 25, 2025; and U.S. Provisional Application No. 63 / 874,535, filed September 2, 2025; each of which is incorporated by reference herein in its entirety.BACKGROUND OF THE INVENTION

[0002] Diabetes and obesity have become escalating global health concerns, with both conditions closely linked to a range of severe comorbidities including cardiovascular disease, obstructive sleep apnea, stroke, osteoarthritis, and metabolic dysfunction -associated steatohepatitis. Although GLP-1 receptor agonists have significantly improved weight management and glycemic control, a substantial proportion of patients continue to face plateaued efficacy and insufficient clinical responses. Addressing this growing epidemic necessitates innovative therapies capable of producing greater, sustained metabolic benefits. GLP-1R agonists operate by stimulating glucose -dependent insulin secretion, suppressing appetite, delaying gastric emptying, and curbing food intake, thereby inducing meaningful but often insufficient weight loss. Combination therapies such as dual agonists targeting GLP-1R and GIPR have shown enhanced effects for glycemic status and weight loss, but these improvements may still fall short for patients with severe metabolic disease or multiple comorbid conditions.

[0003] 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.

[0004] The rationale for designing a triple agonist peptide — simultaneously acting on the GLP-1, GIP, and glucagon receptors — arises from a goal of achieving a unique, complementary combination of benefits that each hormone individually fails to capture. GLP-1 promotes insulin secretion and reduces appetite; GIP enhances incretin action, positively affects lipid profile, and boosts bone metabolism; and glucagon action increases energy expenditure and fat metabolism. Crucially, the diabetogenic risk of glucagon activation can be effectively mitigated by the concurrent action of GLP-1 and GIP, supporting the safety and efficacy of a trifiinctional peptide.

[0005] Balanced triple agonist peptides possess the potential to deliver superior clinical outcomes compared to single- or dual-receptor agonists. Preclinical and clinical studies demonstrate that triple agonist peptides can achieve greater reductions in body fat, improved glycemic control, and reversal of metabolic disease features, including fatty liver, compared to any currently available pharmacologic option. However, there are currently no triple agonist peptides available on the market, nor are there any formulations engineered for extended duration and balanced activity available to patients. The fieldWSGR Docket No. 36271-720.601 stands in urgent need of safe and effective triple agonist peptides with sufficiently long duration of action to treat metabolic diseases with complex conditions.SUMMARY OF THE INVENTION|0006] Disclosed herein is a peptide conjugate comprising: a) a peptide comprising the sequence:X1-X2-X3-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41, wherein:XIis Tyr or CFsCH2-Tyr;X2is Aib, Gly, Ala, or D-Ser;X3is Gin or His;X6is Phe, aMe-Phe, aMe-Phe2F, aMe-Phe2F6F, Phe2F, or Phe2Br;X10is Tyr, Vai, Leu, CpA, Trp, Glu, Phe, or Cys;XI Iis Ser or aMe-Ser;X13is Tyr, aMe-Leu, Ac6c, aMe-Phe, Iva, or Cys;X15is Asp or Glu;X16is Lys, Lys(Ac), or Om;X17is Cys or Lys(Ac), or He;X19is Ala, Gin, or Hgl;X20is Aib, Cys, or Gin;X21is Ala, Glu, Cys, or Tie;X23is He, Vai, or Tie;X24is Cys or Glu;X25is Trp, Tyr, aMe-Trp, Trp2Me, or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;X28is Glu, Hgl, Cys, Ser, or Ala;X29is Gly or Ala;X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys; andX40is Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, Gly, or absent; andX41is Ser or absent; wherein the C-terminus of the peptide is -COOH or -CONH2; and b) a staple attached to the peptide at a first amino acid and a second amino acid; wherein the staple is of Formula (II):WSGR Docket No. 36271-720.601Formula (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 atached to the first amino acid of the peptide, XBis attached to the second amino acid of the peptide, and XAand XBare identical;R is hydrogen or -(L)s-Y ; each L is independently -(CR’R2)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, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, Cs-Cs cycloalkyl, C2-Cs 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; or R1and R2are taken together to form a Ci-Ce cycloalkyl or Ci-Ce heterocycloalkyl; each R3is independently hydrogen, -S(=O)Rb, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, - C(=O)NRcRd, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, Cs-Cs cycloalkyl, C2-Cs 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;Y is hydrogen, Ci-C6alkyl, -CO2H, -P(=O)(OH)2, -CO2(Ci-C6alkyl), -CO2NH2, -CO2N(alkyl)2, - CO2NH(alkyl), or 5 -membered heteroaryl; s is 0-20;Rais hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, Cs-Cs cycloalkyl, C2-Cs 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;WSGR Docket No. 36271-720.601 and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2;Rbis Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Cs-Cs 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; and each Rcand Rdis independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Cs-Cs 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, Ci-Ce alkyl, Ci-Ce 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or - NH2.

[0007] In some embodiments, the first amino acid and the second amino acid are independently a sulfydryl containing amino acid. In some embodiments, the first amino acid and second amino acids are cysteines. In some embodiments, the first amino acid and the second amino acid are independently an amine-containing amino acid. In some embodiments, the first amino acid and the second amino acids are lysines. In some embodiments, the first amino acid has a position i in the peptide and the second amino acid has a position i + n in the peptide, wherein n is 4-16. In some embodiments, the peptide modulates a GLP-1 receptor. In some embodiments, the peptide binds to a GLP-1 receptor. In some embodiments, the peptide modulates a GIP receptor. In some embodiments, the peptide binds to a GIP receptor. In some embodiments, the peptide is a GLP-1 receptor agonist. In some embodiments, the peptide is a GIP receptor agonist. In some embodiments, the peptide modulates a glucagon receptor. In some embodiments, the peptide binds to a glucagon receptor. In some embodiments, the peptide is a glucagon receptor agonist. In some embodiments, the peptide is a dual GLP-1 receptor and GIP receptor agonist. In some embodiments, the peptide is a triple GLP-1 receptor, GIP receptor agonist, and glucagon receptor agonist.

[0008] Also provided herein is a peptide, wherein the peptide is|0 09] Also provided herein is a pharmaceutical composition comprising the peptide conjugate described herein and a pharmaceutically acceptable excipient.

[0001] 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 conjugate described herein.

[0011] 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,WSGR Docket No. 36271-720.601 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), dyslipidemia, metabolic syndrome, metabolic dysfunction- associated steatohepatitis (MASH). In some embodiments, the disease or condition is Alzheimer’s disease, Parkinson’s disease or Huntington’s disease.|0012] Also provided herein is a peptide comprising a sequence at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NO. 2-157. In some embodiments, the peptide comprises an amino acid sequence that is at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO. 149.

[0013] Also provided herein is a compound having a structure of one of the following formulae:wherein is 0 or 1; mi is 1-4; and m2 is 6-20.

[0001] Also provided herein is a process for manufacturing a peptide conjugate (e.g., comprising a peptide and a staple disclosed herein), the process comprising (i) combining in a liquid solvent medium (a) a compound (e.g., as described above), (b) a peptide (e.g., comprising any one of SEQ ID NO. 2-157), and (c) a base; and (ii) reacting (a), (b), and (c), optionally comprising stirring and / or heating or cooling, for a period of at least 5 minutes and less than about 5 hours (e.g., about 1-2 hours); and (iii) optionally quenching step (ii) by addition of a sufficient amount of acid to lower the pH below 7 ; and (iv) optionally purifying the peptide conjugate (e.g., via HPLC).BRIEF DESCRIPTION OF FIGURES

[0015] FIG. 1A, FIG. IB and FIG. 1C display example components of a peptide, such as amino acids.

[0016] FIG. 2 shows the dose-response curve for (3-arrestin 2 recruitment at the human GLP-1R following serially diluted preparations of peptide conjugates 153, 155, 168, 170, 173, 174, retatrutide, and semaglutide.|0017] FIG. 3 shows the dose-response curve for (3-arrestin 2 recruitment at the human GLP-1R following serially diluted preparations of peptide conjugates 167, 174, retatrutide, and semaglutide.WSGR Docket No. 36271-720.601

[0018] FIG. 4 shows the dose-response curve for (3-arrestin 2 recruitment at the human GIPR following serially diluted preparations of peptide conjugates 167, 174, retatrutide, and hGIP.

[0019] FIG. 5 shows the dose-response curve for (3-arrestin 2 recruitment at the human GCGR following serially diluted preparations of peptide conjugates 167, 174, retatrutide, and hGCG.

[0020] FIG. 6 shows the dose-response curve for GLP-1R internalization following serially diluted preparations of human GLP-1, semaglutide, retatrutide, and conjugate 174.

[0021] FIG. 7 shows the plasma concentration of retatrutide after subcutaneous dosing at 0. 1 mg / kg.

[0022] FIG. 8 shows the plasma concentration of conjugate 174 after intravenous dosing at 0.1 mg / kg.

[0023] FIG. 9 shows the change in bodyweight in Diet-Induced Obese (DIO) mice over 15 days following once daily administration of conjugate or vehicle by SC injection.

[0024] FIG. 10 shows the change in cumulative food intake in DIO mice over 13 days following once daily administration of conjugate or vehicle by SC injection.

[0025] FIG. 11 shows the day 14 fat mass in DIO mice, after 14 days of once daily administration of retatrutide, conjugate 174, or vehicle.|0026] FIG. 12 shows the day 14 lean / fat mass ratio in DIO mice, after 14 days of once daily administration of retatrutide, conjugate 174, or vehicle.

[0027] FIG. 13 shows the day 15 serum cholesterol in DIO mice, after 14 days of once daily administration of conjugate or vehicle by SC injection.

[0028] FIG. 14 shows the day 6 fed blood glucose in DIO mice, after 6 days of once daily administration of conjugate or vehicle by SC injection.

[0029] FIG. 15 shows the day 15 liver fat mass in DIO mice, after 14 days of once daily administration of conjugate or vehicle by SC injection.DETAILED DESCRIPTION OF THE INVENTION

[0030] 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 around 34% of all Food and Drug Administration (FDA) approved drugs target 108 members of the GPCR family. 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 of27-141 residues in length. Nine of these receptors are targeted by ligands that are structurally related to one another, examples of whichWSGR Docket No. 36271-720.601 include glucagon -like peptides (GLP-1 and GLP-2), glucagon (GCG), glucose-dependent insulinotropic polypeptide (GIP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase- activating polypeptide (PACAP) and growth hormone-releasing hormone (GHRH).

[0031] The glucagon (GCG) receptor is a member of the class B G-protein coupled family of receptors and plays a role in maintenance of glucose homeostasis. The binding of glucagon to the glucagon receptor results in an activation of Gas-coupled proteins, increasing intracellular cAMP and calcium. This signaling cascade activates Protein Kinase A (PKA), which phosphorylates the transcription factor cAMP -response-element-binding (CREB) protein, thus increasing plasma glucose concentration via glycogen breakdown. GCGR activation can promote liver glycogenolysis, increase blood sugar levels, promote fat decomposition, and enhance fatty acid oxidation. GCG may have positive effect on reducing food intake, increasing energy consumption of adipose tissue, and reducing body fat content.

[0032] 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-1 R) 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. Lurthermore, GLP-1 decreases the rate of gastric emptying, and reduces appetite, thus resulting in weight loss.

[0033] GLP-1 receptor agonists (GLP-lRAs) 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-lRAs 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-lRAs 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-lRAs are currently given as a s.c. injection. In some aspects, provided herein are GLP-lRAs connected to a fatty-acid derived sidechain staple to increase half-life.

[0034] 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.

[0035] LY3437943 (retatrutide), a triple GCG, GIP, and GLP-1 receptor agonist, has also been reported to promote glycemic control and weight loss in proof-of-concept clinical trials. GlucagonWSGR Docket No. 36271-720.601 receptor agonism promotes lipolysis and enhances hepatic fat oxidation, facilitating the mobilization and utilization of stored lipids for energy production. Activation of GCGR stimulates thermogenesis and increases resting energy expenditure, processes that collectively contribute to reductions in adiposity. The addition of GCGR agonism to GLP-1R / GIPR agonism produces a synergistic effect, resulting in more targeted fat loss and a more favorable alteration in body composition compared to GLP-1R or GLP- 1R / GIPR agonists alone (e.g., semaglutide, tirzepatide). In preclinical studies, animals treated with single and dual receptor agonists display significant weight loss, with reductions of both fat and lean mass, resulting in unfavorable changes in body composition. Clinical evidence from a Phase 2 study of dual GLP-1R / GCGR agonist demonstrates that GCGR agonism supports lean mass preservation during weight loss, distinguishing it from other incretins associated with disproportionate lean tissue loss.

[0036] In preclinical studies, obese mice that were administered the triple GCG, GIP, and GLP-1 receptor agonist peptide conjugate 174 (disclosed herein) at doses of 3, 10, 30, and 100 nmol / kg achieved a lean-to-fat mass ratio approaching that of a wild -type, healthy control mouse (see, FIG. 12), supporting the theory that GCGR agonism plays a necessary function in promoting healthy weight loss (i.e., loss of fat mass while preserving lean mass).

[0037] In certain embodiments, further provided herein are triple GCG, GIP, and GLP-1 receptor agonists comprising novel peptides, and / or peptide conjugates comprising a peptide and a staple . In some embodiments, the staple extends the half-life of the molecule, and / or improves the potency, efficacy, or pharmacokinetics of the peptide conjugate (e.g., compared to an unconjugated peptide, or compared to a conjugated peptide such as retatrutide).

[0038] Provided herein are peptides and peptide conjugates comprising a therapeutic peptide stapled to a molecule, such as a half-life extending molecule.

[0039] In certain embodiments, the stapled peptides comprise incretin peptides or incretin peptide mimetics. Incretin peptides generally bind to their cognate receptors in an a-helical conformation, therefore certain embodiments herein provide for modifications that stabilize the a-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.

[0040] 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

[0041] In one aspect, provided herein are peptides and peptide conjugates comprising a peptide that modulates the GLP-1 receptor and / or the GIP receptor and / or the GCG receptor. In some embodiments, the peptide modulates the GLP-1 receptor, the GIP receptor, and the GCG 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. In some embodiments,WSGR Docket No. 36271-720.601 a peptide that modulates the GCG receptor is a GCG receptor agonist. In some embodiments, provided herein is a peptide that is a triple agonist of GLP-1 receptor, GIP receptor, and GCG receptor.

[0042] 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 and / or GCG 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.

[0043] 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. Each of the one or more sulfhydryl containing amino acid residues may be independently selected from the group consisting of: cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid.

[0044] 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.

[0045] 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.

[0046] 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 or more 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.WSGR Docket No. 36271-720.601

[0047] 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.

[0048] 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 aMeL (alpha-methyl Leu). In some embodiments, the peptide comprises Om (ornithine). In some embodiments, the peptide comprises aMeY (alpha-methyl tyrosine). In some embodiments, the peptide comprises CFsCLL-Tyr (F3Et-Y, trifluoroethyl tyrosine).

[0049] 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-1C.

[0050] In some embodiments, the peptide comprises the sequence: X1-X2-X3-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41(-NH2) (SEQ ID NO. 160 or 161), wherein:XIis Tyr or CF2CH2-Tyr;X2is Aib, Gly, Ala, or D-Ser;X3is Gin or His;X6is Phe, aMe-Phe, aMe-Phe2F, aMe-Phe2F6F, Phe2F, or Phe2Br; X10is Tyr, Vai, Leu, CpA, Trp, Glu, Phe, or Cys;XI Iis Ser or aMe-Ser;X13is Tyr, aMe-Leu, Ac6c, aMe-Phe, Iva, or Cys;X15is Asp or Glu;X16is Lys, Lys(Ac), or Om;X17is Cys or Lys(Ac), or He; X19is Ala, Gin, or Hgl; X20is Aib, Cys, or Gin; X21is Ala, Glu, Cys, or Tie; X23is He, Vai, or Tie;WSGR Docket No. 36271-720.601X24is Cys or Glu;X25is Trp, Tyr, aMe-Trp, Trp2Me, or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;X28is Glu, Hgl, Cys, Ser, or Ala;X29is Gly or Ala;X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys;X40is Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, Gly, or absent;X41is Ser or absent; and wherein the C-terminus of the peptide is -COOH or -CONH2.[005.1 j In some embodiments, the peptide comprises the sequence:X1-X2-X3-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41-NH2(SEQ ID NO. 161); wherein each of X1, X2, X3, X6, X10, X11, X13, X15, X16, X17, X19, X20, X21, X23, X24, X25, X26, X27, X28, X29, X33, X39, X40, and X41is as defined above.

[0052] In some embodiments, the peptide comprises the sequence:X1-X2-X3-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41-OH (SEQ ID NO. 160); wherein each of X1, X2, X3, X6, X10, X11, X13, X15, X16, X17, X19, X20, X21, X23, X24, X25, X26, X27, X28, X29, X33, X39, X40, and X41is as defined above.

[0053] In some embodiments, the peptide comprises a sequence:X1-Aib-Gln-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23-X24-X25-X26-X27-X28-Gly-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41(-NH2), wherein:XIis Tyr or CFX IL-Tyr:X6is Phe, aMe-Phe, or Phe2F;X10is Tyr, Vai, Trp, or Cys;XI Iis Ser or aMe-Ser;X13is Tyr, aMe-Leu, aMe-Phe, Iva, or Cys;X15is Asp or Om;X16is Lys, Lys(Ac), or Om;X17is Cys, Lys(Ac), or He;X19is Ala or Gin;X20is Aib, Cys, or Gin;X21is Ala, Glu, or Cys;X23is He or Vai;X24is Cys or Glu;WSGR Docket No. 36271-720.601X25is Trp, Tyr, or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;X28is Glu, Hgl, Cys, or Ala;X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys;X40is Gly, Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, or absent; and X41is Ser or absent.

[0054] In some embodiments, the peptide comprising a sequence:X1-Aib-Gln-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41(-NH2) (SEQ ID NO. 162 or SEQ ID NO. 163) wherein;XIis Tyr or CF2CH2-Tyr;X2is Aib, Gly, Ala, or D-Ser;X3is Gin or His;X6is Phe, aMe-Phe, or Phe2F;X10is Tyr or Vai;XI Iis Ser or aMe-Ser;X13is Tyr, aMe-Leu, aMe-Phe, or Iva;X15is Asp or Glu;X16is Lys, Lys(Ac), or Om;X17is Cys or He;X19is Gin;X20is Aib or Gin;X21is Ala or Glu;X23is He or Vai;X24is Cys or Glu;X25is Tyr or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;X28is Glu, Cys, or Ala;X29is Gly or Ala;X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys; andX40is Gly, Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, or absent, andX41is Ser or absent.|0055] In some embodiments, X1is Tyr. In some embodiments, X1is CFsQL-Tyr.WSGR Docket No. 36271-720.601[00561 In some embodiments, X2is Aib, Gly, Ala, or D-Ser. In some embodiments, X2is Aib. In some embodiments, X2is Gly. In some embodiments, X2is Aib or Ala. In some embodiments, X2is Ala. In some embodiments, X2is D-Ser.

[0057] In some embodiments, X3is Gin or His. In some embodiments, X3is Gin. In some embodiments, X3is His.|0058] In some embodiments, X6is Phe. In some embodiments, X6is aMe-Phe (amF). In some embodiments, X6is Phe2F (F2F). In some embodiments, X6is aMe-Phe2F (amF2F). In some embodiments, X6is aMe-Phe2F6F (amF2,6F). In some embodiments, X6is Phe2Br (F2Br).

[0059] In some embodiments, X10is Tyr. In some embodiments, X10is Vai. In some embodiments, X10is Leu. In some embodiments, X10is CpA. In some embodiments, X10is Trp. In some embodiments, X10is Glu. In some embodiments, X10is Phe. In some embodiments, X10is Cys.

[0060] In some embodiments, X11is Ser. In some embodiments, X11is aMe-Ser.

[0061] In some embodiments, X13is Tyr. In some embodiments, X13is aMe-Leu. In some embodiments, X13is Ac6c. In some embodiments, X13is aMe-Phe. In some embodiments, X13is Iva. In some embodiments, X13is Cys.

[0062] In some embodiments, X15is Asp. In some embodiments, X15is Glu.

[0063] In some embodiments, X16is Lys. In some embodiments, X16is Lys(Ac). In some embodiments, X16is Om.

[0064] In some embodiments, X19is Ala. In some embodiments, X19is Gin. In some embodiments, X19is Hgn.

[0065] In some embodiments, X21is Ala. In some embodiments, X21is Glu. In some embodiments, X21is Cys. In some embodiments, X21is Tie.|0066] In some embodiments, X23is He. In some embodiments, X23is Vai. In some embodiments, X23is Tie.

[0067] In some embodiments, X24 is Cys. In some embodiments, X24is Glu.

[0068] In some embodiments, X25is Trp. In some embodiments, X25is Tyr. In some embodiments, X25is aMe-Trp. In some embodiments, X25is aMe-Tyr. In some embodiments, X25is Trp2Me.

[0069] In some embodiments, X26is Leu. In some embodiments, X26is Vai.

[0070] In some embodiments, X27is He. In some embodiments, X27is Leu.

[0071] In some embodiments, X28is Glu. In some embodiments, X28is Hgl. In some embodiments, X28is Cys. In some embodiments, X28is Ser. In some embodiments, X28is Ala.|0072] In some embodiments, X29is Gly. In some embodiments, X29is Ala.

[0073] In some embodiments, X33is Ser. In some embodiments, X33is Lys. In some embodiments, X33is aMe-Lys.

[0074] In some embodiments, X39is Ser. In some embodiments, X39is Lys.

[0075] In some embodiments, X40is Lys. In some embodiments, X40is D-Lys. In some embodiments,X40is Om. In some embodiments, X40is D-Om. In some embodiments, X40is Dab. In someWSGR Docket No. 36271-720.601 embodiments, X40is D-Dab. In some embodiments, X40is Dap. In some embodiments, X40is D-Dap. In some embodiments, X40is absent. In some embodiments, X40is Gly.

[0076] In some embodiments, X41is Ser or absent. In some embodiments, X41is Ser. In some embodiments, X41is absent. In some embodiments, X40and X41are both absent. In some embodiments, X40is Gly and X41is Ser.|0 77] In some embodiments, the peptide comprises a sequence of any one of SEQ ID NOs: 2-157. 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: 2-157. In some cases, the peptide comprises a sequence at least about 90% identical to any one of SEQ ID NOs: 2-157. In some cases, the peptide comprises a sequence at least about 95% identical to any one of SEQ ID NOs: 2-157. In some cases, the peptide comprises a sequence at least about 99% identical to any one of SEQ ID NOs: 2-157. In some cases, the peptide comprises 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: 2-157.

[0078] In some embodiments, 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 Y(Aib)QGTFTSDYSI(aml)LDKCAQ(Aib)AFICYLLEGGPSSGAPPPS-NH2(SEQ ID NO. 2).

[0079] In some embodiments, 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 Y(Aib)QGT(amF)TSDV-(amS)I(amL)LDKCAA(Aib)EFIC(amY)-LLEGG-PSSGA-PPPS-NH2(SEQ ID NO. 22).

[0080] In some embodiments, 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 Y(Aib)QGT-(amF)TSDY-(amS)I(amL)LD-KCAA(Aib)-EFIC(amY)-LLEGG-PSSGA-PPPS-NH2(SEQ ID NO. 25).

[0081] In some embodiments, 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 F3Et-Y(Aib)QGT-(F2F)TSDY-SI(amL)LD-(Om)CAQ(Aib)-AFICY-LLEGG-PSKGA-PPPSG-S (SEQ ID NO. 149). In some embodiments, the peptide is F3Et-Y(Aib)QGT-(F2F)TSDY-SI(amL)LD- (Om)CAQ(Aib)-AFICY-LLEGG-PSKGA-PPPSG-S-NH2(SEQ ID NO. 149). In some embodiments, the peptide conjugate comprises the peptide F3Et-Y(Aib)QGT-(F2F)TSDY-SI(amL)LD-(Om)C*AQ(Aib)- AFIC*Y-LLEGG-PSKGA-PPPSG-S-NH2(SEQ ID NO. 349), wherein C* indicates a bond between a sulfur atom of a cysteine of the peptide and the staple, and -NH2represents a carboxamide at the C- terminus of the peptide.

[0082] In some embodiments, 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 Y(Aib)QGT-FTSDY-SI(aml)LD-KCAQ(Aib)-AFICY-LLEGG-PSSGA-PPPSGS (SEQ ID NO. 134).WSGR Docket No. 36271-720.601In some embodiments, the peptide is H2N-Y(Aib)QGT-FTSDY-SI(aml)LD-KCAQ(Aib)-AFICY- LLEGG-PSSGA-PPPSGS-NH2 (SEQ ID NO. 134). In some embodiments, the peptide conjugate comprises the peptide H2N-Y(Aib)QGT-FTSDY-SI(aml)LD-KC*AQ(Aib)-AFIC*Y-LLEGG-PSSGA- PPPSGS-NH2 (SEQ ID NO. 134), wherein C* indicates a bond between a sulfur atom of a cysteine of the peptide and the staple, H2N- represents an unsubstituted amine at the N- terminus of the peptide; and -NH2 represents a carboxamide at the C-terminus of the peptide.|0083 ] An aspect of the present disclosure is the provision of a peptide comprising any one of SEQ ID NO. 2-157, which may include fusions of one or more additional amino acids at the C-terminus and / or N- terminus. In some embodiments, a peptide disclosed herein is provided from N-terminus to C-terminus (left to right). In some embodiments, the N-terminal amino acid is tyrosine (Y) or trifluoroethyl tyrosine (“F3EtY”), also abbreviated X1. In some embodiments, the peptide comprises one or more amino acids conjugated to the amine of the tyrosine or trifluoroethyl tyrosine (e.g., 1, 2, 3, 4, etc. amino acids). In some embodiments, the peptide comprises one or two N-terminal substituents selected from the group consisting of C1-22 alkyl, C1-22 haloalkyl, [PEG]i-ioOH, and C1-22 acyl-COOH, to the amine of the tyrosine or trifluoroethyl tyrosine. In some embodiments, the N-terminal amino acid comprises an unsubstituted amine (e.g., H2N-). In some embodiments, the N-terminal amino acid comprises a trifluoroethylsubstituted amine (e.g., CF3CH2NH-or “F3Et-”).

[0084] In some embodiments, the C-terminal amino acid of the peptide sequence is serine or lysine, also abbreviated X39, X40, or X41. In some embodiments, the peptide comprises one or more amino acids conjugated to the carbonyl of the serine or lysine (e.g., 1, 2, 3, 4, etc. amino acids). In some embodiments, the C-terminal amino acid of the peptide comprises a C-terminal substituent selected from the group consisting of -OH, -ORC, -NH2, -NHRC, and -N(RC)2, wherein each Rcis independently Ci.22alkyl, Ci-22haloalkyl, [PEG]i-ioOH, or Ci-22 acyl-COOH. In some embodiments, the C-terminal amino acid of the peptide comprises a C-terminal substituent that is -OH or -NH2, which may alternatively be written as “-COOH” or “-CONH2” respectively, to encompass the C-terminal carbonyl. In some embodiments, the C-terminal amino acid is substituted with 1, 2, 3, or 4 additional amino acids, wherein the C-terminal substituent comprises a -NH2C-terminus modification.

[0085] In some embodiments, a peptide disclosed herein is provided from C-terminus to N-terminus (left to right), wherein the C-terminus is tyrosine or trifluoroethyl tyrosine, and the N-terminus is serine or lysine. In some embodiments, the N-terminus comprises a trifluoroalkyl substituent. In some embodiments, the C-terminus comprises a carboxamide substituent.|0086] In some embodiments, provided herein is a peptide comprising one of SEQ ID NO. 2-157. In some embodiments, provided herein is a peptide comprising a sequence that is 95%, 96%, 97%, 98%, 99%, or 100% identical to one of SEQ ID NO. 2-157. In some embodiments, provided herein is a peptide that is 95%, 96%, 97%, 98%, 99%, or 100% identical to one of SEQ ID NO. 2-157. In some embodiments, provided herein is a peptide comprising any one of SEQ ID NO. 2-157. In some embodiments, provided herein is a peptide as defined in any one of SEQ ID NO. 2-157. In someWSGR Docket No. 36271-720.601 embodiments, provided herein is a peptide as defined in any one of SEQ ID NO. 2-157, wherein the C- terminal amino acid is bonded to an amine (-NH2) to form a terminal carboxamide.Table 1. Amino Acid Sequences|0 87] Non-limiting examples of peptides according to the present disclosure include SEQ ID NO. 2- 157, having the following sequences:WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601wherein the C-terminus of the peptide comprising SEQ ID NO. 2-157 may be amidated to form -CONH2.

[0088] Unless otherwise specified, each of SEQ ID NO. 2-157 is not limited with regard to C-terminal modifications or substitutions. The C-terminus of any one of SEQ ID NO. 2-157 may be amidated to form -CONH2. In some embodiments, the C-terminus of any one of SEQ ID NO. 2-157 may be -COOH. 10089]Staple

[0090] In some embodiments, the peptide conjugate comprises a staple. In some embodiments, the stable is attached to the peptide at a first amino acid and a second 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 first amino acid of the peptide, XBis attached to the second amino acid of the peptide, and XAand XBare identical;R is hydrogen or -(L)s-Y ; each L is independently -(CR’R2)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, Ci-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Cs-Cs 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 heteroarylWSGR Docket No. 36271-720.601 is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or - NRcRd; or R1and R2are taken together to form a Ci-Ce cycloalkyl or Ci-Ce heterocycloalkyl; each R3is independently hydrogen, -S(=O)Rb, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Rb, -CO2R1, - C(=O)NRcRd, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, C3-G 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;Y is hydrogen, Ci-C6alkyl, -CO2H, -P(=O)(OH)2, -CO2(Ci-C6alkyl), -CO2NH2, -CO2N(alkyl)2, - CC>2NH(alkyl), or 5 -membered heteroaryl; s is 0-20;Rais hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Cs-Cs 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, Ci- Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2;Rbis Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Cs-Cs 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, Ci- Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; and each Rcand Rdis independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Cs-Cs 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, Ci-Ce alkyl, Ci-Ce 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2.

[0091] 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.

[0092] 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.

[0093] In some embodiments, A is -NR3-alkylene-NR3-. In some embodiments, A is -N-.WSGR Docket No. 36271-720.601

[0094] In some embodiments, XAand XBare identical. In some embodiments, XAand XBare different.

[0095] 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-.

[0096] In some embodiments, each R3is independently hydrogen or Ci-Ce alkyl. In some embodiments, each R3is hydrogen.

[0097] In some embodiments, >A-R has the following structure:, wherein rl and r2 are each independently 0-4.

[0098] In some embodiments, rl and r2 are each independently 0-2. In some embodiments, rl and r2 are each 0. In some embodiments, rl and r2 are each 1. In some embodiments, rl and r2 are each 3. In some embodiments, rl and r2 are each 2.

[0099] In some embodiments, >A-R has the following structure:[001001 In some embodiments, >A-R has the following structure:, wherein pl is 1 -5.

[0101] In some embodiments, pl is 1-3. In some embodiments, pl is 1-2. In some embodiments, pl is 1. In some embodiments, pl is 2. In some embodiments, pl is 3. In some embodiments, pl is 4. In some embodiments, pl is 5.

[0102] In some embodiments, >A-R has the following structure:

[0103] In some embodiments, >A-R has the following structure:WSGR Docket No. 36271-720.601

[0104] 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.

[0105] In some embodiments, Y is hydrogen or -CO2H. In some embodiments, Y is hydrogen. In some embodiments, Y is -CO2H.

[0106] In some embodiments, each L is independently -(CR’R2)V-, -alkylene-O-, -C(=O)-, - C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; and v is 2-20.

[0107] In some embodiments, each L is independently -(CR’R2)V-, -alkylene-O-, -C(=O)-, - C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; and v is 2-16.|00108] 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.

[0109] In some embodiments, each R1or R2is independently hydrogen, halogen, -CN, -ORa, -NRcRd, -C(=O)Rb, -CO2Ra, -C(=O)NRcRd, or Ci-C6alkyl.

[0011] In some embodiments, each R1or R2is independently hydrogen, halogen, -CO2R1. - C(=O)NRcRd, or Ci-Ce alkyl. In some embodiments, each R1or R2is independently hydrogen, -C O2R1. or -C(=O)NRcRd. In some embodiments, each R1or R2is independently hydrogen or -CO2R1.

[0111] In some embodiments, the staple i

[0112] In some embodiments, the staple attached to the peptidewherein each L1is independently -(CR1R2) -. -alkylene-O-, -O-alkylene-, -C(=O)NR3-, -NR3C(=O)-, - alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and si is 1-15.

[0113] In some embodiments, the staple attached to the peptide iswherein each L2is independently -(CR’R2)v-, -alkylene-O-, -WSGR Docket No. 36271-720.601O-alkylene-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s2 is 1-15.

[0114] In some embodiments, the staple attached to the peptide iswherein each L3is independently -(CR’R2)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.

[0115] In some embodiments, the staple attached to the peptide iswherein each L4is independently -(CR’R2)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.

[0116] In some embodiments, the staple attached to the peptide iswherein eachL5is independently -(CR’R2)V-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene- NR3C(=O)-; v is 2-20; and s5 is 1-10.|00117] In some embodiments, the staple attached to the peptide iswherein each L6is independently -(CR’R2)V-, -C(=O)NR3-, -NR3C(=O)-, -alkylene -C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s6 is 1-5.WSGR Docket No. 36271-720.601

[0118] In some embodiments, the staple attached to the peptide iswherein each L7is independently -(CR’R2)V-, -C(=O)NR3-, or -NR3C(=O)-; v is 2-20; and s7 is 1-5.

[0119] In some embodiments, the staple attached to the peptide is-(CR' R2) - and v is 10-20.[00120| In some embodiments, the staple attached to the peptide iswherein the “NS” represents a sulfur atom of a cysteine, homocysteine, 2-amino-5 -mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue; m is 0 or 1; mi is 1-4; and m2is 6-20.[00121 | In some embodiments, m2is 12-20. In some embodiments, m2is 13. In some embodiments, m2is 15. In some embodiments, m2is 17. In some embodiments, m2is 19. In some embodiments, m is 1. In some embodiments, m is 0. In some embodiments, mi is 3. In some embodiments, m is 1, rm is 3, and m2is 6-20. In some embodiments, the “NS” represents a sulfur atom of a cysteine. In some embodiments, the “NS” represents a sulfur atom of a cysteine of a peptide comprising the amino acid sequence of SEQ ID NO. 2-159 (e g., SEQ ID NO: 149 or SEQ ID NO: 159).

[0122] In some embodiments, the staple attached to the peptide iswherein each L9is independently -WSGR Docket No. 36271-720.601(CR’R2)V-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s9 is 1-5.

[0123] In some embodiments, the staple attached to the peptide is|00124] In some embodiments, the staple attached to the peptide iswherein each L12is independently -(CR'R2)V-, -alkylene-O-, -O- alkylene-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and sl2 is 1-15.

[0125] In some embodiments, the staple attached to the peptide iswherein each L13is independently -(CR’R2)v-, - alkylene-O-, -O-alkylene-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s 13 is 1-15.

[0126] In some embodiments, the staple attached to the peptide is. wherein each L14is independently -(CR'R2)V-, -alkylene-O-, -O-alkylene-, -C(=O)NR3-, -NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene- NR3C(=O)-; v is 2-20; and sl4 is 1-15.WSGR Docket No. 36271-720.601

[0127] In some embodiments, the staple attached to the peptide isindependently -(CR’R2)V-, -C(=O)NR3-, -NR3C(=O)-, -alkylene -C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and s 15 is 1-10.

[0128] In some embodiments, the staple attached to the peptide is(CR’R2)v-, -C(=O)NR3-, or -NR3C(=O)-; v is 2-20; and sl6 is 1-5.[00.129] In some embodiments, the staple attached to the peptide isindependently -(CR’R2)V-, -C(=O)NR3-, or -NR3C(=O)-; v is 2-20; and sl7 is 1-5.

[0130] In some embodiments, the staple attached to the peptide is(CR' R2) - and v is 10-20.

[0131] In some embodiments, the staple attached to the peptide iswherein each LI9is independently -(CR’R2)v-, -C(=O)NR3-,-NR3C(=O)-, -alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; v is 2-20; and sl9 is 1-5.WSGR Docket No. 36271-720.601[00.132| In some embodiments, the staple attached to the peptide iswherein L20is -(CR'R2)V- and v is 10-20.[001 31 In some embodiments, the staple attached to the peptide is: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; is 0 or 1; m and mi are each independently 1-4; m2is 6-20; and each * denotes the attachment point to the peptide.[00.134] In some embodiments, the staple attached to the peptide is: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; is 0 or 1; m and mi are each independently 1-4; m2 is 6-20; and each * denotes the attachment point to the peptide.

[0135] In some embodiments, R10is -OH. In some embodiments, R10is -NH2.

[0136] In some embodiments, R11is -OH. In some embodiments, R11is -P(=O)(OH)2. In some embodiments, R11is hydrogen.WSGR Docket No. 36271-720.601[00.137| 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.

[0138] In some embodiments, ni is 1. In some embodiments, ni is 0.

[0139] In some embodiments, m is 1-3. In some embodiments, m is 3. In some embodiments, m is 2.In some embodiments, m is 1 .

[0140] In some embodiments, mi is 1-3. In some embodiments, mi is 3. In some embodiments, mi is 2. In some embodiments, mi is 1.

[0141] In some embodiments, m2 is 6-18. In some embodiments, m2 is 10-18. In some embodiments, m2 is 10. In some embodiments, m2 is 11. In some embodiments, m2 is 12. In some embodiments, m2 is13. In some embodiments, m2 is 14. In some embodiments, m2 is 15. In some embodiments, m2 is 16. In some embodiments, m2 is 17. In some embodiments, m2 is 18. In some embodiments, m2 is 19. In some embodiments, m2 is 20.

[0142] In some embodiments, the staple attached to the peptide is:WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601the “I-S” being part of a cysteine, homocysteine, 2 -amino -5 -mercaptopentanoic acid, or 2-amino-6- mercaptohexanoic acid residue and the “i-NH” being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.

[0143] In some embodiments, the staple attached to the peptide is:WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601wherein each * represents a bond to a sulfur atom of a cysteine. In some embodiments, each cysteine is the first amino acid and the second amino acid of the peptide (e.g., the triple agonist peptide, e.g., of SEQ ID NO. 2-159)).|00144] In some embodiments, provided herein is a peptide conjugate comprising:(a) a peptide comprising the sequence:X1-X2-X3-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23- X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41-R42,(SEQ ID NO. 160 or 161), wherein:X1is Tyr or CF CFE-Tyr:X2is Aib, Gly, Ala, or D-Ser;X3is Gin or His;WSGR Docket No. 36271-720.601X6is Phe, aMe-Phe, aMe-Phe2F, aMe-Phe2F6F, Phe2F, or Phe2Br;X10is Tyr, Vai, Leu, CpA, Trp, Glu, Phe, or Cys;X11is Ser or aMe-Ser;X13is Tyr, aMe-Leu, Ac6c, aMe-Phe, Iva, or Cys;X15is Asp or Glu;X16is Lys, Lys(Ac), or Om;X17is Cys or Lys(Ac), or He;X19is Ala, Gin, or Hgl;X20is Aib, Cys, or Gin;X21is Ala, Glu, Cys, or Tie;X23is He, Vai, or Tie;X24is Cys or Glu;X25is Trp, Tyr, aMe-Trp, Trp2Me, or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;X28is Glu, Hgl, Cys, Ser, or Ala;X29is Gly or Ala;X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys; andX40is Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, Gly, or absent;X41is Ser or absent;R42is -OH or -NH2; and(b) a staple attached to the peptide at a first amino acid and a second amino acid; wherein the staple isWSGR Docket No. 36271-720.601wherein, ni is 0 or 1; n2 and mi are each independently 1-4; m2is 6-20; and each * denotes the attachment point to the peptide.

[0145] In some embodiments, the first amino acid and second amino acid of the peptide are each independently a sulfhydryl containing amino acid residue; and the staple is:wherein, n2is 1-4; m2is 6-20; andWSGR Docket No. 36271-720.601 each “[-S” represents a sulfur atom the first amino acid and second amino acid of the peptide.

[0146] In some embodiments, m2 is 12-18. In some embodiments, m2 is 13-17. In some embodiments, m2is 17. In some embodiments, m2is 15.

[0147] In some embodiments, provided herein is a peptide conjugate comprising:(a) a peptide comprising the sequence:X1-X2-X3-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe- X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41(-NH2) (SEQ ID NO. 160 or 161),(b) a staple attached to the peptide the Cys17and Cys24; wherein the staple iswherein, m is 1-4; m2 is 6-20; and each “[-S” represents a sulfur atom the Cys17or the Cys24of the peptide.[001481 In one aspect, disclosed herein are peptide conjugates comprising: a peptide and a staple attached to the peptide at a first amino acid and a second amino acid.

[0149] 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 first amino acid has position i, and the second amino acid has position i + 7, i + 11, i + 13, i + 15, or i + 16. For example, the first amino acid has a position i in the peptide and the second amino acid has a position i + n in the peptide, wherein n is 4-16. In some embodiments, the first amino acid is at the 14 position and the second amino acid is at the 21 position in the peptide. In some embodiments, the first amino acid is at the 17 position and the second amino acid is at the 24 position in the peptide.

[0150] For example, the first amino acid has a position i in the peptide and the second amino acid has a position i + 4 in the peptide. For example, the first amino acid has a position i in the peptide and the second amino acid has a position i + 5 in the peptide. For example, the first amino acid has a position i in the peptide and the second amino acid has a position i + 6 in the peptide. For example, the first amino acid has a position i in the peptide and the second amino acid has a position i + 7 in the peptide. For example, the first amino acid has a position i in the peptide and the second amino acid has a position i + 8 in the peptide. For example, the first amino acid has a position i in the peptide and the second amino acid has a position i + 9 in the peptide. For example, the first amino acid has a position i in the peptide and theWSGR Docket No. 36271-720.601 second amino acid has a position i + 10 in the peptide. For example, the first amino acid has a position i in the peptide and the second amino acid has a position i + 11 in the peptide. For example, the first amino acid has a position i in the peptide and the second amino acid has a position i + 12 in the peptide. For example, the first amino acid has a position i in the peptide and the second amino acid has a position i + 13 in the peptide. For example, the first amino acid has a position i in the peptide and the second amino acid has a position i + 14 in the peptide. For example, the first amino acid has a position i in the peptide and the second amino acid has a position i + 15 in the peptide. For example, the first amino acid has a position i in the peptide and the second amino acid has a position i + 16 in the peptide.

[0151] In some embodiments, the first amino acid and the second amino acid are independently selected from the group consisting of an amine -containing amino acid and a sulfhydryl-containing amino acid.

[0152] In some embodiments, the first amino acid and second amino acid is independently selected from cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, and 2-amino-6-mercaptohexanoic acid. In some embodiments, the first amino acid and second amino acid are cysteines.

[0153] In some embodiments, the first amino acid and second amino acid is independently selected from lysine, ornithine, diaminobutyric acid, diaminopropionic acid and homolysine.

[0154] In some embodiments, the first amino acid and second amino acid are lysines.[001551 In some embodiments, the first amino acid and second amino acid are ornithines.Staple Compounds

[0156] In some embodiments, the staple compound is:wherein, is 0 or 1; m and mi are each independently 1-4; and m2 is 6-20.

[0157] In some embodiments, the staple compound is:wherein, is 0 or 1;WSGR Docket No. 36271-720.601 mi is 1-4; and m2 is 6-20.

[0158] In some embodiments, the staple compound is:Br-Staple-C4-[PEG2] 1 -eK-C 19phosphonate.WSGR Docket No. 36271-720.601Peptide Conjugates

[0159] In an aspect, disclosed herein is a peptide conjugate comprising: a) a peptide; and b) a staple attached to the peptide at a first amino acid and a second amino acid.

[0160] In some embodiments, the peptide is a triple GCG, GLP-1, and GIP receptor agonist. In some embodiments, the peptide comprises the amino acid sequence of any one (or more) of SEQ ID NO. 2- 159. In some embodiments, the peptide comprises or consists essentially of an amino acid sequence according to one of SEQ ID NO. 2-159. In some embodiments, the peptide (e.g., according to one of SEQ ID NO. 2-159) comprises a C-terminal and / or N-terminal modification. For example, in some embodiments, the peptide is C-terminally amidated. In some embodiments, the peptide is N-terminally substituted. In some embodiments, the peptide is N-terminally alkylated. In some embodiments, the peptide is N-terminally haloalkylated.

[0161] In some embodiments, the staple extends the half-life of the conjugate relative to an unconjugated peptide. In some embodiments, the staple extends the half -life of the conjugate relative to a reference peptide conjugate. In some embodiments, provided herein is a peptide conjugate comprising a peptide and a half-life extending staple cross-linking two amine -containing amino acid residues of the peptide, or cross-linking two sulfhydryl-containing amino acid residues of the peptide. In some embodiments, provided herein is a peptide conjugate comprising a peptide and a half-life extending staple, wherein the stapled peptide has a plasma half-life that is longer than that of a reference peptide conjugate. In some embodiments, provided herein is a peptide conjugate comprising a peptide and a staple cross-linking two sulfhydryl-containing amino acid residues (e.g., cysteines) of the peptide, wherein the stapled peptide has a plasma half-life that is at least 10% longer (or more, i.e., 20% longer, 30% longer, 40% longer, 50% longer, 60% longer, 70% longer, 80% longer, etc.) than that of a reference peptide or reference peptide conjugate (e.g., retatrutide).

[0012] In some embodiments, the plasma half-life of a peptide conjugate provided herein is at least 10% longer than an equivalent dose of a reference conjugate (e.g., retatrutide). In some embodiments, the plasma half-life of a peptide conjugate provided herein (e.g., Peptide Conjugate No. 2-177), following IV administration, is at least 10% longer than an equivalent dose of a reference conjugate (e.g., retatrutide) following SC administration. In some embodiments, the plasma half-life of a peptide conjugate provided herein is at least 10%, at least 20% longer, at least 30% longer, at least 40% longer, or at least 50% longer, than an equivalent dose of a reference conjugate (e.g., retatrutide). In some embodiments, the plasma half-life of a peptide conjugate provided herein is at least 50% longer than that of an equivalent dose of a reference conjugate (e.g., retatrutide). In some embodiments, the peptide conjugate of the present disclosure has a plasma half-life that is at least 70 hours, at least 80 hours, at least 90 hours, or at least 95 hours. In some embodiments, the peptide conjugate of the present disclosure has a plasma halflife that is about 100 hours. In some embodiments, the peptide conjugate of the present disclosure has a plasma half-life that is about 100 hours or longer (e.g., following IV administration). In someWSGR Docket No. 36271-720.601 embodiments, the peptide conjugate of the present disclosure has a plasma half-life that is about 100 hours or longer (e.g., following IV administration).

[0163] In some embodiments, the peptide conjugate of the present disclosure has slower clearance rate (Cl) than that of a reference peptide conjugate. In some embodiments, the peptide conjugate of the present disclosure has clearance rate that is about 90% or lower than that of a reference peptide conjugate. In some embodiments, the peptide conjugate of the present disclosure has clearance rate that is about 80% or lower, about 70% or lower, about 60% or lower, about 50% or lower, about 40% or lower, about 30% or lower, or about 20% or lower, than that of a reference peptide conjugate. In some embodiments, the peptide conjugate of the present disclosure has a clearance rate that is about 40% to about 60% (e.g., about 50%) that of retatrutide. In some embodiments, the peptide conjugate of the present disclosure has a clearance rate following IV administration of a dose that is about 30% to about 70% (e.g., about 50%) of an equivalent dose of retatrutide following SC administration.

[0164] In some embodiments, provided herein is a peptide conjugate comprising: a) a peptide comprising a sequence: Y(Aib)QGT-FTSDY-SI(amL)LD-KCAQ(Aib)-AFICY- LLEGG-PSSGA-PPPS-NH2(SEQ ID NO. 202); and b) a staple attached to the peptide at a first cysteine and a second cysteine; wherein the staple is :wherein * denotes the attachment to the first and second cysteine of the peptide.

[0165] In some embodiments, provided herein is a peptide conjugate comprising: a) a peptide comprising a sequence: Y (Aib)QGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)- EFIC(amY)-LLEGG-PSSGA-PPPS-NH2(SEQ ID NO. 222); and b) a staple attached to the peptide at a first cysteine and a second cysteine; wherein the staple is :wherein * denotes the attachment to the first and second cysteine of the peptide sequence, wherein the staple is attached at cysteine 17 and cysteine 24.

[0166] In some embodiments provided herein is a peptide conjugate comprising: a) a peptide comprising a sequence: Y (Aib)QGT-(amF)TSDY -(amS)I(amL)LD-KCAA(Aib)- EFIC(amY)-LLEGG-PSSGA-PPPS-NH2(SEQ ID NO. 225); andWSGR Docket No. 36271-720.601 b) a staple attached to the peptide at a first cysteine and a second cysteine; wherein the staple is :wherein * denotes the attachment to the cysteine of the peptide sequence, wherein the staple is attached at cysteine 17 and cysteine 24.

[0167] In some embodiments provided herein is a peptide conjugate comprising: a) a peptide comprising a sequence: Y (Aib)QGT-(amF)TSDY -(amS)I(amL)LD-KCAA(Aib)- EFIC(amY)-LLEGG-PSSGA-PPPS-NH2(SEQ ID NO. 225); and b) a staple attached to the peptide at a first cysteine and a second cysteine; wherein the staple is :|00168] wherein * denotes the attachment to the cysteine of the peptide sequence, wherein the staple is attached at cysteine 21 and cysteine 28.

[0169] In some embodiments provided herein is a peptide conjugate comprising: a) a peptide sequence comprisingF3EtY(Aib)QGT(F2F)TSDYSI(amL)LD(Om)C*AQ(Aib)AFIC*YLLEGGPSKGAPPPS GS (SEQ ID NO. 349); and b) a staple attached at a first cysteine and a second cysteine having the following structure:wherein * represents a bond between the staple and the peptide sequence.

[0170] In some embodiments provided herein is a peptide conjugate comprising: a) a peptide sequence comprisingF3EtY(Aib)QGT(F2F)TSDYSI(amL)LD(Om)C*AQ(Aib)AFIC*YLLEGGPSKGAPPPS GS-NH2 (SEQ ID NO. 349); and b) a staple attached at a first cysteine and a second cysteine having the following structure:WSGR Docket No. 36271-720.601wherein * represents a bond between the staple and the peptide sequence.

[0171] In some embodiments provided herein is a peptide conjugate comprisingF3EtY(Aib)QGT(F2F)TSDYSI(amL)LD(Om)C*AQ(Aib)AFIC*YLLEGGPSKGAPPPSGS (SEQ IDNO. 349); and having the following structure:

[0172] In some embodiments provided herein is a peptide conjugate comprising : a) a peptide sequence comprising Y (Aib)QGT-FTSDY -SI(aml)LD-KC*AQ(Aib)-AFIC*Y - LLEGG-PSSGA-PPPSGS (SEQ ID NO. 335); and b) a staple attached at a first cysteine and a second cysteine having the following structure:wherein * represents a bond between the staple and the peptide sequence.

[0173] In some embodiments, a peptide conjugate described herein is as shown in Table 2.WSGR Docket No. 36271-720.601Table 2: Exemplary Peptide ConjugatesWSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601wherein:H2N- represents an unsubstituted amine at the N- terminus of the peptide;F3Et- represents a trifluoroethyl -substituted amine at the N- terminus of the peptide;-OH represents a carboxylic acid at the C- terminus of the peptide;-NH2 represents a carboxamide at the C-terminus of the peptide;(s) = d-Serine;Ac6c = 6-aminohexanoic acid;Aib = Alpha-aminoisobutyric acid; amF = Alpha-methyl phenylalanine; amF2F = Alpha-methyl 2-fluoro phenylalanine; amD = Alpha-methyl aspartic acid; ami = Alpha-methyl isoleucine; amY = Alpha-methyl tyrosine;WSGR Docket No. 36271-720.601 amL = Alpha-methyl leucine; amS = Alpha-methyl serine; amW = Alpha-methyl tryptophan; cpA = Aminocaproic acid;D-Dap = D -2, 3 -diaminopropionic acid;Dab = 2,4-diaminobutyric acid;Dap = 2,3-diaminopropionic acid;F2F = 2-fluoro phenylalanine;F2Br = 2-bromo phenylalanine;Hgl = Homoleucine;Hgn = Homoglutamine;Nle = Norleucine;Om = Ornithine;Nle = Norleucine;Tie = 2-amino-3,3-dimethylbutanoic acid;W2Me = 2-Methyl tryptophan;C*-C* = Staple-C4-[PEG2]2-eK-C18diacid / L5A / C18L5A =C*-C* = Staple-C4-[PEG2]2-eK-C16diacid / C16L5A =C*-C* = Staple-C4-[PEG2]l-eK-C19phosphonate =WSGR Docket No. 36271-720.601wherein each * denotes a bond between the staple and the peptide .Pharmacokinetics

[0174] 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, a GCG receptor, or a GLP-1 receptor, GIP receptor, GCG 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: 2-159.

[0175] 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.WSGR Docket No. 36271-720.601

[0176] 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.

[0177] 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.

[0178] 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

[0179] 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.

[0180] 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. TheWSGR Docket No. 36271-720.601 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.

[0181] 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 be obesity. 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-WilliSyndrome, Kearns-Sayre syndrome, Zellweger syndrome, Gaucher's disease, or Niemann Pick disease.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.WSGR Docket No. 36271-720.601

[0188] 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.

[0189] Provided herein is a method of preventing or treating malnutrition, for example conditions such as the wasting syndrome cachexia and anorexia.

[0190] 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. 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. Provided herein is a method of preventing or treating a disease or condition which benefits from a modulator and / or binder of a GCG receptor in a subject in need thereof comprising administering to the subject a peptide conjugate described herein. 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 and / or GIP receptor and / or GCG receptor, in a subject in need thereof comprising administering to the subject a peptide conjugate described herein.

[0191] Provided herein is a method of preventing or treating a disease or condition which benefits from a triple GLP-l / GIP / GCG receptor agonist in a subject in need thereof comprising administering to the subject a peptide conjugate described herein.Combinations

[0192] Disclosed herein are pharmaceutical compositions comprising a peptide or peptide conjugate described herein and one or more additional therapeutic agents.

[0193] 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.

[0194] 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.

[0195] 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.WSGR Docket No. 36271-720.601Processes

[0196] Also provided herein is a process for manufacturing a peptide conjugate (e.g., comprising a peptide and a staple disclosed herein), the process comprising:(i) combining in a liquid solvent medium(a) a compound of either of the following formulae:wherein: ni is 0 or 1; mi is 1-4; and m2 is 6-20.(b) a peptide (e.g., comprising any one of SEQ ID NO. 2-159), and(c) a base; and(ii) reacting (a), (b), and (c), optionally comprising stirring and / or heating or cooling, for a period of at least 5 minutes and less than about 5 hours (e.g., about 1 -2 hours); and(iii) optionally quenching step (ii) by addition of a sufficient amount of acid to lower the pH below 7; and(iv) optionally purifying the peptide conjugate (e.g., via HPLC).

[0197] In some embodiments, provided herein is a process for preparing a peptide conjugate comprising:(i) combining in a liquid solvent medium a peptide, a compound, and a base, thereby creating a reaction mixture, wherein: the peptide comprises any one of SEQ ID NO. 2-159; and the compound is:WSGR Docket No. 36271-720.601or a pharmaceutically acceptable salt thereof, wherein: ni is 0 or 1; m and mi are each independently 1-4; m2 is 6-20; andR1is hydrogen, -OH, or -P(=O)(OH)2;(ii) reacting the reaction mixture for at least 5 minutes and less than about 5 hours; and(iii) quenching step (ii) by addition of an acid, thereby acidifying the reaction mixture; and(iv) isolating the peptide conjugate from the reaction mixture.

[0198] In some embodiments, the compound is:solvate thereof. In some embodiments, the peptide comprises SEQ ID NO: 149.

[0199] In some embodiments, the base is a carbonate or bicarbonate base. In some embodiments, the base is ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, or magnesium bicarbonate. In some embodiments, the base is ammonium bicarbonate. In some embodiments, the base is triethylamine or N,N, -diisopropylethylamine (DIPEA / DIEA). In some embodiments, the base is added until pH is between about 8 and 9. In some embodiments, the liquid solvent medium is acetonitrile. In some embodiments, the liquid solvent medium is water. In some embodiments, the liquid solvent medium comprises a mixture of acetonitrile and water. In some embodiments, the liquid solvent medium is a 1 / 1 mixture of acetonitrile and water. In some embodiments, the liquid solvent medium and the base are sequentially added to the peptide, before combining the compound. In some embodiments, the compound is combined with the liquid solvent medium before combining with the base and the peptide. In some embodiments, the compound is combined dropwise. In some embodiments, the compound is dissolved in the liquid solvent medium and combined dropwise.

[0200] In some embodiments, the reacting comprises cooling (e.g., to between about 0 and 15 °C). In some embodiments, the reacting comprises stirring. In some embodiments, the reacting comprises stirring at room temperature. In some embodiments, room temperature is 20-25 °C. In some embodiments, room temperature is about 25 °C. In some embodiments, the reacting comprises heating (e.g., to between about 40 and 60 °C). In some embodiments, the reacting comprises stirring at room temperature for a period of 10 minutes to 2 hours. In some embodiments, the reacting comprises stirringWSGR Docket No. 36271-720.601 for about 30 minutes to about 3 hours. In some embodiments, the reacting comprises stirring for about 1 to 2 hours.

[0201] In some embodiments, the quenching comprises adding sufficient acid to lower the pH to 5-6. In some embodiments, the acid is hydrochloric or hydrobromic acid. In some embodiments, the acid is citric acid. In some embodiments, the acid is acetic or trifluoroacetic acid. In some embodiments, the acid is 0.5 to 2.0 N HC1. In some embodiments, the acid is 1 .0 N HC1 or HBr. In some embodiments, the acid is 1.0 N HC1.

[0202] In some embodiments, step (iv) comprises liquid extraction, rotary evaporation, lyophilization, reverse-phase high-pressure liquid chromatography, or ion exchange chromatography. In some embodiments, step (iv) comprises HPLC. In some embodiments, step (iv) comprises C18 column chromatography. In some embodiments, step (iv) comprises forced evaporation of liquid under sub- atmospheric pressure (e.g., rotary evaporation, lyophilization, vacuum desiccation, etc).Abbreviations

[0203] The abbreviations used throughout the present disclosure shall be understood to have the following meanings, unless otherwise specified:Ac6c: 1 -aminocyclohexane 1 -carboxylic acid:Aib: alpha-aminoisobutyric acid:amL: alpha-methyl-L-leucine:amS: alpha-methyl -L-serine:amF: alpha-methyl-L-phenylalanine,WSGR Docket No. 36271-720.601F3EtY: trifluoroethyl-L-tyrosine (also F3Et-TyrWSGR Docket No. 36271-720.601Iva: isovaline, or alternatively, (S)-2-amino-2 -methylbutanoic acid:KAc: '-s-acctyl-L-lysinc. or Lys(Om: ornithine:Tie: L-tert-leucine:W2Me: 2-methyl-L-tryptophan:Definitions

[0204] 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,WSGR Docket No. 36271-720.601 method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.

[0205] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0206] “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-l -propyl, 2 -methyl-2 -propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl- 3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2- pentyl, 3 -methyl-2 -pentyl, 4 -methyl-2 -pentyl, 2,2-dimethyl-l -butyl, 3,3 -dimethyl- 1 -butyl, 2-ethyl-l- 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 “Ci-Ce alkyl” 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 Ci-Cio alkyl, a C1-C9 alkyl, a Ci-Cs alkyl, a C1-C7 alkyl, a Ci-Ce alkyl, a C1-C5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a Ci alkyl. 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-C6 alkenyl” 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-C10 alkenyl, a C2-C9 alkenyl, a C2-C8 alkenyl, a C2-C7 alkenyl, a C2-C6 alkenyl, a C2-C5 alkenyl, a C2-C4 alkenyl, a C2-C3 alkenyl, 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-C6 alkynyl” 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 C 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,WSGR Docket No. 36271-720.601 halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0207] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Whenever it appears herein, a numerical range such as “Ci-Ce 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 Ci-Cs alkylene, a C1-C7 alkylene, a Ci-Ce alkylene, a C1-C5 alkylene, a C1-C4 alkylene, a C1-C3 alkylene, a C1-C2 alkylene, or a Ci 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.

[0208] “Alkoxy” refers to a radical of the formula -ORa where Ra is 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.

[0209] “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.

[0210] “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 isWSGR Docket No. 36271-720.601 bonded 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 (Cs-Cs cycloalkyl), from three to six carbon atoms (Cs-Ce 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, norbomyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo [2. l .l]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.

[0211] “Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0212] “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.

[0213] “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-C15 heterocycloalkyl), from two to ten carbon atoms (C2-C10 heterocycloalkyl), from two to eight carbon atoms (C2-C8 heterocycloalkyl), from two to six carbon atoms (C2-C6 heterocycloalkyl), from two to five carbon atoms (C2-C5 heterocycloalkyl), or two to four carbon atoms (C2-C4 heterocycloalkyl). 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 quatemized. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,WSGR Docket No. 36271-720.601 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-l-yl, 3- oxo-1, 3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,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, - CFs, -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.

[0214] “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 Ci-Ce heteroalkyl 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.

[0215] “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 quatemized. In some embodiments, the heteroaryl is a 5 - to 10-membered heteroaryl. In someWSGR Docket No. 36271-720.601 embodiments, 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][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphtho furanyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[I,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazo lyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1 -oxidopyrazinyl, 1 -oxidopyridazinyl, 1 -phenyl- IH-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.

[0216] 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.

[0217] 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 programWSGR Docket No. 36271-720.601ALIGN-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 AUIGN-2 program is publicly available from Genentech, Inc., South San Francisco, Calif., or may be compiled from the source code. The AUIGN-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 AUIGN-2 program and do not vary. In situations where AUIGN-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 AUIGN-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 AUIGN-2 computer program.

[0218] “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.

[0219] “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.

[0220] “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.

[0221] “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient, or carrier with which at least one antibody of the present disclosure is administered.

[0222] 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 improvedWSGR Docket No. 36271-720.601 prognosis. 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.

[0223] “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.

[0224] ‘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.

[0225] ‘ ‘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.

[0226] ‘ ‘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). As non-limiting examples, the peptide that modulates the GLP-1 receptor is a GLP-1 R agonist. As non-limiting examples, the peptide that modulates both the GLP-1 receptor and the GCG receptor is a dual GLP-1 R / GCGR agonist. As non-limiting examples, the peptide that modulates both the GLP-1 receptor and the GIP receptor is a dual GLP-1 R / GIPR agonist. As non-limiting examples, the peptide that modulates the GLP-1 receptor, the GIP receptor, and the GCG receptor is a triple GLP-1 R / GIPR / GCGR agonist.

[0227] ‘ ‘Unmodified peptide” refers to either an unmodified sequence (wild type peptide) or a modified sequence without a staple.WSGR Docket No. 36271-720.601EXAMPLES

[0228] Peptides were synthesized by standard solid-phase peptide synthesis (SPPS) techniques and purified via HPLC.

[0229] 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 KMnCL.

[0230] Flash chromatography purifications were performed on silica gel prepacked columns (40 pm, 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%).

[0231] Semi-preparative chromatography were performed on a Shimadzu HPLC with a Phenomenex Luna column (C18, 100 A pore size, 10 pm particle size, 250 x 10.0 mm, flow: 4 mL / min) or on an Agilent 1200 HPLC with a Phenomenex Luna column (Cl 8, 100 A pore size, 5 pm particle size, 150 x 21.2 mm, flow: 20 mL / min).

[0232] 1H and13C NMR spectra were recorded on a Bruker 400 system in de-DMSO, CDCls orCD3OD. 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).

[0233] Low resolution mass spectra were recorded on a Waters Acquity UPLC with a Phemomenex Luna Omega C18 column (C18, 100 A pore size, 1.6 pm particle size, 50 x 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.

[0234] 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 pm particle size, 150 x 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

[0235] Fmoc-Lys(ivDde)-OH (60 mg, 100 pmol) was coupled to 2 -chlorotrityl chloride resin (Novabiochem) (100 mg, 80 pmol) by mixing the amino acid, resin, and DIEA (70 pL, 400 pmol) 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

[0236] 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).WSGR Docket No. 36271-720.601General protocol C for deprotection of ivDde protecting group

[0237] After washing with DMF and DCM, the resin was treated with 2% hydrazine in DMF (5 mL, 2 x 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

[0238] 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

[0239] 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

[0240] 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 C*-C* = Staple-C4-[PEG2]2-eK-C20diacid (L5A I C18L5A)

[0241] Scheme 1.Staple L5A

[0242] Synthesis: The staple compound was synthesized using standard Fmoc chemistry.

[0243] 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), the mixture was agitated with N2 at 25 °C for 2.5 h. The MeOH (4.00 mL) was added in the resin and agitated with N2 at 25 °C for 0.5 h. Then the mixture was fdtered to get the resin. The resin was washed with DMF (50.0 mL * 5).

[0244] Deprotection'. 20% piperidine in DMF (50.0 mL) was added and agitated the resin with N2 at 25 °C for 15 min. The resin was washed with DMF (50.0 mL * 5) and fdtered to get the resin.

[0245] Coupling'. A solution of HBTU (2.85 eq) and C 18Diacid(tBu) (3.00 eq) in DMF (50.0 mL) was added to the resin, then the DIEA (6.00 eq) was added, the mixture was agitated with N2 at 25 °C for 30 min. The resin was washed with DMF (50.0 mL * 5).

[0246] After the coupling of C 18Diacid(tBu), add 3% H2N NH2 / DMF (50.0 mL) and react on 30 min and then repeat it for one more time. Drain and wash with DMF (50.0 mL) for 5 times.

[0247] Repeat above step 2 to 3 for the coupling of following amino acids: (3-5)

[0248] Deprotection-. 20% piperidine in DMF (50.0 mL) was added and agitated the resin with N2 at 25 °C for 15 min. The resin was washed with DMF (50.0 mL * 5) and filtered to get the resin.WSGR Docket No. 36271-720.601

[0249] Coupling'. A solution of 2-bromoacetic acid (6.00 eq) in DMF (50.0 mL) was added to the resin, then the DIC (6.00 eq) was added, the mixture was agitated with N2 at 25 °C for 30 min. The resin was washed with DMF (50.0 mL * 5).

[0250] Drain and wash with DMF (50.0 mL) for 5 times and filtered to get the resin (7. 1g).

[0251] Cleavage and Purification: Add cleavage solution (75.0 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.

[0252] Precipitated the peptide with cold isopropyl ether (750 mL). Filter and collect the filter cake. The filter cake was washed with isopropyl ether (750 mL * 2). Dry the crude staple compound under vacuum 2 h to get the crude staple (2.51 g), the crude staple was confirmed via LCMS (EW50514-2- PlAl, Rt=1.629 min).

[0253] The crude staple compound was purified by prep-HPLC (TFA condition: A: 0.075 % TFA in H2O, B: ACN) to give Staple L5A (1.3 g, 846.93 pmol, 42.35% yield, 84.83% purity, TFA) as a white solid. The staple L5A was confirmed via LC-MS (Rt= 1.628 min) and HPLC (Rt= 15.601min).

[0254] Purification conditions: The peptide staple was purified by HPLC.WSGR Docket No. 36271-720.601Example 2: Preparation of Peptide Conjugate No. 11

[0255] Scheme 2:Y(Aib)QGTFTSDYSI(aPeptide Conjugate No. 11

[0256] Synthesis: Peptide Conjugate No. 11 was synthesized according to the following procedure. Additional peptide conjugates of the present disclosure may be synthesized analogously. SEQ ID NO. 2 and 202 differ in that the cysteines of SEQ ID NO. 2 are unmodified, whereas the cysteines of SEQ ID NO. 202 are bonded to the staple.

[0257] Peptide staple conjugation and purification. The dicysteine -containing peptide (2 mM, >85% pure) (Shanghai Apeptide Co., Shanghai, China) and the cross-linker (1.5 eq) were dissolved in CHsCN / SO mM NH4HCO3 buffer (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 (Cis, 100 A pore size, 5 pm 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.WSGR Docket No. 36271-720.601Peptide Conjugate No. 11

[0258] Characterization: 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-Cis, 3.6 pm 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.Example 3: Synthesis of Peptide Staple Br-Staple-C4-[PEG2]l-eK-C19phosphonate

[0259] Scheme 3:

[0260] Synthesis: The peptide staple was synthesized using resin-based peptide synthesis and Fmoc chemistry, as set forth in the following steps 1-8:1) Resin preparation: To a solution of 2-CTC Resin (30.0 mmol, 1.00 eq, Sub 0.50mmol / g) and Fmoc-Lys(Dde) -OH (1.00 eq) in DCM (0.5 L) was added DIEA (4.00 eq), the mixture was agitated with N2 at 25 °C for 2.5 h. The MeOH (60 m ) was added in the resin and agitated with N2 at 25 °C for 0.5 h. Then the mixture was filtered to get the resin. The resin was washed with DMF (1.0 L*5).2) Deprotection: 20% piperidine in DMF (1.0 L) was added and agitated the resin with N2 at 25 °C for 15 min. The resin was washed with DMF (1.0 L*5) and filtered to get the resin.3) Coupling: A solution of HATU (1.425 eq) and 19 -(diphenoxypho sphoryl)nonadecanoic acid (1.50 eq) in DMF (500.0 mL) was added to the resin, then the DIEA (3.00 eq) was added, the mixture was agitated with N2 at 25 °C for 30 min. The resin was washed with DMF (1.0L*5).WSGR Docket No. 36271-720.6014) After the coupling of 19-(diphenoxyphosphoryl)nonadecanoic acid, add 3% H2N NH2 / DMF (1.0 L) and react on 30 min and then repeat it for one more time. Drain and wash with DMF (1.0 L) for 5 times.5) Repeat above step 2 to 3 for the coupling of following amino acids: (3-5)Amino acids 3-5:6) Deprotection: 20% piperidine in DMF (750.0 mL) was added and agitated the resin with N2 at 25 °C for 15 min. The resin was washed with DMF (750.0 mL*5) and filtered to get the resin.7) Coupling: A solution of 2-bromoacetic acid (6.00 eq) in DMF (500.0 mL) was added to the resin, then the DIC (6.00 eq) was added, the mixture was agitated with N2 at 25 °C for 30 min. The resin was washed with DMF (750.0 mL*5).8) Drain and wash with DMF (750.0 mL) for 5 times and filtered to get the resin (95.77g).

[0261] Cleavage, Purification, and Characterization: The resin-bound staple compound was cleaved from the resin, purified, and characterized according to the following steps 9-11:9) Add cleavage solution (1000.0 mL, 87.5% TFA / 2.50% TIS / 2.50% H2O / 7.5% 3- Mercaptopropionic acid) to the flask containing resin at room temperature and stirred for 3 h.10) Precipitated the peptide with cold isopropyl ether (10.0 L). Filter and collect the filter cake. The filter cake was washed with isopropyl ether (8.0 L*2). Dry the crude peptide under vacuum 6 h to get the crude peptide (32.2 g), the crude peptide was confirmed via LCMS (Rt=1.75 min).11) The crude peptide was purified by prep-HPLC (TFA condition: A: 0.075 % TFA in H2O, B: ACN) to give the final product Br-Staple-C4-[PEG2] l-eK-C19phosphonate (10.7 g, 9.79 mmol, 32.6% yield, 96.27% purity, TFA). The Br-Staple-C4-[PEG2] l-eK-C19phosphonate was confirmed via LCMS (Rt= 1.300 min, MS cal.: 1092.94, MS observed: [M+H]+= 1093.40) and HPLC (Rt= 11.217 min).WSGR Docket No. 36271-720.601

[0262] Purification conditions: The peptide staple was purified by HPLC.Example 4: Preparation of Dicysteine Peptide (SEQ ID NO. 149)

[0263] Scheme 4WSGR Docket No. 36271-720.601F3EtY(Aib)QGT(F2F)TSDYSI(amL)LD(Om)CAQ(Aib)AFICYLLEGGPSKGAPPPSGS-NH2 (SEQ ID NO. 149)

[0264] Synthesis: The dicysteine peptide (SEQ ID NO. 149) was synthesized using standard Fmoc- based chemistry and resin-bound peptide synthesis, as described in the following steps 1-4.1) Resin preparation: To the Rink Amide MBHA Resin (13 mmol, 1.00 eq, Sub: 0.31 mmol / g) in DMF (1 .5 L) was agitated with N2 for 2 h at 20°C.2) Then 20% piperidine in DMF (1.5 L) was added and the mixture was agitated with N2 for 10 min at 20°C. The resin was washed with DMF (1 .0 L * 5) and filtered to get the resin.3) Coupling: A solution of Fmoc-Ser(tBu)-OH (14.95 g, 39 mmol, 3.0 eq), DIEA (13.586 mL, 78.0 mmol, 6.00 eq) and HATU (14.08 g, 37.0 mmol, 2.85 eq) in DMF (500 mL) was added to the resin and agitated with N2 for 30 min at 20°C. The resin was then washed with DMF (1.0 L * 5).4) Repeat above step 2 to 3 for the coupling of following amino acids: (2-41).

[0265] Amino Acids (2-41):WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601

[0266] Cleavage, Purification, and Characterization: The resin -bound dicysteine peptide was cleaved from the resin, purified, and characterized according to the following steps 5-7:5) After last step, the resin was washed with MeOH (1 .5 L) for 3 times and dried under vacuum to get 113 ,8g peptide resin. Then the peptide resin was treated with the cleavage cocktail 1 .2 L (92.5% TFA / 2.5% H2O / 2.5%3-MPA / 2.5% TIS) at 20°C for 2 h.6) Precipitated the peptide with cold isopropyl ether (6.0 L). Filter and collect the filter cake. The filter cake was washed with isopropyl ether (6.0 L * 2). Dry the crude peptide under vacuum 2 h to get the crude peptide (53.42 g), the crude peptide was confirmed via LCMS (Rt= 1.429min).7) The residue was purified by prep-HPLC (TFA Condition: A:0.075%TFA in H2O, B: ACN) to give the final product Peptide No. 149 (6.17g, 1.417mmol, 10.9% yield, 96.49% purity TFA) was obtained. The dicysteine peptide having SEQ ID NO. 149 was confirmed via LCMS (Rt= 1.176 min, MS cal.: 4352.85, MS observed: [M+3H]3+= 1451.7) and HPLC (Rt= 11.406 min)

[0267] Purification conditions:WSGR Docket No. 36271-720.601Example 5: Preparation of Peptide Conjugate No. 174

[0268] Scheme 5F3EtY(Aib)QGT(F2F)TSDYSI(amL)LD(Om)CAQ(Aib)AFICYLLEGGPSKGAPPPSGS-NH2 (SEQ ID NO. 149) +Peptide Conjugate No. 174

[0269] Synthesis: To a mixture of the dicysteine peptide of Example 4 (6.17 g, 1.417 mmol, 1.00 equiv) in ACN (1.5 L) and H2O (1.5 L) was added NH4HCO3 (IM, 50 ml) until the PH=8~9, then was added drop-wise the peptide staple of Example 3 (“Br-Staple-C4-[PEG2] l-eK-C19phosphonate,” 1.626 g, 1.488 mmol, 1.05 equiv) in ACN (100 ml) and H2O (150 ml). The mixture was stirred at 25 °C for 1.0 hr. The reaction mixture was adjusted PH=~5-6 with IM HC1 aq. Then the reaction mixture was lyophilized.

[0270] Purification and Characterization: The crude peptide conjugate was purified by prep-HPLC (TFA condition: A: 0.075 % TFA in H2O, B: ACN) and (HAc condition: A: 0.2M NH4Ac / 0.05% HAc, B: ACN) to give Peptide Conjugate No. 174 (2.1 g, 397.4 pmol, 97.37% purity, HAc). Peptide Conjugate No. 174 (HAc Salt) was confirmed via LC-MS (Rt = 1.218 min, MS cal.: 5283.97, MS observed: [M+3H]3+= 1762.22) and HPLC (Rt = 11.809 min). SEQ ID NO. 149 and 349 differ in that the cysteines of SEQ ID NO. 149 are unmodified, whereas the cysteines of SEQ ID NO. 349 are bonded to the staple.WSGR Docket No. 36271-720.601Peptide Conjugate No. 174

[0271] TFA Purification conditions:

[0272] CH3COO- Purification conditions:WSGR Docket No. 36271-720.601

[0273] 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-Gio (Promega, WI) luciferase reagent following manufacturer’s instruction. The EC50 of each peptide was determined using GraphPad Prism 6 software (GraphPad, San Diego, CA).

[0274] cAMP assay

[0275] CHOK1 cells stably overexpressed human GLP-1R or GIPR (40 pL 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 assay medium (F12 media) containing no FBS (for 0% FBS group), 1% human serum albumin (for 1% HSA group), or 0. 1% caseine (for caseine group). Cells were treated with 5 pL peptide in 12-point dose response, in assay 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 pL 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-1 665 nm and, EM-2 620 nm. Graphs were plotted with Ratio or AF using Prism software and EC50 values were then obtained:RatlO Agg5nm / B620nm X 10% AF= (standard or sample ratio - rationeg) / rationeg x 100.

[0276] 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.Table 3. In Vitro Receptor Activation (GLP-1R, GIPR, GCGR) with or without human serum albumin (HSA)WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601*: inactiveExample C: Potency in endogenously expressed target receptors in rat insulinoma cell line (GLP- 1R / GIPR activation) and mouse and human hepatocytes (GCGR activation)

[0277] Human and mouse hepatocytes were purchased from Life Technology. The potency of Peptide Conjugate No. 167 and 174 were confirmed using endogenously expressed target receptors in rat insulinoma cell lines (INS-1 832 / 3 and INS1-1E), showing GLP-1R / GIPR activation, and in mouse and human hepatocytes, showing GCGR activation.

[0278] The in vitro potency of Peptide Conjugate No. 167 and 174 are provided in Table 4 alongside a reference conjugate (Retatrutide). Both 167 and 174 were as potent or more potent than Retatrutide in GLP-lR / GIPR-expressing rat insulinoma cells, and both showed less activity in GCGR-expressing hepatocytes compared to Retatrutide.Table 4. In Vitro Potency of 167, 174, and Retatrutide in GLP-1R / GIPR and GCGR cellsExample D: Biased Agonism Towards cAMP Signaling

[0279] Peptide conjugates like Retatrutide act as cAMP -biased ligands at GLP-1R, eliciting only 52% [3- arrestin recruitment relative to Semaglutide. cAMP -biased signaling may minimize receptor degradation potentially leading to prolonged pharmacological activity and potentially reduced AEs.

[0280] General Procedure: Agonist-induced recruitment of [3-arrestin 2 to GLP-1R, GIPR, and GCGR was quantified using the PathHunter® eXpress GLP-1R, GIPR and GCGR CHO-K1 [3-Arrestin GPCR Assays (Eurofins DiscoverX). [3-Arrestin CHO-K1 cells were seeded in a total volume of 20 pL into white 384-well microplates and incubated at 37 °C for 48 hours. Compounds were added to cells and incubated at 37 °C for 90 min. Assay signal was generated through a single addition of 12.5 pL PathHunter Detection reagent cocktail (Eurofins DiscoverX), followed by 60-minute incubation at roomWSGR Docket No. 36271-720.601 temperature. Signals were collected in Pherastar plate reader, plotted and normalized to the maximal response of positive controls, semeglutide, hGIP, hGCG separately. Data are expressed as means ± SD from three independent experiments.

[0281] GLP-1R-. In a [3-arrestin 2 recruitment assay for GLP-1R as described above, Peptide Conjugate No. 155, 173, and 174 demonstrated a reduced maximal [3-arrestin recruitment response compared to retatrutide and the positive control semaglutide, as shown in FIG. 2.

[0282] [3-arrestin 2 recruitment at the human GLP-1R was assessed using the PathHunter Enzyme Fragment Complementation assay (Eurofms DiscoverX, Freemont,CA). Cryopreserved PathHunter GLP- 1 [3-arrestin 2 cells were thawed, resuspended, and plated in 384-well plates. After 48 hours of incubation, cells were treated with serial dilutions of semaglutide, retatrutide, the conjugates. Following a 90-minute incubation at 37 °C, 10 pL of PathHunter Detection Reagent was added, and plates were incubated for 60 minutes at room temperature. Chemiluminescence was measured using a Pherastar FS plate reader. Emax values were determined from the maximum effect of fitted curves using GraphPad Prism 9.2 software and expressed as a percentage of the maximum response produced by the positive control (semaglutide). As shown in FIG. 3, Peptide Conjugate No. 167 and 174 both demonstrated a reduced maximal [3-arrestin recruitment response compared to retatrutide and the positive control semaglutide.

[0283] GIPR: [3-arrestin 2 recruitment at the human GIP was assessed using the PathHunter Enzyme Fragment Complementation assay (Eurofms DiscoverX, Freemont,CA). Cryopreserved PathHunter GIPR [3-arrestin 2 cells were thawed, resuspended, and plated in 384-well plates. After 48 hours of incubation, cells were treated with serial dilutions of hGIP, retatrutide, the conjugates. Following a 90-minute incubation at 37 °C, 10 pL of PathHunter Detection Reagent was added, and plates were incubated for 60 minutes at room temperature. Chemiluminescence was measured using a Pherastar FS plate reader. Emax values were determined from the maximum effect of fitted curves using GraphPad Prism 9.2 software and expressed as a percentage of the maximum response produced by the positive control (hGIP).

[0284] In the GIPR [3-arrestin recruitment assay, conjugates 167 and 174 exhibited high potency, with conjugate 174 displaying maximal potency at GIPR, exceeding that of retatrutide and matching the native ligand, as shown in FIG. 4.

[0285] GCGR: [3-arrestin 2 recruitment at the human GGCR was assessed using the PathHunter Enzyme Fragment Complementation assay (Eurofms DiscoverX, Freemont,CA). Cryopreserved PathHunter GCGR [3-arrestin 2 cells were thawed, resuspended, and plated in 384-well plates. After 48 hours of incubation, cells were treated with serial dilutions of hGCG, retatrutide, the conjugates. Following a 90- minute incubation at 37 °C, 10 pL of PathHunter Detection Reagent was added, and plates were incubated for 60 minutes at room temperature. Chemiluminescence was measured using a Pherastar FS plate reader. Emax values were determined from the maximum effect of fitted curves using GraphPad Prism 9.2 software and expressed as a percentage of the maximum response produced by the positive control (hGCG).WSGR Docket No. 36271-720.601

[0286] In the GCGR [3-arrestin recruitment assay, conjugates 167 and 174 exhibited comparable maximal response compared to retatrutide, as shown in FIG. 5.Example E: Ligand-Mediated GLP-1 Receptor Internalization

[0287] GLP-1 receptor internalization was quantified using the PathHunter® total GPCR internalization assay. The total GPCR internalization cell lines are engineered to co-express a first [3-galactosidase enzyme fragment tag, localized to the endosomes, and a GLP-1 receptor tagged with second [3- galactosidase enzyme fragment. Ligand-induced activation of the GLP-1 receptor leads to internalization of the receptor via the tagged endosomes (agonist-mediated endocytosis), whereupon the first and second P-galactosidase enzyme fragments form a complementary pair resulting in a functional enzyme, which hydrolyzes a substrate to generate a chemiluminescent signal. The assay enables chemiluminescent signal generation directly proportional to the extent of receptor internalization .

[0288] The internalization assay was performed with human GLP-1 (“hGLP-1”), semaglutide, retatrutide, and conjugate 174, at multiple concentrations to generate the GLP-1R Internalization dose response curve of FIG. 6. Displayed below in table 5, conjugate 174 is shown to achieve the lowest degree of GLP-1 receptor internalization (Emax = 44%) compared to human GLP-1 (100%), semaglutide (102%), and retatrutide (92%), possibly as a result of its CAMP -biased agonism). Conjugate 174 is also the least potent at inducing GLP-1 R internalization, having an effective concentration that achieves a half-maximal effect (“EC50”) of 36 nM for conjugate 174, compared to 13 nM for retatrutide, and <5 nM for semaglutide).Table 5. GLP-1R Ligand-Mediated Internalization

[0289] Conjugate 174 induces significantly less GLP-1R internalization than both semaglutide and retatrutide, and thus receptor desensitization could be mitigated by use of Conjugate 174. This profile may mitigate the waning weight loss response observed with current GLP-1 agents and support more durable clinical efficacy.Example F: Pharmacokinetics in Cynomolgus Monkeys

[0290] Fasted male Cynomolgus monkeys were administered either (a) retatrutide via subcutaneous injection at a dose of 0.100 milligrams of drug per kilogram of animal’s body mass; or (b) Conjugate 174 via intravenous injection at the same dose (0. 100 mg / kg). Plasma samples were collected at timepoints 0,WSGR Docket No. 36271-720.6015 min, 30 min, 1 hr, 3 hr, 7 hr, Id (24 hr), 2 d (48 hr), 3 d (72 hr), 4 d (96 hr), 5 d (120 hr), 7 d (168 hr), 10 d (240 hr), 14 d (336 hr), and 21 d (504 hr) timepoints, and analyzed for peptides using LC-MS. The plasma concentration following drug administration over 21 days is provided in FIG. 7 (retatrutide) and FIG. 8 (conjugate 174). The plasma half-life for retatrutide after s.c. injection was 60.7 hours, compared to 96.2 hours for conjugate 174 after i.v. injection.Example G: Efficacy in Diet-Induced Obese (DIO) mice

[0291] Twenty one-week-old C57BL-6 DIO mice and age-matched controls were supplied by Taconic Biosciences, Inc. (Germantown, NY). Mice were allocated to their respective treatment groups four days prior to experimental start date using a randomization sequence based on body weight and EchoMRI readouts for fat mass. Mice were then dosed once daily by SC injection at a dose volume of 5 mL / kg for14 days, dosed 30-90 min priori to start of the dark cycle. Body weight and food intake was measured five times a week, conjugate 174 produced dose-dependent reduction in body weight along (as shown in FIG. 9), with significant reduction in food consumption (as shown in FIG. 10) in DIO mice during the entire treatment period.

[0292] DIO mice treated with conjugate 174 at 30 nmol / kg qd, SC, reached approximately 50% bodyweight at day 15. Significant reduction of fat mass was observed, in a dose -dependent manner, as shown in FIG. 11. Improvements in body composition were also observed in a dose-dependent manner for conjugate 174, with the lean-to-fat mass ratio approaching that of wild-type healthy rodents, indicating a healthier weight loss profile, as shown in FIG. 12.

[0293] Other positive outcomes were observed, such as reductions in serum cholesterol at Day 15 (as shown in FIG. 13), non -fasted blood glucose levels at Day 6 (as shown in FIG. 14), and liver fat at Day15 (as shown in FIG. 15).

[0294] Embodiments:Embodiment 1. A peptide conjugate comprising: a) a peptide comprising the sequence:X1-X2-X3-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe- X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41(-NH2) (SEQ ID NO. 160 or 161), wherein:X1is Tyr or C FXTE-Tyr:X2is Aib, Gly, Ala, or D-Ser;X3is Gin or His;WSGR Docket No. 36271-720.601X6is Phe, aMe-Phe, aMe-Phe2F, aMe-Phe2F6F, Phe2F, or Phe2Br;X10is Tyr, Vai, Leu, CpA, Trp, Glu, Phe, or Cys;X11is Ser or aMe-Ser;X13is Tyr, aMe-Leu, Ac6c, aMe-Phe, Iva, or Cys;X15is Asp or Glu;X16is Lys, Lys(Ac), or Om;X17is Cys or Lys(Ac), or He;X19is Ala, Gin, or Hgl;X20is Aib, Cys, or Gin;X21is Ala, Glu, Cys, or Tie;X23is He, Vai, or Tie;X24is Cys or Glu;X25is Trp, Tyr, aMe-Trp, Trp2Me, or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;X28is Glu, Hgl, Cys, Ser, or Ala;X29is Gly or Ala;X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys; andX40is Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, Gly or absent;X41is Ser or absent; wherein the C-terminus of the peptide is optionally -COOH or -CONH2; and b) a staple attached to the peptide at a first amino acid and a second 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 first amino acid of the peptide, XBis attached to the second amino acid of the peptide, and XAand XBare identical;R is hydrogen or -(L)s-Y ; each L is independently -(CR’R2)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)-,WSGR Docket No. 36271-720.601-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, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, Cs-Cs cycloalkyl, C2-Cs 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; or R1and R2are taken together to form a Ci-Ce cycloalkyl or Ci-Ce heterocycloalkyl; each R3is independently hydrogen, -S(=O)Rb, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, - C(=O)NRcRd, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, C3-G cycloalkyl, C2-Cs 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;Y is hydrogen, Ci-C6alkyl, -CO2H, -P(=O)(OH)2, -CO2(Ci-C6alkyl), -CO2NH2, -CO2N(alkyl)2, - CO2NH(alkyl), or 5 -membered heteroaryl; s is 0-20;Rais hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, Cs-Cs cycloalkyl, C2-Cs 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2;Rbis Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, Cs-Cs cycloalkyl, C2-Cs 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; and each Rcand Rdis independently hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, Cs-Cs cycloalkyl, C2-Cs 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or - NH2;WSGR Docket No. 36271-720.601 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2.Embodiment 2. The peptide conjugate of embodiment 1, wherein the peptide comprises the sequence: X1-X2-X3-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe- X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41(-NH2) (SEQ ID NO. 160 or 161), wherein:XIis Tyr or CF3CH2-Tyr;X2is Aib, Gly, Ala, or D-Ser;X3is Gin or His;X6is Phe, aMe-Phe, or Phe2F;X10is Tyr, Vai, Trp, or Cys;XI Iis Ser or aMe-Ser;X13is Ac6c, Tyr, aMe-Leu, aMe-Phe, Iva, or Cys;X15is Asp or Glu;X16is Lys, Lys(Ac), or Om;X17is Lys(Ac), Cys or He;X19is Ala or Gin;X20is Aib, Cys, or Gin;X21is Ala, Glu, or Cys;X23is He or Vai;X24is Cys or Glu;X25is Tyr, or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;X28is Glu, Hgl, Cys, or Ala;X29is Gly;X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys;X40is Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, Gly, or absent; and X41is Ser or absent.Embodiment 3. The peptide conjugate of embodiment 1, wherein the peptide comprises the sequence: X1-Aib-Gln-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe- X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41(-NH2) (SEQ ID NO. 162 or SEQ ID NO. 163) wherein:WSGR Docket No. 36271-720.601XIis Tyr or CFsCH2-Tyr;X6is Phe, aMe-Phe, or Phe2F;X10is Tyr, Vai, Trp, or Cys;XI Iis Ser or aMe-Ser;X13is Tyr, aMe-Leu, aMe-Phe, Iva, or Cys;X15is Asp or Glu;X16is Lys, Lys(Ac), or Om;X17is Cys or He;X19is Ala or Gin;X20is Aib, Cys, or Gin;X21is Ala, Glu, or Cys;X23is He or Vai;X24is Cys or Glu;X25is Trp, Tyr, or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;X28is Glu, Hgl, Cys, or Ala;X29is Gly;X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys;X40is Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, Gly, or absent; and X41is Ser or absent.Embodiment 4. The peptide conjugate of embodiment 1 or 2, wherein the peptide comprises the sequence:X1-X2-X3-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe- X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41(-NH2) (SEQ ID NO. 160 or 161), wherein;XIis Tyr or CFsCFL-Tyr;X2is Aib, Gly, Ala, or D-Ser;X3is Gin or His;X6is Phe, aMe-Phe, or Phe2F;X10is Tyr or Vai;XI Iis Ser or aMe-Ser;X13is Ac6c, Tyr, aMe-Leu, aMe-Phe, or Iva;X15is Asp or Glu;X16is Lys, Lys(Ac), or Om;X17is Lys(Ac), Cys or He;WSGR Docket No. 36271-720.601X19is Gin;X20is Aib or Gin;X21is Cys, Ala or Glu;X23is He or Vai;X24is Cys or Glu;X25is Tyr or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;X28is Glu, Cys, or Ala;X29is Gly;X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys;X40is Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, Gly, or absent; andX41is Ser or absent.Embodiment 5. The peptide conjugate of embodiment 1 or 2, wherein the peptide comprises the sequence:X1-X2-Gln-Gly-Thr-X6-Thr-Ser-Asp-Tyr-Ser-Ile-aMe-Leu-Asp-X16-Cys-Ala-Gln-Aib-X21-Phe-Ile-X24-X25-Leu-Leu-Glu-Gly-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-Ser-X40-X41(-NH2)(SEQ ID NO. 164 or SEQ ID NO. 165), wherein;X1is Tyr or CFsCFL-Tyr;X2is Aib or Ala;X6is Phe or Phe2F;X16is Lys or Om;X21is Ala or Glu;X24is Cys or Glu;X25is Tyr or aMe-Tyr;X33is Ser, Lys, or aMe-Lys;X40is Gly or absent; andX41is Ser or absent.Embodiment 6. The peptide conjugate of any one of embodiments 1-5, wherein X1is CFsCFL-Tyr.Embodiment 7. The peptide conjugate of any one of embodiments 1-6, wherein X2is Aib.Embodiment 8. The peptide conjugate of any one of embodiments 1-7, wherein X6is Phe2F.Embodiment 9. The peptide conjugate of any one of embodiments 1-8, wherein X16is Om.WSGR Docket No. 36271-720.601Embodiment 10. The peptide conjugate of any one of embodiments 1-9, wherein X33is Lys.Embodiment 11. The peptide conjugate of any one of embodiments 1-10, wherein X40is Gly.Embodiment 12. The peptide conjugate of any one of embodiments 1-11, wherein X41is Ser.Embodiment 13. The peptide conjugate of any one of embodiments 1-12, wherein X40is Gly and X41is Ser.Embodiment 14. The peptide conjugate of any one of embodiments 1-13, wherein:X1is CF3CH2-Tyr;X6is Phe2F;X16is Om;X33is Lys;X40is Gly; and / orX41is Ser.Embodiment 15. The peptide conjugate of any one of embodiments 1-5, wherein:X1is Tyr;X6is Phe;X16is Lys;X33is Ser;X40is Gly; and / orX41is Ser.Embodiment 16. The peptide conjugate of any one of embodiments 1-15, 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. 202-357.Embodiment 17. The peptide conjugate of any one of embodiments 1-16, wherein the peptide has the amino acid sequence of any one of SEQ ID NOs. 2-159 or 202-357.Embodiment 18. The peptide conjugate of any one of embodiments 1-15, comprising the sequence: F3EtY(Aib)QGT(F2F)TSDYSI(amL)LD(Om)C*AQ(Aib)AFIC*YLLEGGPSKGAPPPSGS- NH2 (SEQ ID NO . 349).Embodiment 19. The peptide conjugate of any one of embodiments 1-16, comprising the sequence: Y(Aib)QGTFTSDYSI(aml)LDKC*AQ(Aib)AFIC*YLLEGGPSSGAPPPSGS-NH2 (SEQ ID NO. 334).Embodiment 20. The peptide conjugate of any one of embodiments 1-5, wherein the peptide modulates a GLP-1 receptor.WSGR Docket No. 36271-720.601Embodiment 21. The peptide conjugate of any one of embodiments 1-5, wherein the peptide binds to a GLP-1 receptor.Embodiment 22. The peptide conjugate of any one of embodiments 1-5, wherein the peptide modulates a GIP receptor.Embodiment 23. The peptide conjugate of any one of embodiments 1-5, wherein the peptide binds to a GIP receptor.Embodiment 24. The peptide conjugate of any one of embodiments 1-5, wherein the peptide modulates to a glucagon receptor.Embodiment 25. The peptide conjugate of any one of embodiments 1-5, wherein the peptide binds to a glucagon receptor.Embodiment 26. The peptide conjugate of any one of embodiments 1-25, wherein the peptide is a GLP-1 receptor agonist.Embodiment 27. The peptide conjugate of any one of embodiments 1-26, wherein the peptide is a GIP receptor agonist.Embodiment 28. The peptide conjugate of any one of embodiments 1-26, wherein the peptide is a glucagon receptor agonist.Embodiment 29. The peptide conjugate of any one of embodiments 1-28, wherein the peptide is a GLP-1 receptor, GIP receptor agonist, and glucagon receptor triple agonist.Embodiment 30. The peptide conjugate of any one of embodiments 1-29, wherein the peptide is resistant to proteolysis by a gastrointestinal protease.Embodiment 31 . The peptide conjugate of embodiment 1, wherein the first amino acid and the second amino acid are each cysteine.Embodiment 32. The peptide conjugate of embodiment 1 or 30, wherein the first amino acid has a position i in the peptide and the second amino acid has a position i + n in the peptide, wherein n is 4-16.Embodiment 33. The peptide conjugate of embodiment 1 or 30, wherein the first amino acid has a position i in the peptide and the second amino acid has a position i + 4 in the peptide.Embodiment 34. The peptide conjugate of embodiment 1 or 30 wherein the first amino acid has a position i in the peptide and the second amino acid has a position i + 7 in the peptide.WSGR Docket No. 36271-720.601Embodiment 35. The peptide conjugate of any one of embodiments 1-34, wherein XAand XBare -C(=O).Embodiment 36. The peptide conjugate of any one of embodiments 1-34, wherein XAand XBare - alkylene-C(=O)- or -C(=O)alkylene-.Embodiment 37. The peptide conjugate of any one of embodiments 1-34, wherein XAand XBare -CEI2- C(=O)- or -C(=O)-CH2-.Embodiment 38. The peptide conjugate of any one of embodiments 1-34, wherein XAand XBare - alkylene-C(=O)NR3- or -C(=O)NR3-alkylene-.Embodiment 39. The peptide conjugate of any one of embodiments 1-34, wherein XAand XBare -CEI2- C(=O)NR3- or -C(=O)NR3-CH2-.Embodiment 40. The peptide conjugate of any one of embodiments 1-34, wherein XAand XBare - alkylene-C(=O)NR3-alkylene- or -alkylene-NR3C(=O)-alkylene-.Embodiment 41. The peptide conjugate of any one of embodiments 1-34, wherein XAand XBare -CH2- C(=O)NR3-CH2CH2- or -CH2-NR3C(=O)-CH2CH2-.Embodiment 42. The peptide conjugate of any one of embodiments 1-34, wherein XAand XBare -CH2- C(=O)NH-CH2CH2- or -CH2-NHC(=O)-CH2CH2-.Embodiment 43. The peptide conjugate of any one of embodiments 1-42, wherein >A-R has the following structure:Embodiment 44. The peptide conjugate of embodiment 43, wherein s is 1-15.Embodiment 45. The peptide conjugate of embodiment 43, wherein s is 1-10.Embodiment 46. The peptide conjugate of embodiment 43, wherein s is 1-5.Embodiment 47. The peptide conjugate of any one of embodiments 1-46, wherein Y is -P(=O)(OH)2, or -CO2H.Embodiment 48. The peptide conjugate of any one of embodiments 1-47, wherein each L is independently -(CR1R2) -. -alkylene-O-, -C(=O)-, -C(=O)NR3-, -NR3C(=O)-, -alkylene- C(=O)NR3-, or -alkylene-NR3C(=O)-; and v is 1-20.Embodiment 49. The peptide conjugate of embodiment 48 wherein each R1and R2is independently hydrogen, -CO2H, or -CO2NH2.WSGR Docket No. 36271-720.601Embodiment 50. The peptide conjugate of any one of embodiments 1-34 or 40-45, wherein the peptide conjugate comprises (e.g., the staple is):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; is 0 or 1; n2and mi are each independently 1-4; m2 is 6-20; and each * denotes the attachment to the peptide.Embodiment 51 . The peptide conjugate of any one of embodiments 1-34 or 40-45, wherein the peptide conjugate comprises (e.g., the staple is):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; ni is 0 or 1; m and mi are each independently 1-4; m2 is 6-20; and each * denotes the attachment to the peptide.Embodiment 52. The peptide conjugate of embodiment 50 or 51, wherein is 0.Embodiment 53. The peptide conjugate of embodiment 50 or 51, wherein ni is 1.Embodiment 54. The peptide conjugate of any one of embodiments 50-53, wherein n2is 1.WSGR Docket No. 36271-720.601Embodiment 55. The peptide conjugate of any one of embodiments 50-54, wherein the staple is:or a pharmaceutically acceptable salt thereof, wherein: is 0 or 1; mi is 1-4; m2 is 6-20; and each * denotes the attachment point to the peptide.Embodiment 56. The peptide conjugate of any one of embodiments 50-55, wherein mi is 3.Embodiment 57. The peptide conjugate of any one of embodiments 50-56, wherein R10is -OH and R11is hydrogen.Embodiment 58. The peptide conjugate of any one of embodiments 50-57, wherein ZAis -CO2H.Embodiment 59. The peptide conjugate of any one of embodiments 50-58, wherein ZAis -P(=O)(OH)2.Embodiment 60. The peptide conjugate of any one of embodiments 50-59, wherein each R3is independently hydrogen.Embodiment 61 . The peptide conjugate of any one of embodiments 1 or 30-60, wherein the peptide conjugate comprises (e.g., the staple is):WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601wherein each * denotes the attachment point to the peptide.Embodiment 62. The peptide conjugate of embodiment 1, wherein the peptide conjugate comprises: a) a peptide sequence comprising F3Et-Y (Aib)QGT-(F2F)TSDY-SI(amL)LD-(Om)C*AQ(Aib)-AFIC*Y-LLEGG-PSKGA-PPPSG-S (SEQ ID NO. 349); and b) a staple attached at a first cysteine and a second cysteine having the following structure:wherein * represents a bond between the staple and the peptide sequence.Embodiment 63. The peptide conjugate of embodiment 1, wherein the peptide conjugate comprises:WSGR Docket No. 36271-720.601 a) a peptide sequence comprising Y (Aib)QGT-FTSDY -SI(aml)LD-KC*AQ(Aib)-AFIC*Y - LLEGG-PSSGA-PPPSGS (SEQ ID NO. 334); and b) a staple attached at a first cysteine and a second cysteine having the following structure:wherein * represents a bond between the staple and the peptide sequence.Embodiment 64. The peptide conjugate of embodiment 1, wherein the peptide conjugate comprises: a) a peptide sequence comprising Y (Aib)QGT-FTSDY -SI(amL)LD-KCAQ(Aib)-AFICY - LLEGG-PSSGA-PPPS (SEQ ID NO. 202); and b) a staple attached at a first cysteine and a second cysteine having the following structure:wherein * denotes the attachment to the first and second cysteine of the peptide sequence, wherein the staple is attached at cysteine 17 and cysteine 24.Embodiment 65. The peptide conjugate of embodiment 1, wherein the peptide conjugate comprises: a) a peptide sequence comprising Y (Aib)QGT -(amF)TSDV -(amS)I(amL)LD-KCAA(Aib)-EFIC(amY)-LLEGG-PSSGA-PPPS (SEQ ID NO. 222); and b) a staple attached at a first cysteine and a second cysteine having the following structure:wherein * denotes the attachment to the first and second cysteine of the peptide sequence.Embodiment 66. The peptide conjugate of embodiment 1, wherein the peptide conjugate comprises: a) a peptide sequence comprising Y (Aib)QGT -(amF)TSDY -(amS)I(amL)LD-KCAA(Aib)- EFIC(amY)-LLEGG-PSSGA-PPPS (SEQ ID NO. 225); and b) a staple attached at a first cysteine and a second cysteine having the following structure:WSGR Docket No. 36271-720.601wherein * denotes the attachment to the first and second cysteine of the peptide sequence, wherein the staple is attached at cysteine 17 and cysteine 24.Embodiment 67. The peptide conjugate of embodiment 1, wherein the peptide conjugate comprises: a) a peptide sequence comprising Y (Aib)QGT-(amF)TSDY -SI(amL)LD-K(KAc)AQ(Aib)-CFIE(amY)-LICGG-PSSGA-PPPS (SEQ ID NO. 296); and b) a staple attached at a first cysteine and a second cysteine having the following structure:wherein * denotes the attachment to the first and second cysteine of the peptide sequence, wherein the staple is attached at cysteine 21 and cysteine 28.Embodiment 68. A peptide conjugate having the structure of any one of Peptide Conjugate Nos. 2-182.Embodiment 69. A pharmaceutical composition comprising the peptide conjugate of any one of embodiments 1-68, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.Embodiment 70. A method for treating a disease or condition in a subject in need thereof, selected from the group consisting of diabetes mellitus, obesity, chronic weight management, metabolic dysfunction-associated steatohepatitis, dyslipidemia, metabolic syndrome, chronic kidney disease, osteoarthritis, obstructive sleep apnea, polycystic ovary syndrome, Alzheimer’s disease, and inflammatory diseases, the method comprising administering to the subject a composition comprising a therapeutically effective amount of the peptide conjugate of any one of embodiments 1-68 or the pharmaceutical composition of embodiment 69.Embodiment 71 . The method of embodiment 70, wherein the disease or condition is diabetes or obesity.Embodiment 72. The method of embodiment 70, 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.WSGR Docket No. 36271-720.601Embodiment 73. The method of embodiment 70, wherein the disease or condition is non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), dyslipidemia, metabolic syndrome, or metabolic dysfunction-associated steatohepatitis (MASH).Embodiment 74. The method of embodiment 70, wherein the disease or condition is a neurodegenerative disease.Embodiment 75. The method of embodiment 74, wherein the neurodegenerative disease is Alzheimer’s disease, Parkinson’s disease, or Huntington’s disease.Embodiment 76. The method of any one of embodiments 70-75, the method further comprising administering to the subject one or more additional therapeutic agents.Embodiment 77. A peptide conjugate comprising (a) a peptide and (b) a staple, wherein the staple is conjugated to the peptide at a first amino acid and a second amino acid of the peptide, wherein: (a) the peptide comprises the amino acid sequence: X1-X2-X3-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23- X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41-R42, (SEQ ID NO. 160 or 161), wherein:XIis Tyr or CF3CH2-Tyr;X2is Aib, Gly, Ala, or D-Ser;X3is Gin or His;X6is Phe, aMe-Phe, aMe-Phe2F, aMe-Phe2F6F, Phe2F, or Phe2Br;X10is Tyr, Vai, Leu, CpA, Trp, Glu, Phe, or Cys;XI Iis Ser or aMe-Ser;X13is Tyr, aMe-Leu, Ac6c, aMe-Phe, Iva, or Cys;X15is Asp or Glu;X16is Lys, Lys(Ac), or Om;X17is Cys or Lys(Ac), or He;X19is Ala, Gin, or Hgl;X20is Aib, Cys, or Gin;X21is Ala, Glu, Cys, or Tie;X23is He, Vai, or Tie;X24is Cys or Glu;X25is Trp, Tyr, aMe-Trp, Trp2Me, or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;X28is Glu, Hgl, Cys, Ser, or Ala;X29is Gly or Ala;WSGR Docket No. 36271-720.601X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys; andX40is Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, Gly, or absent;X41is Ser or absent;R42is -OH or -NH2; and(b) the staple has one of the following structures:WSGR Docket No. 36271-720.601or a pharmaceutically acceptable salt thereof, wherein: is 0 or 1; m and mi are each independently 1-4; m2 is 6-20; and each * denotes the attachment point to the peptide.Embodiment 78. The peptide conjugate of embodiment 77, wherein the staple has the following structure:or a pharmaceutically acceptable salt thereof, wherein: is 0 or 1; mi is 1-4; m2 is 6-20; and each * denotes the attachment point to the peptide.Embodiment 79. The peptide conjugate of embodiment 77, wherein the staple has the following structure:or a pharmaceutically acceptable salt thereof, wherein each * denotes the attachment point to the peptide.Embodiment 80. The peptide conjugate of embodiment 77, wherein the peptide is selected from Peptide No. 2-159 (SEQ ID NO. 2-159).Embodiment 81 . The peptide conjugate of embodiment 77, wherein the peptide is selected from Peptide No. 202-357 (SEQ ID NO. 202-357).WSGR Docket No. 36271-720.601Embodiment 82. The peptide conjugate of embodiment 77, having the structure of any one of Peptide Conjugate Nos. 2-182.Embodiment 83. The peptide conjugate of embodiment 77, wherein X1is CF3CH2-Tyr.Embodiment 84. The peptide conjugate of embodiment 77 or 83, wherein X2is Aib.Embodiment 85. The peptide conjugate of embodiment 77, 83, or 84, wherein X6is Phe2F.Embodiment 86. The peptide conjugate of any one of embodiments 77, or 83-85, wherein X16is Om.Embodiment 87. The peptide conjugate of any one of embodiments 77, or 83-86, wherein X33is Lys.Embodiment 88. The peptide conjugate of any one of embodiments 77, or 83-87, wherein X40is Gly.Embodiment 89. The peptide conjugate of any one of embodiments 77, or 83-88, wherein X41is Ser.Embodiment 90. The peptide conjugate of any one of embodiments 77, or 83-89, wherein X40is Gly andX41is Ser.Embodiment 91 . The peptide conjugate of any one of embodiments 77, or 83-90, wherein:X1is CF3CH2-Tyr;X6is Phe2F;X16is Om;X33is Lys;X40is Gly; and / orX41is Ser.Embodiment 92. The peptide conjugate of embodiment 77, wherein the peptide is F3Et-Y(Aib)QGT- (F2F)TSDY-SI(amL)LD-(Om)CAQ(Aib)-AFICY-LLEGG-PSKGA-PPPSG-S (SEQ ID NO. 149).Embodiment 93. The peptide conjugate of embodiment 77, wherein the peptide is F3Et-Y(Aib)QGT- (F2F)TSDY-SI(amL)LD-(Om)C*AQ(Aib)-AFIC*Y-LLEGG-PSKGA-PPPSG-S-NH2(SEQ ID NO. 349), wherein C* indicates a bond between a sulfur atom of a cysteine of the peptide and the staple, and -NH2represents a carboxamide at the C-terminus of the peptide.Embodiment 94. The peptide conjugate of any one of embodiments 77, or 83-93, having the structure of peptide conjugate 174:WSGR Docket No. 36271-720.601or a pharmaceutically acceptable salt thereof, wherein C* is a cysteine bonded to the staple.Embodiment 95. A pharmaceutical composition comprising the peptide conjugate of any one of embodiments 77-94, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.Embodiment 96. 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 embodiments 77-94 or the pharmaceutical composition of embodiment 95.Embodiment 97. A peptide comprising the amino acid sequence:X1-X2-X3-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe- X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41-R42, wherein:XIis Tyr or CFT FE-Tyr:X2is Aib, Gly, Ala, or D-Ser;X3is Gin or His;X6is Phe, aMe-Phe, aMe-Phe2F, aMe-Phe2F6F, Phe2F, or Phe2Br;X10is Tyr, Vai, Leu, CpA, Trp, Glu, Phe, or Cys;XI Iis Ser or aMe-Ser;X13is Tyr, aMe-Leu, Ac6c, aMe-Phe, Iva, or Cys;X15is Asp or Glu;X16is Lys, Lys(Ac), or Om;X17is Cys or Lys(Ac), or He;X19is Ala, Gin, or Hgl;X20is Aib, Cys, or Gin;X21is Ala, Glu, Cys, or Tie;X23is He, Vai, or Tie;X24is Cys or Glu;X25is Trp, Tyr, aMe-Trp, Trp2Me, or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;X28is Glu, Hgl, Cys, Ser, or Ala;WSGR Docket No. 36271-720.601X29is Gly or Ala;X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys; andX40is Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, Gly, or absent;X41is Ser or absent;R42is -OH or -NH2.Embodiment 98. The peptide of embodiment 97, wherein X1is CF3CH2-Tyr.Embodiment 99. The peptide of embodiment 97 or 98, wherein X2is Aib.Embodiment 100. The peptide of any one of embodiments 97-99, wherein X6is Phe2F.Embodiment 101. The peptide of any one of embodiments 97-100, wherein X16is Om.Embodiment 102. The peptide of any one of embodiments 97-101, wherein X33is Lys.Embodiment 103. The peptide of any one of embodiments 97-102, wherein X40is Gly and X41is Ser.Embodiment 104. The peptide of any one of embodiments 97-103, wherein:X1is CF3CH2-Tyr;X6is Phe2F;X16is Om;X33is Lys;X40is Gly; and / orX41is Ser.Embodiment 105. A peptide comprising a sequence at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NO. 2-159.Embodiment 106. The peptide of embodiment 105, comprising a sequence at least about 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO. 149.Embodiment 107. The peptide of any one of embodiments 95-106, wherein the peptide has the amino acid sequence F3Et-Y(Aib)QGT-(F2F)TSDY-SI(amL)LD-(Om)CAQ(Aib)-AFICY-LLEGG- PSKGA-PPPSG-S (SEQ ID NO. 149) wherein the C-terminus of SEQ ID NO. 149 is optionally amidated to form -CONH2.Embodiment 108. A pharmaceutical composition comprising the peptide of any one of embodiments 95- 107, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.Embodiment 109. A compound having a structure of one of the following formulae:WSGR Docket No. 36271-720.601wherein: ni is 0 or 1; mi is 1-4; and m2 is 6-20.Embodiment 110. The compound of embodiment 109, having a structure of the following formula:wherein, mi is 1-4; and m2 is 6-20.Embodiment 111. The compound of any one of embodiments 109 -110, wherein ml is 2, 3, or 4.Embodiment 112. The compound of any one of embodiments 109 -111, wherein ml is 3.Embodiment 113. The compound of any one of embodiments 109 -112, wherein m2 is 12-20.Embodiment 114. The compound of any one of embodiments 109 -113, wherein m2 is 13, 15, 17, or 19.Embodiment 115. The compound of any one of embodiments 109 -114, having the structure:Embodiment 116. The compound of any one of embodiments 109 -115, for use in the manufacture of a medicament.WSGR Docket No. 36271-720.601Embodiment 117. A process for preparing a peptide conjugate comprising:(i) combining in a liquid solvent medium(a) the compound of any one of embodiments 109-115,(b) the peptide of any one of embodiments 95-107, and(c) a base; and(ii) reacting, optionally comprising stirring and / or heating or cooling, for a period of at least 5 minutes and less than about 5 hours (e.g., about 1-2 hours); and(iii) optionally quenching step (ii) by addition of a sufficient amount of acid to lower the pH below 7; and(iv) optionally purifying the peptide conjugate (e.g., via HPLC).Embodiment 118. The process of embodiment 117, wherein the compound is the compound of embodiment 115.Embodiment 119. The process of embodiment 117 or 118, wherein the peptide is the peptide of embodiment 107.Embodiment 120. The peptide conjugate of any one of embodiments 1-68, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 69, for use in treating (or for use in the manufacture of a medicament for treating) a disease or condition selected from the group consisting of diabetes mellitus, obesity, chronic weight management, metabolic dysfunction-associated steatohepatitis, dyslipidemia, metabolic syndrome, chronic kidney disease, osteoarthritis, obstructive sleep apnea, polycystic ovary syndrome, Alzheimer’s disease, and inflammatory diseases.Embodiment 121. The peptide conjugate of any one of embodiments 1-68, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 69, for use in treating (or for use in the manufacture of a medicament for treating) a disease or condition selected from the group consisting of obesity, Type 1 diabetes mellitus, Type 2 diabetes mellitus, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), dyslipidemia, metabolic syndrome, and metabolic dysfunction-associated steatohepatitis (MASH),.Embodiment 122. Use of the peptide conjugate of any one of embodiments 1-68, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 69, for treating (or for the manufacture of a medicament for treating) a disease or condition selected from the group consisting of diabetes mellitus, obesity, chronic weight management, metabolic dysfunction- associated steatohepatitis, dyslipidemia, metabolic syndrome, chronic kidney disease, osteoarthritis, obstructive sleep apnea, polycystic ovary syndrome, Alzheimer’s disease, and inflammatory diseases.WSGR Docket No. 36271-720.601Embodiment 123. Use of the peptide conjugate of any one of embodiments 1 -68, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 69, for treating (or for the manufacture of a medicament for treating) a disease or condition selected from the group consisting of obesity, Type 1 diabetes mellitus, Type 2 diabetes mellitus, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), dyslipidemia, metabolic syndrome, and metabolic dysfunction -associated steatohepatitis (MASH).

Claims

1. WSGR Docket No. 36271-720.601CLAIMSWhat is claimed is:

1. A peptide conjugate comprising: a) a peptide comprising the sequence:X1-X2-X3-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41(-NH2) (SEQ ID NO. 160 or 161), wherein:XIis Tyr or CFX IL-Tyr:X2is Aib, Gly, Ala, or D-Ser;X3is Gin or His;X6is Phe, aMe-Phe, aMe-Phe2F, aMe-Phe2F6F, Phe2F, or Phe2Br;X10is Tyr, Vai, Leu, CpA, Trp, Glu, Phe, or Cys;XI Iis Ser or aMe-Ser;X13is Tyr, aMe-Leu, Ac6c, aMe-Phe, Iva, or Cys;X15is Asp or Glu;X16is Lys, Lys(Ac), or Om;X17is Cys or Lys(Ac), or He;X19is Ala, Gin, or Hgl;X20is Aib, Cys, or Gin;X21is Ala, Glu, Cys, or Tie;X23is He, Vai, or Tie;X24is Cys or Glu;X25is Trp, Tyr, aMe-Trp, Trp2Me, or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;X28is Glu, Hgl, Cys, Ser, or Ala;X29is Gly or Ala;X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys; andX40is Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, Gly or absent;X41is Ser or absent; wherein the C-terminus of the peptide is -COOH or -CONH2; and b) a staple attached to the peptide at a first amino acid and a second amino acid; wherein the first amino acid has a position i in the peptide and the second amino acid has a position i + n in the peptide, wherein n is 4-11, and wherein the staple is of Formula (II):WSGR Docket No. 36271-720.601Formula (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 atached to the first amino acid of the peptide, XBis attached to the second amino acid of the peptide, and XAand XBare identical;R is hydrogen or -(L)s-Y ; each L is independently -(CR’R2)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, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, Cs-Cs cycloalkyl, C2-Cs 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd; or R1and R2are taken together to form a Ci-Ce cycloalkyl or Ci-Ce heterocycloalkyl; each R3is independently hydrogen, -S(=O)Rb, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Rb, -CO2Ra, - C(=O)NRcRd, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, G-G cycloalkyl, C2- 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORa, or -NRcRd;Y is hydrogen, Ci-C6alkyl, -CO2H, -P(=O)(OH)2, -CO2(Ci-C6alkyl), -CO2NH2, -CO2N(alkyl)2, - CO2NH(alkyl), or 5 -membered heteroaryl; s is 0-20;Rais hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce heteroalkyl, G-G cycloalkyl, G-G 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;WSGR Docket No. 36271-720.601 and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2;Rbis Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Cs-Cs 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or -NH2; and each Rcand Rdis independently hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce heteroalkyl, Cs-Cs 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, Ci-Ce alkyl, Ci-Ce 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, Ci-Ce alkyl, Ci-Ce haloalkyl, -OH, -OMe, or - NH2.

2. The peptide conjugate of claim 1, wherein the peptide comprises a sequence:X1-Aib-Gln-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe- X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41(-NH2) (SEQ ID NO. 162 or SEQ ID NO. 163) wherein:XIis Tyr or CF CTE-Tyr:X6is Phe, aMe-Phe, or Phe2F;X10is Tyr, Vai, Trp, or Cys;XI Iis Ser or aMe-Ser;X13is Tyr, aMe-Leu, aMe-Phe, Iva, or Cys;X15is Asp or Glu;X16is Lys, Lys(Ac), or Om;X17is Cys or He;X19is Ala or Gin;X20is Aib, Cys, or Gin;X21is Ala, Glu, or Cys;X23is He or Vai;X24is Cys or Glu;X25is Trp, Tyr, or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;WSGR Docket No. 36271-720.601X28is Glu, Hgl, Cys, or Ala;X29is Gly;X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys;X40is Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, Gly, or absent; and X41is Ser or absent.

3. The peptide conjugate of claim 1, wherein X33is Lys.

4. The peptide conjugate of claim 1, wherein X16is Om.

5. The peptide conjugate of claim 1, wherein X6is Phe2F.

6. The peptide conjugate of claim 1, wherein X1is CFsCFL-Tyr.

7. The peptide conjugate of claim 1, wherein X40is Gly and X41is Ser.

8. The peptide conjugate of claim 1, wherein:X1is CF3CH2-Tyr;X6is Phe2F;X16is Om;X33is Lys;X40is Gly; andX41is Ser.

9. The peptide conjugate of claim 1, wherein the peptide comprises any one of SEQ ID NOs. 202 to 357.

10. The peptide conjugate of claim 1, wherein the peptide comprises the sequence: F3EtY (Aib)QGT- (F2F)TSDY-SI(amL)LD-(Om)C*AQ(Aib)-AFIC*Y-LLEGG-PSKGA-PPPSGS-NH2 (SEQ ID NO. 349).11 . The peptide conjugate of claim 1, wherein the peptide is a GLP-1 receptor, GIP receptor, and GCG receptor triple agonist.

12. The peptide conjugate of claim 1, wherein: the first amino acid and the second amino acid are each cysteine;XAand XBare -alkylene-C(=O)NR3-alkylene- or -alkylene-NR3C(=O)-alkylene-;WSGR Docket No. 36271-720.601 each L is independently -(CR1R2)I-2O-, -alkylene-O-, -C(=0)-, -C(=O)NR3-, -NR3C(=O)-, - alkylene-C(=O)NR3-, or -alkylene-NR3C(=O)-; andY is -P(=O)(OH)2, -CO2H, or 5 -membered heteroaryl.

13. The peptide conjugate of claim 1, wherein the staple has one of the following structures:or a pharmaceutically acceptable salt thereof, wherein: is 0 or 1; n2and mi are each independently 1-4; m2 is 6-20;R1is hydrogen, -OH, or -P(=O)(OH)2; and each * denotes the attachment point to the peptide.

14. The peptide conjugate of claim 1, wherein the staple is:WSGR Docket No. 36271-720.601WSGR Docket No. 36271-720.601wherein each * denotes the attachment point to the peptide .

15. The peptide conjugate of claim 1, wherein the staple is:or a pharmaceutically acceptable salt thereof, wherein: is 0 or 1; mi is 1-4; m2is 6-20;R1is hydrogen, -OH, or -P(=O)(OH)2; and each * denotes the attachment point to the peptide.

16. The peptide conjugate of claim 1, wherein the staple is:wherein each * denotes the attachment point to the peptide.

17. The peptide conjugate of claim 1, wherein: the peptide comprises the sequence F3EtY(Aib)QGT-(F2F)TSDY-SI(amL)LD-(Om)C*AQ(Aib)- AFIC*Y-LLEGG-PSKGA-PPPSGS-NH2 (SEQ ID NO. 349), and wherein the staple is:WSGR Docket No. 36271-720.601 the peptide comprises the sequence Y(Aib)QGT-FTSDY-SI(amL)LD-KCAQ(Aib)-AFICY-LLEGG-PSSGA-PPPS (SEQ ID NO. 202), and wherein the staple is:the peptide comprises the sequence Y(Aib)QGT-(amF)TSDV-(amS)I(amL)LD-KCAA(Aib)-EFIC(amY)-LLEGG-PSSGA-PPPS (SEQ ID NO. 222); and wherein the staple is:the peptide comprises the sequence: Y(Aib)QGT-(amF)TSDY-(amS)I(amL)LD-KCAA(Aib)-EFIC(amY)-LLEGG-PSSGA-PPPS (SEQ ID NO. 225); and wherein the staple isthe peptide comprises the sequence: Y(Aib)QGT-(amF)TSDY-SI(amL)LD-K(KAc)AQ(Aib)-C*FIE(amY)-LIC*GG-PSSGA-PPPS-NH2 (SEQ ID NO. 296); and wherein the staple iswherein each * denotes a covalent bond between the staple and the peptide.

18. A peptide conjugate having the structure of any one of Peptide Conjugate Nos. 2-182.

19. The peptide conjugate of claim 18, having the structure of Peptide Conjugate No. 174:WSGR Docket No. 36271-720.601or a pharmaceutically acceptable salt thereof, wherein each C* is a cysteine bonded to the staple.

20. A pharmaceutical composition comprising the peptide conjugate of any one of claims 1 -19, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.21 . A method for treating a disease or condition in a subject in need thereof, selected from the group consisting of diabetes mellitus, obesity, chronic weight management, metabolic dysfunction- associated steatohepatitis, dyslipidemia, metabolic syndrome, chronic kidney disease, osteoarthritis, obstructive sleep apnea, polycystic ovary syndrome, Alzheimer’s disease, and inflammatory diseases, the method comprising administering to the subject a composition comprising a therapeutically effective amount of the peptide conjugate of any one of claims 1-19, or the pharmaceutical composition of claim 20.

22. A peptide comprising the amino acid sequence:X1-X2-X3-Gly-Thr-X6-Thr-Ser-Asp-X10-X11-Ile-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe- X23-X24-X25-X26-X27-X28-X29-Gly-Pro-Ser-X33-Gly-Ala-Pro-Pro-Pro-X39-X40-X41-R42, (SEQ ID NO. 160 or 161), wherein:XIis Tyr or CFT FE-Tyr:X2is Aib, Gly, Ala, or D-Ser;X3is Gin or His;X6is Phe, aMe-Phe, aMe-Phe2F, aMe-Phe2F6F, Phe2F, or Phe2Br;X10is Tyr, Vai, Leu, CpA, Trp, Glu, Phe, or Cys;XI Iis Ser or aMe-Ser;X13is Tyr, aMe-Leu, Ac6c, aMe-Phe, Iva, or Cys;X15is Asp or Glu;X16is Lys, Lys(Ac), or Om;X17is Cys or Lys(Ac), or He;X19is Ala, Gin, or Hgl;X20is Aib, Cys, or Gin;X21is Ala, Glu, Cys, or Tie;X23is He, Vai, or Tie;X24is Cys or Glu;WSGR Docket No. 36271-720.601X25is Trp, Tyr, aMe-Trp, Trp2Me, or aMe-Tyr;X26is Leu or Vai;X27is He or Leu;X28is Glu, Hgl, Cys, Ser, or Ala;X29is Gly or Ala;X33is Ser, Lys, or aMe-Lys;X39is Ser or Lys; andX40is Lys, D-Lys, Om, D-Om, Dab, D-Dab, Dap, D-Dap, Gly, or absent;X41is Ser or absent;R42is -OH or -NH2.

23. The peptide of claim 22, comprising one of SEQ ID NO. 2-159, or a peptide that is at least 90% identical to one of SEQ ID NO. 2-159.

24. The peptide of claim 22, wherein:X1is CF3CH2-Tyr;X6is Phe2F;X16is Om;X33is Lys;X40is Gly; andX41is Ser.

25. The peptide of claim 22, comprising the sequence: F3EtY(Aib)QGT-(F2F)TSDY-SI(amL)LD- (Om)CAQ(Aib)-AFICY-LLEGG-PSKGA-PPPSG-S (SEQ ID NO. 149).

26. A compound of the following formula:wherein: ni is 0 or 1; mi is 1-4; and m2is 6-20.The compound of claim 26, having the structure:WSGR Docket No. 36271-720.60128. A process for preparing a peptide conjugate comprising :(i) combining in a liquid solvent medium a peptide, a compound, and a base, thereby creating a reaction mixture, wherein: the peptide comprises any one of SEQ ID NO. 2-159; and the compound is:or a pharmaceutically acceptable salt thereof, wherein: ni is 0 or 1; n2and mi are each independently 1-4; m2is 6-20; andR1is hydrogen, -OH, or -P(=O)(OH)2;(ii) reacting the reaction mixture for at least 5 minutes and less than about 5 hours; and(iii) quenching step (ii) by addition of an acid, thereby acidifying the reaction mixture; and(iv) isolating the peptide conjugate from the reaction mixture.

29. The process of claim 28, wherein the peptide comprises SEQ ID NO. 149.WSGR Docket No. 36271-720.60130. The process of claim 28, wherein the compound isor a salt thereof.

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