Mono- and dual-agonist compounds of human GLP1r and GIPR for obesity & t2dm

Abstract

The present disclosure relates to peptide compounds which are mono- or dual-agonists of the human glucagon-like peptide- 1 (GLP-1) receptor (GLP1R) and the human glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR). The invention also relates to peptide compounds that are suitable for oral administration. Thes peptide compounds of the invention may be useful in the treatment of type 2 diabetes mellitus (T2DM) and obesity.

Description

MONO- AND DUAL-AGONIST COMPOUNDS OF HUMAN GLP1R AND GIPRFOR OBESITY & T2DMCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 637,800, filed April 23, 2024, U.S. Provisional Application No. 63 / 669,141, filed July 9, 2024, U.S.Provisional Application No. 63 / 688,796, filed August 29, 2024, U.S. Provisional Application No. 63 / 693,960, filed September 12, 2024, U.S. Provisional Application No. 63 / 708,614, filed October 17, 2024, U.S. Provisional Application No. 63 / 743,497, filed January 9, 2025, and U.S. Provisional Application No. 63 / 760,276, filed February 19, 2025, the contents of which are hereby incorporated by reference in their entireties for all purposes.STATEMENT REGARDING SEQUENCE LISTING

[0002] The Sequence Listing XML associated with this application is provided in XML file format and is hereby incorporated by reference into the specification. The name of the XML file containing the Sequence Listing XML is PRTH_101_07WO_ST26.xml. The XML file is 745,748 bytes, and created on March 28, 2025, and is being submitted electronically via USPTO Patent Center.FIELD OF THE INVENTION

[0003] The present disclosure relates to peptide compounds which are mono- or dual agonists of the human glucagon-like peptide-1 (GLP-1) receptor (GLP1R) and / or the human glucosedependent insulinotropic polypeptide (GIP) receptor (GIPR). The invention also relates to peptide compounds that are suitable for oral administration. The peptide compounds of the invention may be useful in the treatment of type 2 diabetes mellitus (T2DM) and obesity.BACKGROUND

[0004] Obesity is associated with a number of medical conditions / comorbidities, including insulin resistance, glucose intolerance, diabetes mellitus, nonalcoholic fatty liver disease (NAFLD, hypertension, dyslipidemia, sleep apnea, arthritis, hyperuricemia, gall bladder disease, certain types of cancer, heart and coronary artery disease, and stroke. There are numerous drugs used as weight-reducing agents. The regimens recognized by the United States Food and Drug Administration (FDA) for prolonged use fornonsyndromic obesity are orlistat, phentermine-topiramate, naltrexone-bupropion, liraglutide, and semaglutide.

[0005] GLP-1 is an incretin hormone secreted from L cells located in the small intestine in response to food intake. GLP-1 infusion in humans results in reduced calorie intake and reduced appetite. GLP-1 RAs (Receptor Agonists) have been developed initially for the treatment of T2D, but because of their efficacy for weight loss and reducing appetite, they are prescribed at higher doses as treatments for obesity.

[0006] In 2014, liraglutide became the first GLP1R agonist to be approved for the treatment of obesity, at approximately twice the highest dose used in its treatment of T2D. Clinical studies showed that after 1 year of treatment, subjects had a mean decrease of 8% of body weight. In 2021, the GLPR1R agonist semaglutide gained regulatory approval for obesity, and clinical studies showed that subjects had improved weight loss as compared to liraglutide. Oral semaglutide (oral formulation of semaglutide) was approved in 2019 for T2D. Oral semaglutide for obesity is in Phase 3 clinical trials.

[0007] In 2022, tirzepatide, a dual co-agonist acting on GLP-1R and GIPR, was approved for T2D, and in 2023, the FDA approved its use for obesity. GIP is the natural ligand for GIPR, and GIP is also an incretin hormone peptide secreted by K cells in the duodenum and jejunum. In comparison with semaglutide, tirzepatide was shown to improve weight loss.

[0008] There remains a need for improved peptide compounds that are agonists of GLP1R and / or GIPR, which are as potent or more potent than semaglutide or tirzepatide and / or are suitable for oral administration.SUMMARY OF THE INVENTION

[0009] The present disclosure provides peptide compounds that are that are mono-agonists of GLP1R or GIPR or dual-agonists of both GLP1R and GIPR. In some aspects, the peptide compounds of the invention have nanomolar or sub-nanomolar potency for GLP1R, GIPR, or for both GLP1R and GIPR (i.e., EC50 in a HEK293 cAMP assay). In additional aspects, the peptide compounds have sub-nanomolar potencies for GLP1R, GIPR, or both GLP1R and GIPR, as well as having stability in simulated gastric fluid (SGF) and / or simulated intestinal fluid (SIF) assays (i.e., T1 / 2 of the non-degraded peptide in these assays).

[0010] In one aspect, the invention provides peptides that are at least agonists of humanGLP1R, wherein the peptide comprises or consist of a sequence according to Formula (I): R^xi-x -xs-xd-xs-xe-x -xs-X -xio-xi i-xn-xis-xid-xis-xie-xn-xis-xi - X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2is NH2, OH, Palm, or absent;XI is 2Me3ImidazolePA, 2Pal, 3Pal, 4Pal, aMe His, aOH Imidazole PropanoicAcid, Asn, Cit, dH, hHis, His, His lMe, His_3Me, His Bzl, Imidazole Propanoic Acid, Lys Dimethyl, Lys_Me3, NMe His, Om, Phe, Pyrrole PA, Quin_3, or Tyr;X2 is Aib, Ala, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe_Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Cys, dHcy, Gly, Hey, Hhc, Iva, Pen, HhPen, or Vai;X3 is aMe Glu, Asp, Cysteate, Glu, Gia, Gin, He, Leu, Tetl, or Tet2;X4 is Ala, Aib, Asn, Gly, Lys, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Glu, Hey, Hhc, HhPen, He, Leu, Lys, NMe_K, 03 S, 03 S Reduced, Pen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 40H_Val, Asn, Asp, Dap, Diaminobutanoic Acid, Ser, Thr, Thr Ac, Thr Me, TThioamide, or Vai;X8 is Aad, Ala, Abu, aMe_Ser, Asp, Dap, dS, Fur, Gin, Gly, hSer, Ser, Ser_Bz, orS Thioamide;X9 is Aad, aMe_Asp, aMe_Glu, Api, Arg, Asp, Asp_OMe, bE, bMeAsp, Cysteate, dD, diMe Asp, Gia, Glu, Hhc, Lys, Lys_PEG2_IsoGlu_Palm, NMe_E, 03 S, O3S_Reduced, Tetl, Tet2, or Tyr;X10: aMeBip2pMe4pOMe, Bip_2pEt4pOC2N, Bip_2pEt4pOC2NC2N,Bip_2pEt4pOC2NDMGN2aeC4, Bip_2pEt4pOC2NDMGN2aeC8,Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm, Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_Dap_MeOPheTag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm,Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheT ag,Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N,Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_C4,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2,Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag,Bip_2pEt4pOC4N_Arg, Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N,Bip_2pEt4pOC4N_ C0C8N,Bip_2pEt4pOC4N_Dap_lPEG2_lPEG2_C18_diacid,_Bip_2pEt4pOC4N_Dap_Albutag,Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_Dap_Palm,Bip_2pEt4pOC4N_DMG_N_2ae_C 18_diacid, Bip_2pEt4pOC4N_DMG_N_2ae_LysAc,Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC4N_MeOPheT ag,Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOC4N_PEG4_NHAc,Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc,Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4N_PEGl 6_NHAc,Bip_2pEt4pOC4N2DMGN2ae, Bip_2pEt4pOC4NDMGN2ae,Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NLys,Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOC4NMe3,_Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, NMeBip2pMe4pOMe, or Tyr;XI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl,34Dimethyoxyphenyl, 35_DiemthylPhenyl, 3choloro4fluorophenyl, 3 chlorophenyl,3 Methoxy phenyl, aMe Ser, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me,Hph, Phe, Phe_2Ad, Pyridin3yl, Quinolin_5_yl, Ser, Thr, Tyr, or Vai;X12 is Gly or absent;XI 3 is Glu, Gly, or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Val or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent;(Formula (I)).

[0011] In one aspect, a peptide of Formula (I) comprises a cyclic structure wherein: (i) X2 and X5 are individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen, which are directly covalently linked or indirectly covalently linked through a cyclization linker, or (ii) X5 is Lys and X13 is Glu which are directly covalently linked through an amide bond (i.e., a cyclic amide, or lactam bond).

[0012] In other aspects for Formula (I) peptides, regarding the residue options for X2 andX5:• If X2 and X5 are not cross-linked (i.e., not cyclized), then in one aspect, X2 is Aib, Ala, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe-Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Gly, or Iva; and X5 is Asn, Asp, Gin, Glu, He, Leu, Lys, NMe_K, 03 S, O3S_Reduced, Thr, or Vai;• If X2 and X5 are directly cross-linked, the cross-link comprises a disulfide bond that was formed between a free thiol group in the side-chains of the two residues (individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen). In some aspects, dCys, dHcy, dHhc, dPen, or dHhPen can be used at X2 and / or X5.• If the intramolecular cross-link between X2 and X5 is indirect (mediated by a cyclization linker) between the side-chains of the two residues, then the two crosslinked residues at X2-X5 are individually or both: Cys, dHcy, Hey, Hhc, Pen, or HhPen; and the cyclization linker is: a Butane Linker, a Carbonyl Linker, a Dimethylcyclopropane Linker, aa Ebutene Linker, a Hexane Linker, an Oxetane Linker a Pentane Linker, a Propane Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker. The free thiol group at X2 and at X5 each forms a thioether bond with a free alkyl moiety of one of these cyclization linkers.

[0013] In another aspect of Formula (I), the peptide comprises an intramolecular cross-link between X5 and X9, wherein the two cross-linked residues are connected by a lactam bond.In one aspect, X5 is Lys or NMe_Lys and X9 is Glu or NMe_Glu. In another aspect, X5 is Glu or NMe_Glu and X9 is Lys or NMe_Lys.

[0014] In one aspect of Formula (I), R1is acetyl and R2is amine.

[0015] In one aspect of Formula (I), R1is absent and R2is amine.

[0016] In another aspect of Formula (I), XI is 2Me3ImidazolePA, aMe His, Asn, Cit, dH, His, Imidazole Propanoic Acid, Phe, or Tyr.

[0017] In another aspect of Formula (I), X2 is Aib, Ala, aMe Pro, Gly, Iva, or Vai.

[0018] In another aspect of Formula (I), X3 is Glu or Tetl.

[0019] In another aspect of Formula (I), X4 is Gly.

[0020] In another aspect of Formula (I), X5 is Thr.

[0021] In another aspect of Formula (I), X6 is aMe_2F_Phe or aMe_Phe_2F.

[0022] In another aspect of Formula (I), X7 is 4OH_Val, Ser, or Thr.

[0023] In another aspect of Formula (I), X8 is aMe Ser or Ser.

[0024] In another aspect of Formula (I), X9 is aMe Asp, aMe Glu, Asp, Hhc, or O3S.

[0025] In another aspect of Formula (I), X10 is Bip_2pEt4pOC2N, Bip_2pEt4pOC2NC2N,Bip_2pEt4pOC2NDMGN2aeC4, Bip_2pEt4pOC2NDMGN2aeC8,Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm,Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_IsoGlu_Palm,Bip_2pEt4pOC2N_Dap_Albutag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm,_Bip_2pEt4pOC2N IsoGlu Palm, Bip_2pEt4pOC2N_MeOPheTag,Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_C4,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2,Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag,Bip_2pEt4pOC4N_Arg. Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N,Bip_2pEt4pOC4N_ COC8N, Bip_2pEt4pOC4N_Dap_lPEG2_lPEG2_C 18_diacid,Bip_2pEt4pOC4N Dap Albutag, Bip_2pEt4pOC4N Dap Palm,Bip_2pEt4pOC4N_DMG_N_2ae_C 18_diacid, Bip_2pEt4pOC4N_DMG_N_2ae_Ly sAc,Bip_2pEt4pOC4N_MeOPheTag, Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOC4N_PEG4_NHAc, Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc, Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4N_PEGl 6_NHAc,Bip_2pEt4pOC2NDMGN2aeC 12,_Bip_2pEt4pOC4N2DMGN2ae,Bip_2pEt4pOC4NDMGN2ae, Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOC4NMe3, Bip_2pMe4pOMe, or Bip_2pEt4pOMe.

[0026] In another aspect of Formula (I), XI 1 is 2Chlorophenyl,3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphneyl, 3 chlorophenyl,3 Methoxy phenyl, Bip_2pMe, Bip24_Me, hhPhe_35Me, Hph, Ser, Thr, Tyr, or Vai.

[0027] In another aspect of Formula (I), X12 is absent (and there are no additional residues C-terminal to XI 1.

[0028] In another aspect of Formula (I), X12 through X26 are absent.

[0029] In another aspect of Formula (I), the peptide further comprises or consists of the following residues connected to and following (C-terminal to) X12 and preceding R2: Gly- Glu-Ala-Ser-Glu-Leu-Ser-Thr-Ala-Ala-Leu-Gly-Arg-Leu-Ser-Ala-Glu-Leu-His-Glu-Leu- Ala-Thr-Leu-Pro-Arg-Thr-Glu-Thr-Gly-Ser-Gly-Ser-Pro.

[0030] In another aspect of Formula (I), the peptide does not comprise a cyclic structure.

[0031] In another aspect of Formula (I), the peptide comprises a sequence according to any of the sub-formulas of Formula (I), i.e., Formula (I. A) et al., described in the Detailed Description herein.

[0032] In another aspect of Formula (I), the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1 A-1NN peptides with +, ++, +++, or ++++), less than 1 nM (++, +++, ++++), less than 0.100 nM (e.g., +++ or ++++), or less than 0.010 nM (e.g., ++++) in a human GLP1R HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant human GLP1R on their cell surface at high density. Herein, high-density(HD) cell surface receptor expression of human GLP1R is about greater than about 200,000receptors / cell. (See Examples for the cAMP accumulation assay and cell surface receptor density determination).

[0033] In aspects relating to potency and HEK 293 cAMP accumulation assays, EC50 is the measure of the concentration of a peptide of the invention which induces cAMP accumulation halfway between the baseline and maximum in the HEK293 cAMP accumulation assay as described herein (see Examples). It should also be noted that in these aspects, the EC50 can also be referred to as IC50, although EC50 is the more appropriate term as the peptides of the invention are agonists of human GLP1R and / or human GIPR.

[0034] In another aspect of Formula (I), the peptide has an EC50 potency less than 10 micromolar (e.g., see Figs. 1A-1NN peptides with +, ++, +++, or ++++), less than 1 micromolar (e.g., ++, +++, ++++), less than 100 nM (e.g., +++ or ++++), or less than 10 nM (e.g., ++++) in a human GLP1R HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant GLP1R on their cell surface at low density. Herein, low- density (LD) cell surface receptor expression of human GLP1R is about less than 2,000 receptors / cell.

[0035] In Figs. 1 A-1NN, the GLP1R EC50 values, i.e., ++++, +++, ++, or + are based on data from the cAMP accumulation assay using at least one of the hGLPIR HEK293 high- density (HD) or low-density (LD) cell clones described in the Examples.

[0036] In another aspect of Formula (I), the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1 A-1NN, peptides with +, ++, +++, or ++++), less than 1 nM (++, +++, ++++), less than 0.100 nM (+++ or ++++), or less than 0.010 nM (++++) in a human GIPR HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant human GIPR on their cell surface at a density between about 45,000 and 55,000 receptors / cell.

[0037] In another aspect of Formula (I), the peptide has a half-life time of stability greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay or an SIF assay, or in both assays. In a related aspect, a peptide of the invention that has a half-life time of stability greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay or an SIF assay, or in both assays, is suitable for oraladministration / oral formulation. In one aspect, a peptide of the invention that has a half-life time of stability greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay is suitable for oral administration / oral formulation.

[0038] In another aspect of Formula (I), the peptide has a ++++ EC50 potency in a human high density (HD) or low density (LD) GLP1R HEK293 cAMP accumulation assay, and also has a half-life time of stability of greater than 2 hours or 24 hours in both an SGF assay and an SIF assay. As explained herein, a “++++” EC50 potency in a human HD GLP1R HEK293 cAMP assay means that the peptide has an EC50 less than 0.010 nM is said HD assay, and a “++++” EC50 potency in a human LD GLP1R HEK293 cAMP assay means that the peptide has an EC50 less than 10 nM in said LD assay.

[0039] In another aspect, the invention provides peptides that are mono- or dual- agonists of GLP1R and GIPR, wherein the peptide comprises or consist of a sequence according to Formula (I. A):R^xi^-xs-xd-xs-xe-x -xs-xo-xio-xii-xn-XB-XM-xis-xie-xn-xis-xio- X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is Ra-C(O)- or hydrogen, wherein Ra is Cl-20 alkyl or C3-8 cycloalkyl; or R1 is acetyl, isovaleric acid, cyclohexanecarboxylic acid, or absent;R2is NH2 or OH or absent;XI is 2Pal, 3Pal, 4Pal, His, Imidazole Propanoic Acid, NMe His, or Tyr;X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_Ile, aMe_Leu, aMe_Pro, aMe Ser, aMe Val, Cap, Cys, dHcy, Hey, Hhc, Pen, or HhPen;X3 is aMe Glu, Glu, Gia, Gin, or Tetl;X4 is Ala, Aib, Asn, Gly, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Hey, Hhc, Pen, HhPen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Thr or Thr Ac;X8 is Abu, aMe_Ser, hSer, or Ser;X9 is aMe_Asp, aMe_Glu, Asp, Gia, Glu, or Tetl;X10: Bip_2pEt4pOMe, Bip_2pMe4pOMe, or Tyr;XI I is Bip_2pMe, HHPhe_35Me, Hph, or Ser;X12 is Gly or absent;XI 3 is Gly or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Vai or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent; wherein the peptide optionally comprises a cyclic structure wherein X2 and X5 are individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen, which are directly covalently linked or indirectly covalently linked through a cyclization linker.(Formula (I. A).)

[0040] In other aspects for Formula (I. A) peptides, regarding the residue options for X2 andX5: if X2 and X5 are not cross-linked (i.e., not cyclized), then in one aspect, X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_Ile, aMe_Leu, aMe_Pro, aMe_Ser, aMe_Val, or Cap; and X5 is Asn, Asp, Gin, or Thr; or if X2 and X5 are directly cross-linked, the cross-link comprises a disulfide bond that was formed between a free thiol group in the side-chains of the two residues (individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen). In some aspects, dCys, dHcy, dHhc, dPen, or dHhPen can be used at X2 and / or X5.

[0041] In other aspects for Formula (I. A) peptides, regarding the residue options for X2 andX5: if the intramolecular cross-link between X2 and X5 is indirect (mediated by a cyclization linker) between the side-chains of the two residues, then the two cross-linked residues at X2-X5 are individually or both: Cys, dHcy, Hey, Hhc, Pen, or HhPen; and the cyclization linker is: a Carbonyl Linker, a Dimethylcyclopropane Linker, a Ebutene Linker,a Hexane Linker, an Oxetane Linker a Pentane Linker, a Propane Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker. The free thiol group at X2 and at X5 each forms a thioether bond with a free alkyl moiety of one of these cyclization linkers.

[0042] In one aspect of Formula (I. A), R1 is acetyl and R2 is amine.

[0043] In another aspect of Formula (LA), X12 through X26 are absent.

[0044] In another aspect, the invention provides peptides that are at least agonists of human GLP1R, wherein the peptide comprises or consist of a sequence according to Formula (LB): Rkxi^-xs-xd-xs-xe-x -xs-X -xio-xi i-xn-xis-xid-xis-xie-xn-xis-xi - X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2is NH2, OH, Palm, or absent;XI is 2Pal, 3Pal, 4Pal, aMe His, Asn, Cit, dH, His, His lMe, His_3Me, His Bzl, Imidazole Propanoic Acid, Lys Dimethyl, Lys_Me3, NMe His, Om, Quin_3, or Tyr; X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe_Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Cys, dHcy, Hey, Hhc, Iva, Pen, or HhPen;X3 is aMe_Glu, Asp, Cysteate, Glu, Gia, Gin, Tetl, or Tet2;X4 is Ala, Aib, Asn, Gly, Lys, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Glu, Hey, Hhc, HhPen, Lys, Pen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Asn, Asp, Dap, Ser, Thr, Thr Ac, Thr Me, TThioamide, or Vai;X8 is Aad, Ala, Abu, aMe_Ser, Asp, Dap, dS, Fur, Gin, Gly, hSer, Ser, Ser_Bz, or S Thioamide;X9 is Aad, aMe_Asp, aMe_Glu, Api, Arg, Asp, Asp_OMe, bE, bMeAsp, Cysteate, dD, Gia, Glu, Lys, Lys_PEG2_IsoGlu_Palm, Tetl, Tet2, or Tyr;X10: aMeBip2pMe4pOMe, Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, NMeBip2pMe4pOMe, or Tyr;XI I is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, aMe_Ser, Bip_2pMe, Bip24_Me, HHPhe_35Me, Hph, Phe, Phe_2Ad, or Ser;X12 is Gly or absent;XI 3 is Glu, Gly, or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Vai or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent; wherein the peptide optionally comprises a cyclic structure wherein: (i) X2 and X5 are individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen, which are directly covalently linked or indirectly covalently linked through a cyclization linker, or (ii) X5 is Lys and XI 3 is Glu which are directly covalently linked through an amide bond (i.e., a cyclic amide, or lactam bond).(Formula (I.B)

[0045] In other aspects for Formula (I.B) peptides, regarding the residue options for X2 andX5: if X2 and X5 are not cross-linked (i.e., not cyclized), then in one aspect, X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_Ile, aMe_Leu, aMe_Pro, aMe_Ser, aMe_Val, or Cap; and X5 is Asn, Asp, Gin, or Thr; or if X2 and X5 are directly cross-linked, the cross-link comprises a disulfide bond that was formed between a free thiol group in the side-chains of the two residues (individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen). In some aspects, dCys, dHcy, dHhc, dPen, or dHhPen can be used at X2 and / or X5.

[0046] In other aspects for Formula (I.B) peptides, regarding the residue options for X2 andX5: if the intramolecular cross-link between X2 and X5 is indirect (mediated by a cyclization linker) between the side-chains of the two residues, then the two cross-linked residues at X2-X5 are individually or both: Cys, dHcy, Hey, Hhc, Pen, or HhPen; and thecyclization linker is: a Butane Linker, a Carbonyl Linker, a Dimethylcyclopropane Linker, aa Ebutene Linker, a Hexane Linker, an Oxetane Linker a Pentane Linker, a Propane Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker. The free thiol group at X2 and at X5 each forms a thioether bond with a free alkyl moiety of one of these cyclization linkers.

[0047] In one aspect of Formula (LB), R1is acetyl and R2is amine.

[0048] In one aspect of Formula (LB), R1is absent and R2is amine.

[0049] In another aspect of Formula (LB), X12 through X26 are absent.

[0050] In another aspect of Formula (LB), the peptide does not comprise a cyclic structure.

[0051] In another aspect, the invention provides peptides that are at least agonists of human GLP1R, wherein the peptide comprises or consist of a sequence according to Formula (I.C): RLxi^-xs-xd-xs-xe-x -xs-X -xio-xi i-xn-xis-xid-xis-xie-xn-xis-xi - X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2is NH2, OH, Palm, or absent;XI is 2Pal, 3Pal, 4Pal, aMe His, Asn, Cit, dH, His, His lMe, His_3Me, His Bzl, Imidazole Propanoic Acid, Lys Dimethyl, Lys_Me3, NMe His, Om, Quin_3, or Tyr; X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe_Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Cys, dHcy, Hey, Hhc, Iva, Pen, or HhPen;X3 is aMe_Glu, Asp, Cysteate, Glu, Gia, Gin, Tetl, or Tet2;X4 is Ala, Aib, Asn, Gly, Lys, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Glu, Hey, Hhc, HhPen, Lys, Pen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 4OH_Val, Asn, Asp, Dap, Ser, Thr, Thr Ac, Thr Me, TThioamide, or Vai;X8 is Aad, Ala, Abu, aMe_Ser, Asp, Dap, dS, Fur, Gin, Gly, hSer, Ser, Ser_Bz, orS Thioamide;X9 is Aad, aMe_Asp, aMe_Glu, Api, Arg, Asp, Asp_OMe, bE, bMeAsp, Cysteate, dD, Gia, Glu, Lys, Lys_PEG2_IsoGlu_Palm, Tetl, Tet2, or Tyr;X10: aMeBip2pMe4pOMe, Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, NMeBip2pMe4pOMe, or Tyr;XI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphenyl, 3choloro4fluorophenyl, 3 chlorophenyl, 3 Methoxy phenyl, aMe_Ser, Bip_2pMe, Bip24_Me, HHPhe_35Me, Hph, Phe, Phe_2Ad, or Ser;X12 is Gly or absent;XI 3 is Glu, Gly, or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Val or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent;(Formula (I.C).)

[0052] In one aspect, a peptide of Formula (I.C) comprises a cyclic structure wherein: (i) X2 and X5 are individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen, which are directly covalently linked or indirectly covalently linked through a cyclization linker, or (ii) X5 is Lys and X13 is Glu which are directly covalently linked through an amide bond (i.e., a cyclic amide, or lactam bond).

[0053] In other aspects for Formula (I.C) peptides, regarding the residue options for X2 and X5: if X2 and X5 are not cross-linked (i.e., not cyclized), then in one aspect, X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_Ile, aMe_Leu, aMe_Pro, aMe_Ser, aMe_Val, or Cap; and X5 is Asn, Asp, Gin, or Thr; or if X2 and X5 are directly cross-linked, the cross-link comprises a disulfide bond that was formed between a free thiol group in the side-chains of the two residues (individually orboth Cys, dHcy, Hey, Hhc, Pen, or HhPen). In some aspects, dCys, dHcy, dHhc, dPen, or dHhPen can be used at X2 and / or X5.

[0054] In other aspects for Formula (I.C) peptides, regarding the residue options for X2 and X5: if the intramolecular cross-link between X2 and X5 is indirect (mediated by a cyclization linker) between the side-chains of the two residues, then the two cross-linked residues at X2-X5 are individually or both: Cys, dHcy, Hey, Hhc, Pen, or HhPen; and the cyclization linker is: a Butane Linker, a Carbonyl Linker, a Dimethylcyclopropane Linker, aa Ebutene Linker, a Hexane Linker, an Oxetane Linker a Pentane Linker, a Propane Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker. The free thiol group at X2 and at X5 each forms a thioether bond with a free alkyl moiety of one of these cyclization linkers.

[0055] In one aspect of Formula (I.C), R1is acetyl and R2is amine.

[0056] In one aspect of Formula (I.C), R1is absent and R2is amine.

[0057] In another aspect of Formula (I.C), XI is His, Imidazole Propanoic Acid, dH, or Cit.

[0058] In another aspect of Formula (I.C), X2 is Aib, aMe Pro, or Iva.

[0059] In another aspect of Formula (I.C), X3 is Glu or Tetl.

[0060] In another aspect of Formula (I.C), X4 is Gly.

[0061] In another aspect of Formula (I.C), X5 is Thr.

[0062] In another aspect of Formula (I.C), X6 is aMe_2F_Phe or aMe_Phe_2F.

[0063] In another aspect of Formula (I.C), X7 is 4OH_Val, Ser, or Thr.

[0064] In another aspect of Formula (I.C), X8 is aMe Ser or Ser.

[0065] In another aspect of Formula (I.C), X9 is aMe Asp, aMe Glu, or Asp.

[0066] In another aspect of Formula (I.C), X10 is Bip_2pMe4pOMe or Bip_2pEt4pOMe.

[0067] In another aspect of Formula (I.C), XI 1 is 2Chlorophenyl,3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphneyl, 3 chlorophenyl, 3Methoxyphenyl, Bip_2pMe, Bip24_Me, hhPhe_35Me, or Hph.

[0068] In another aspect of Formula (I.C), X12 is absent (and there are no additional residues C-terminal to XI 1.

[0069] In another aspect of Formula (I.C), X12 through X26 are absent.

[0070] In another aspect of Formula (I.C), the peptide further comprises or consists of the following residues connected to and following (C -terminal to) X12 and preceding R2: Gly- Glu-Ala-Ser-Glu-Leu-Ser-Thr-Ala-Ala-Leu-Gly-Arg-Leu-Ser-Ala-Glu-Leu-His-Glu-Leu- Ala-Thr-Leu-Pro-Arg-Thr-Glu-Thr-Gly-Ser-Gly-Ser-Pro.

[0071] In another aspect of Formula (I.C), the peptide does not comprise a cyclic structure.

[0072] In another aspect, the invention provides peptides that are at least agonists of human GLP1R, wherein the peptide comprises or consist of a sequence according to Formula (I D):RCxi^-xs-xd-xs-xe^-xs-X -xio-xi i-xn-xis-XM-xis-xie-xn-xis-xi - X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2is NH2 , OH, Palm, or absent;XI is 2Pal, 3Pal, 4Pal, aMe His, Asn, Cit, dH, hHis, His, His lMe, His_3Me, His Bzl, Imidazole Propanoic Acid, Lys Dimethyl, Lys_Me3, NMe His, Om, Phe, Pyrrole PA, Quin_3, or Tyr;X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe_Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Cys, dHcy, Hey, Hhc, Iva, Pen, or HhPen;X3 is aMe Glu, Asp, Cysteate, Glu, Gia, Gin, He, Leu, Tetl, or Tet2;X4 is Ala, Aib, Asn, Gly, Lys, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Glu, Hey, Hhc, HhPen, He, Leu, Lys, NMe_K, 03 S, 03 S Reduced, Pen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 4OH_Val, Asn, Asp, Dap, Diaminobutanoic Acid, Ser, Thr, Thr Ac, Thr Me, TThioamide, or Vai;X8 is Aad, Ala, Abu, aMe_Ser, Asp, Dap, dS, Fur, Gin, Gly, hSer, Ser, Ser_Bz, or S Thioamide;X9 is Aad, aMe_Asp, aMe_Glu, Api, Arg, Asp, Asp_OMe, bE, bMeAsp, Cysteate, dD, diMe Asp, Gia, Glu, Hhc, Lys, Lys_PEG2_IsoGlu_Palm, NMe_E, 03 S, O3S_Reduced, Tetl, Tet2, or Tyr;X10: aMeBip2pMe4pOMe, Bip_2pEt4pOC2N,Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid, Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag, Bip_2pEt4pOC2N_Dap_MeOPheT ag, Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Dap_Albutag, Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, NMeBip2pMe4pOMe, or Tyr;XI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphenyl, 35_DiemthylPhenyl, 3choloro4fluorophenyl, 3 chlorophenyl, 3 Methoxy phenyl, aMe Ser, Bip_2pMe, Bip24_Me, HHPhe_35Me, Hph, Phe, Phe_2Ad, Pyridin3yl, Quinolin_5_yl, or Ser;X12 is Gly or absent;XI 3 is Glu, Gly, or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Val or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent;(Formula (LD).)

[0073] In one aspect, a peptide of Formula (I.D) comprises a cyclic structure wherein: (i) X2 and X5 are individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen, which are directly covalently linked or indirectly covalently linked through a cyclization linker, or (ii) X5 is Lys and X13 is Glu which are directly covalently linked through an amide bond (i.e., a cyclic amide, or lactam bond).

[0074] In other aspects for Formula (I D) peptides, regarding the residue options for X2 andX5: if X2 and X5 are not cross-linked (i.e., not cyclized), then in one aspect, X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_Ile, aMe_Leu, aMe_Pro, aMe_Ser, aMe_Val, or Cap; and X5 is Asn, Asp, Gin, or Thr; or if X2 and X5 are directly cross-linked, the cross-link comprises a disulfide bond that was formed between a free thiol group in the side-chains of the two residues (individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen). In some aspects, dCys, dHcy, dHhc, dPen, or dHhPen can be used at X2 and / or X5.

[0075] In other aspects for Formula (I.D) peptides, regarding the residue options for X2 and X5: if the intramolecular cross-link between X2 and X5 is indirect (mediated by a cyclization linker) between the side-chains of the two residues, then the two cross-linked residues at X2-X5 are individually or both: Cys, dHcy, Hey, Hhc, Pen, or HhPen; and the cyclization linker is: a Butane Linker, a Carbonyl Linker, a Dimethylcyclopropane Linker, aa Ebutene Linker, a Hexane Linker, an Oxetane Linker a Pentane Linker, a Propane Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker. The free thiol group at X2 and at X5 each forms a thioether bond with a free alkyl moiety of one of these cyclization linkers.

[0076] In another aspect of Formula (I.D), the peptide comprises an intramolecular cross- linke between X5 and X9, wherein the two cross-linked residues are connected by a lactam bond. In one aspect, X5 is Lys or NMe Lys and X9 is Glu or NMe Glu. In another aspect, X5 is Glu or NMe_Glu and X9 is Lys or NMe_Lys.

[0077] In one aspect of Formula (I.D), R1is acetyl and R2is amine.

[0078] In one aspect of Formula (I.D), R1is absent and R2is amine.

[0079] In another aspect of Formula (I.D), XI is aMe His, Asn, His,Imidazole Propanoic Acid, dH, or Cit.

[0080] In another aspect of Formula (I.D), X2 is Aib, aMe Pro, or Iva.

[0081] In another aspect of Formula (I.D), X3 is Glu or Tetl.

[0082] In another aspect of Formula (I.D), X4 is Gly.

[0083] In another aspect of Formula (I.D), X5 is Thr.

[0084] In another aspect of Formula (I D), X6 is aMe_2F_Phe or aMe_Phe_2F.

[0085] In another aspect of Formula (I.D), X7 is 4OH_Val, Ser, or Thr.

[0086] In another aspect of Formula (I.D), X8 is aMe Ser or Ser.

[0087] In another aspect of Formula (I.D), X9 is aMe Asp, aMe Glu, Asp, Hhc, or O3S.

[0088] In another aspect of Formula (I.D), X10 is Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pMe4pOMe, or Bip_2pEt4pOMe.

[0089] In another aspect of Formula (I.D), XI 1 is 2Chlorophenyl, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphneyl, 3 chlorophenyl, 3Methoxyphenyl, Bip_2pMe, Bip24_Me, hhPhe_35Me, or Hph.

[0090] In another aspect of Formula (I.D), X12 is absent (and there are no additional residues C-terminal to XI 1.

[0091] In another aspect of Formula (I.D), X12 through X26 are absent.

[0092] In another aspect of Formula (I.D), the peptide further comprises or consists of the following residues connected to and following (C-terminal to) X12 and preceding R2: Gly- Glu-Ala-Ser-Glu-Leu-Ser-Thr-Ala-Ala-Leu-Gly-Arg-Leu-Ser-Ala-Glu-Leu-His-Glu-Leu- Ala-Thr-Leu-Pro-Arg-Thr-Glu-Thr-Gly-Ser-Gly-Ser-Pro.

[0093] In another aspect of Formula (I.D), the peptide does not comprise a cyclic structure.

[0094] In another aspect of Formula (I.D), the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1 A-1NN peptides with +, ++, +++, or ++++), less than 1 nM (++, +++, ++++), less than 0.100 nM (e.g., +++ or ++++), or less than 0.010 nM (e.g., ++++) in a human GLP1R HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant human GLP1R on their cell surface at high density. Herein, high-density (HD) cell surface receptor expression of human GLP1R is about greater than about 200,000 receptors / cell. (See Examples for the cAMP accumulation assay and cell surface receptor density determination).

[0095] In aspects relating to potency and HEK 293 cAMP accumulation assays, EC50 is the measure of the concentration of a peptide of the invention which induces cAMP accumulation halfway between the baseline and maximum in the HEK293 cAMP accumulation assay as described herein (see Examples). It should also be noted that in theseaspects, the EC50 can also be referred to as IC50, although EC50 is the more appropriate term as the peptides of the invention are agonists of human GLP1R and / or human GIPR.

[0096] In another aspect of Formula (I D), the peptide has an EC50 potency less than 10 micromolar (e.g., see Figs. 1A-1NN, peptides with +, ++, +++, or ++++), less than 1 micromolar (e.g., ++, +++, ++++), less than 100 nM (e.g., +++ or ++++), or less than 10 nM (e.g., ++++) in a human GLP1R HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant GLP1R on their cell surface at low density. Herein, low- density (LD) cell surface receptor expression of human GLP1R is about less than 2,000 receptors / cell.

[0097] In Figs. 1 A-1NN, the GLP1R EC50 values, i.e., ++++, +++, ++, or + are based on data from the cAMP accumulation assay using at least one of the hGLPIR HEK293 high- density (HD) or low-density (LD) cell clones described in the Examples.

[0098] In another aspect of Formula (I.D), the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1 A-1NN, peptides with +, ++, +++, or ++++), less than 1 nM (++, +++, ++++), less than 0.100 nM (+++ or ++++), or less than 0.010 nM (++++) in a human GIPR HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant human GIPR on their cell surface at a density between about 45,000 and 55,000 receptors / cell.

[0099] In another aspect of Formula (I.D), the peptide has a half-life time of stability greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay or an SIF assay, or in both assays. In a related aspect, a peptide of the invention that has a half-life time of stability greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay or an SIF assay, or in both assays, is suitable for oral administration / oral formulation. In one aspect, a peptide of the invention that has a half-life time of stability greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay is suitable for oral administration / oral formulation.

[0100] In another aspect of Formula (I.D), the peptide has a ++++ EC50 potency in a human high density (HD) or low density (LD) GLP1R HEK293 cAMP accumulation assay, and also has a half-life time of stability of greater than 2 hours or 24 hours in both an SGF assay andan SIF assay. As explained herein, a “++++” EC50 potency in a human HD GLP1R HEK293 cAMP assay means that the peptide has an EC50 less than 0.010 nM is said HD assay, and a “++++” EC50 potency in a human LD GLP1R HEK293 cAMP assay means that the peptide has an EC50 less than 10 nM in said LD assay.

[0101] In one aspect, the invention provides peptides that are at least agonists of human GLP1R, wherein the peptide comprises or consist of a sequence according to Formula (I E): RLxi^-xs-xd-xs-xe-x -xs-xo-xio-xi i-xn-XB-xid-xis-xie-xn-xis-xio- X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2is NH2, OH, Palm, or absent;XI is 2Pal, 3Pal, 4Pal, aMe His, aOH Imidazole PropanoicAcid, Asn, Cit, dH, hHis, His, His lMe, His_3Me, His Bzl, Imidazole Propanoic Acid, Lys Dimethyl, Lys_Me3, NMe His, Orn, Phe, Pyrrole PA, Quin_3, or Tyr;X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe_Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Cys, dHcy, Hey, Hhc, Iva, Pen, or HhPen;X3 is aMe Glu, Asp, Cysteate, Glu, Gia, Gin, He, Leu, Tetl, or Tet2;X4 is Ala, Aib, Asn, Gly, Lys, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Glu, Hey, Hhc, HhPen, He, Leu, Lys, NMe_K, 03 S, 03 S Reduced, Pen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 4OH_Val, Asn, Asp, Dap, Diaminobutanoic Acid, Ser, Thr, Thr Ac, Thr Me, TThioamide, or Vai;X8 is Aad, Ala, Abu, aMe_Ser, Asp, Dap, dS, Fur, Gin, Gly, hSer, Ser, Ser_Bz, orS Thioamide;X9 is Aad, aMe_Asp, aMe_Glu, Api, Arg, Asp, Asp_OMe, bE, bMeAsp, Cysteate, dD, diMe Asp, Gia, Glu, Hhc, Lys, Lys_PEG2_IsoGlu_Palm, NMe_E, 03 S, O3S_Reduced, Tetl, Tet2, or Tyr;X10: aMeBip2pMe4pOMe, Bip_2pEt4pOC2N,Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid, Bip_2pEt4pOC2N_Ahx_Palm, Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_Dap_MeOPheTag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm, Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheT ag, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC4N,Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Dap_Albutag, Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_Dap_Palm, Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, NMeBip2pMe4pOMe, or Tyr;XI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphenyl, 35_DiemthylPhenyl, 3choloro4fluorophenyl, 3 chlorophenyl, 3 Methoxy phenyl, aMe Ser, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Phe, Phe_2Ad, Pyridin3yl, Quinolin_5_yl, or Ser;X12 is Gly or absent;XI 3 is Glu, Gly, or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Vai or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent;(Formula (I E).)

[0102] In one aspect, a peptide of Formula (I.E) comprises a cyclic structure wherein: (i) X2 and X5 are individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen, which are directly covalently linked or indirectly covalently linked through a cyclization linker, or (ii) X5 is Lys and X13 is Glu which are directly covalently linked through an amide bond (i.e., a cyclic amide, or lactam bond).In other aspects for Formula (I.E) peptides, regarding the residue options for X2 and X5:if X2 and X5 are not cross-linked (i.e., not cyclized), then in one aspect, X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_Ile, aMe_Leu, aMe_Pro, aMe_Ser, aMe_Val, or Cap; and X5 is Asn, Asp, Gin, or Thr; or if X2 and X5 are directly cross-linked, the cross-link comprises a disulfide bond that was formed between a free thiol group in the side-chains of the two residues (individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen). In some aspects, dCys, dHcy, dHhc, dPen, or dHhPen can be used at X2 and / or X5.

[0103] In other aspects for Formula (I.E) peptides, regarding the residue options for X2 and X5: if the intramolecular cross-link between X2 and X5 is indirect (mediated by a cyclization linker) between the side-chains of the two residues, then the two cross-linked residues at X2-X5 are individually or both: Cys, dHcy, Hey, Hhc, Pen, or HhPen; and the cyclization linker is: a Butane Linker, a Carbonyl Linker, a Dimethylcyclopropane Linker, aa Ebutene Linker, a Hexane Linker, an Oxetane Linker a Pentane Linker, a Propane Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker. The free thiol group at X2 and at X5 each forms a thioether bond with a free alkyl moiety of one of these cyclization linkers.

[0104] In another aspect of Formula (I.E), the peptide comprises an intramolecular cross-link between X5 and X9, wherein the two cross-linked residues are connected by a lactam bond. In one aspect, X5 is Lys or NMe_Lys and X9 is Glu or NMe_Glu. In another aspect, X5 is Glu or NMe_Glu and X9 is Lys or NMe_Lys.

[0105] In one aspect of Formula (I.E), R1is acetyl and R2is amine.

[0106] In one aspect of Formula (I.E), R1is absent and R2is amine.

[0107] In another aspect of Formula (I.E), XI is aMe His, Asn, His,Imidazole Propanoic Acid, dH, or Cit.

[0108] In another aspect of Formula (I.E), X2 is Aib, aMe Pro, or Iva.

[0109] In another aspect of Formula (I.E), X3 is Glu or Tetl.

[0110] In another aspect of Formula (I.E), X4 is Gly.

[0111] In another aspect of Formula (I.E), X5 is Thr.

[0112] In another aspect of Formula (I.E), X6 is aMe_2F_Phe or aMe_Phe_2F.

[0113] In another aspect of Formula (I E), X7 is 4OH_Val, Ser, or Thr.

[0114] In another aspect of Formula (I E), X8 is aMe Ser or Ser.

[0115] In another aspect of Formula (I E), X9 is aMe Asp, aMe Glu, Asp, Hhc, or O3S.

[0116] In another aspect of Formula (I E), X10 is Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pMe4pOMe, or Bip_2pEt4pOMe.

[0117] In another aspect of Formula (I E), XI 1 is 2Chlorophenyl,3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphneyl, 3 chlorophenyl, 3Methoxyphenyl, Bip_2pMe, Bip24_Me, hhPhe_35Me, or Hph.

[0118] In another aspect of Formula (I E), X12 is absent (and there are no additional residues C-terminal to XI 1.

[0119] In another aspect of Formula (I E), X12 through X26 are absent.

[0120] In another aspect of Formula (I E), the peptide further comprises or consists of the following residues connected to and following (C-terminal to) X12 and preceding R2: Gly- Glu-Ala-Ser-Glu-Leu-Ser-Thr-Ala-Ala-Leu-Gly-Arg-Leu-Ser-Ala-Glu-Leu-His-Glu-Leu- Ala-Thr-Leu-Pro-Arg-Thr-Glu-Thr-Gly-Ser-Gly-Ser-Pro.

[0121] In another aspect of Formula (I E), the peptide does not comprise a cyclic structure.

[0122] In another aspect of Formula (I E), the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1 A-1NN, peptides with +, ++, +++, or ++++), less than 1 nM (++, +++, ++++), less than 0.100 nM (e.g., +++ or ++++), or less than 0.010 nM (e.g., ++++) in a human GLP1R HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant human GLP1R on their cell surface at high density. Herein, high-density (HD) cell surface receptor expression of human GLP1R is about greater than about 200,000 receptors / cell. (See Examples for the cAMP accumulation assay and cell surface receptor density determination).

[0123] In aspects relating to potency and HEK 293 cAMP accumulation assays, EC50 is the measure of the concentration of a peptide of the invention which induces cAMP accumulation halfway between the baseline and maximum in the HEK293 cAMP accumulation assay as described herein (see Examples). It should also be noted that in theseaspects, the EC50 can also be referred to as IC50, although EC50 is the more appropriate term as the peptides of the invention are agonists of human GLP1R and / or human GIPR.

[0124] In another aspect of Formula (I E), the peptide has an EC50 potency less than 10 micromolar (e.g., see Figs. 1A-1NN, peptides with +, ++, +++, or ++++), less than 1 micromolar (e.g., ++, +++, ++++), less than 100 nM (e.g., +++ or ++++), or less than 10 nM (e.g., ++++) in a human GLP1R HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant GLP1R on their cell surface at low density. Herein, low- density (LD) cell surface receptor expression of human GLP1R is about less than 2,000 receptors / cell.

[0125] In Figs. 1 A-1NN, the GLP1R EC50 values, i.e., ++++, +++, ++, or + are based on data from the cAMP accumulation assay using at least one of the hGLPIR HEK293 high- density (HD) or low-density (LD) cell clones described in the Examples.

[0126] In another aspect of Formula (I.E), the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1 A-1NN, peptides with +, ++, +++, or ++++), less than 1 nM (++, +++, ++++), less than 0.100 nM (+++ or ++++), or less than 0.010 nM (++++) in a human GIPR HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant human GIPR on their cell surface at a density between about 45,000 and 55,000 receptors / cell.

[0127] In another aspect of Formula (I.E), the peptide has a half-life time of stability greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay or an SIF assay, or in both assays. In a related aspect, a peptide of the invention that has a half-life time of stability greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay or an SIF assay, or in both assays, is suitable for oral administration / oral formulation. In one aspect, a peptide of the invention that has a half-life time of stability greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay is suitable for oral administration / oral formulation.

[0128] In another aspect of Formula (I.E), the peptide has a ++++ EC50 potency in a human high density (HD) or low density (LD) GLP1R HEK293 cAMP accumulation assay, and also has a half-life time of stability of greater than 2 hours or 24 hours in both an SGF assay andan SIF assay. As explained herein, a “++++” EC50 potency in a human HD GLP1R HEK293 cAMP assay means that the peptide has an EC50 less than 0.010 nM is said HD assay, and a “++++” EC50 potency in a human LD GLP1R HEK293 cAMP assay means that the peptide has an EC50 less than 10 nM in said LD assay.

[0129] In another aspect, the invention provides peptides that are at least agonists of human GLP1R, wherein the peptide comprises or consist of a sequence according to Formula (I.F): RLxi^-xs-xd-xs-xe-x -xs-xo-xio-xi i-xn-XB-xid-xis-xie-xn-xis-xio- X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2is NH2, OH, Palm, or absent;XI is 2Me3ImidazolePA, 2Pal, 3Pal, 4Pal, aMe His, aOH Imidazole PropanoicAcid, Asn, Cit, dH, hHis, His, His lMe, His_3Me, His Bzl, Imidazole Propanoic Acid, Lys Dimethyl, Lys_Me3, NMe His, Om, Phe, Pyrrole PA, Quin_3, or Tyr;X2 is Aib, Ala, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe_Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Cys, dHcy, Gly, Hey, Hhc, Iva, Pen, or HhPen;X3 is aMe Glu, Asp, Cysteate, Glu, Gia, Gin, He, Leu, Tetl, or Tet2;X4 is Ala, Aib, Asn, Gly, Lys, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Glu, Hey, Hhc, HhPen, He, Leu, Lys, NMe_K, 03 S, 03 S Reduced, Pen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 4OH_Val, Asn, Asp, Dap, Diaminobutanoic Acid, Ser, Thr, Thr Ac, Thr Me, TThioamide, or Vai;X8 is Aad, Ala, Abu, aMe_Ser, Asp, Dap, dS, Fur, Gin, Gly, hSer, Ser, Ser_Bz, orS Thioamide;X9 is Aad, aMe_Asp, aMe_Glu, Api, Arg, Asp, Asp_OMe, bE, bMeAsp, Cysteate, dD, diMe Asp, Gia, Glu, Hhc, Lys, Lys_PEG2_IsoGlu_Palm, NMe_E, 03 S, O3S_Reduced, Tetl, Tet2, or Tyr;X10: aMeBip2pMe4pOMe, Bip_2pEt4pOC2N, Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm, Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm,Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_Dap_MeOPheTag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm,Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheT ag,Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N,Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2,Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag,Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N, Bip_2pEt4pOC4N_ C0C8N,Bip_2pEt4pOC4N_Dap_Albutag, Bip_2pEt4pOC4N_Dap_MeOPheT ag,Bip_2pEt4pOC4N_Dap_Palm, Bip_2pEt4pOC4N_IsoGlu_Palm,Bip_2pEt4pOC4N_MeOPheTag, Bip_2pEt4pOC4N_PEG4_am,Bip_2pEt4pOC4N_PEG4_NHAc, Bip_2pEt4pOC4N_PEG8_am,Bip_2pEt4pOC4N_PEG8_NHAc, Bip_2pEt4pOC4N_PEGl 6_am,Bip_2pEt4pOC4N_PEGl 6_NHAc, Bip_2pEt4pOC4N2DMGN2ae,Bip_2pEt4pOC4NDMGN2ae, Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NAc,Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, NMeBip2pMe4pOMe, or Tyr;XI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl,34Dimethyoxyphenyl, 35_DiemthylPhenyl, 3choloro4fluorophenyl, 3 chlorophenyl,3 Methoxy phenyl, aMe Ser, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me,Hph, Phe, Phe_2Ad, Pyridin3yl, Quinolin_5_yl, Ser, Thr, Tyr, or Vai;X12 is Gly or absent;XI 3 is Glu, Gly, or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Val or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent;(Formula (I F))

[0130] In one aspect, a peptide of Formula (I.F) comprises a cyclic structure wherein: (i) X2 and X5 are individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen, which are directly covalently linked or indirectly covalently linked through a cyclization linker, or (ii) X5 is Lys and X13 is Glu which are directly covalently linked through an amide bond (i.e., a cyclic amide, or lactam bond).

[0131] In other aspects for Formula (I.F) peptides, regarding the residue options for X2 and X5: if X2 and X5 are not cross-linked (i.e., not cyclized), then in one aspect, X2 is Aib, Ala, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe-Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Gly, or Iva; and X5 is Asn, Asp, Gin, Glu, He, Leu, Lys, NMe_K, 03 S, O3S_Reduced, or Thr; or if X2 and X5 are directly cross-linked, the cross-link comprises a disulfide bond that was formed between a free thiol group in the side-chains of the two residues (individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen). In some aspects, dCys, dHcy, dHhc, dPen, or dHhPen can be used at X2 and / or X5.

[0132] In other aspects for Formula (I.F) peptides, regarding the residue options for X2 and X5: if the intramolecular cross-link between X2 and X5 is indirect (mediated by a cyclization linker) between the side-chains of the two residues, then the two cross-linked residues at X2-X5 are individually or both: Cys, dHcy, Hey, Hhc, Pen, or HhPen; and the cyclization linker is: a Butane Linker, a Carbonyl Linker, a Dimethylcyclopropane Linker, aa Ebutene Linker, a Hexane Linker, an Oxetane Linker a Pentane Linker, a Propane Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker. The free thiol group at X2 and at X5 each forms a thioether bond with a free alkyl moiety of one of these cyclization linkers.

[0133] In another aspect of Formula (I.F), the peptide comprises an intramolecular cross-link between X5 and X9, wherein the two cross-linked residues are connected by a lactam bond.In one aspect, X5 is Lys or NMe_Lys and X9 is Glu or NMe_Glu. In another aspect, X5 is Glu or NMe_Glu and X9 is Lys or NMe_Lys.

[0134] In one aspect of Formula (I.F), R1is acetyl and R2is amine.

[0135] In one aspect of Formula (I.F), R1is absent and R2is amine.

[0136] In another aspect of Formula (I.F), XI is 2Me3ImidazolePA, aMe His, Asn, Cit, dH, His, Imidazole Propanoic Acid, Phe, or Tyr. , or.

[0137] In another aspect of Formula (I.F), X2 is Aib, Ala, aMe Pro, Gly, or Iva.

[0138] In another aspect of Formula (I.F), X3 is Glu or Tetl.

[0139] In another aspect of Formula (I.F), X4 is Gly.

[0140] In another aspect of Formula (I.F), X5 is Thr.

[0141] In another aspect of Formula (I.F), X6 is aMe_2F_Phe or aMe_Phe_2F.

[0142] In another aspect of Formula (I.F), X7 is 4OH_Val, Ser, or Thr.

[0143] In another aspect of Formula (I.F), X8 is aMe Ser or Ser.

[0144] In another aspect of Formula (I.F), X9 is aMe Asp, aMe Glu, Asp, Hhc, or O3S.

[0145] In another aspect of Formula (I.F), X10 is Bip_2pEt4pOC2N,Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm,Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_IsoGlu_Palm,Bip_2pEt4pOC2N_Dap_Albutag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm,_Bip_2pEt4pOC2N IsoGlu Palm, Bip_2pEt4pOC2N_MeOPheTag,Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2,Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N, Bip_2pEt4pOC4N_ COC8N, Bip_2pEt4pOC4N Dap Albutag, Bip_2pEt4pOC4N Dap Palm,Bip_2pEt4pOC4N_MeOPheTag, Bip_2pEt4pOC4N_PEG4_am,Bip_2pEt4pOC4N_PEG4_NHAc, Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc, Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4N_PEGl 6_NHAc,Bip_2pEt4pOC2NDMGN2aeC 12,_Bip_2pEt4pOC4N2DMGN2ae, Bip_2pEt4pOC4NDMGN2ae, Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc, Bip_2pMe4pOMe, or Bip_2pEt4pOMe.

[0146] In another aspect of Formula (I.F), XI 1 is 2Chlorophenyl, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphneyl, 3 chlorophenyl,3 Methoxy phenyl, Bip_2pMe, Bip24_Me, hhPhe_35Me, Hph, Ser, Thr, Tyr, or Vai.

[0147] In another aspect of Formula (I.F), X12 is absent (and there are no additional residues C-terminal to XI 1.

[0148] In another aspect of Formula (I.F), X12 through X26 are absent.

[0149] In another aspect of Formula (I.F), the peptide further comprises or consists of the following residues connected to and following (C-terminal to) X12 and preceding R2: Gly- Glu-Ala-Ser-Glu-Leu-Ser-Thr-Ala-Ala-Leu-Gly-Arg-Leu-Ser-Ala-Glu-Leu-His-Glu-Leu- Ala-Thr-Leu-Pro-Arg-Thr-Glu-Thr-Gly-Ser-Gly-Ser-Pro.

[0150] In another aspect of Formula (I.F), the peptide does not comprise a cyclic structure.

[0151] In another aspect of Formula (I.F), the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1 A-1NN, peptides with +, ++, +++, or ++++), less than 1 nM (++, +++, ++++), less than 0.100 nM (e.g., +++ or ++++), or less than 0.010 nM (e.g., ++++) in a human GLP1R HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant human GLP1R on their cell surface at high density. Herein, high-density (HD) cell surface receptor expression of human GLP1R is about greater than about 200,000 receptors / cell. (See Examples for the cAMP accumulation assay and cell surface receptor density determination).

[0152] In aspects relating to potency and HEK 293 cAMP accumulation assays, EC50 is the measure of the concentration of a peptide of the invention which induces cAMP accumulation halfway between the baseline and maximum in the HEK293 cAMP accumulation assay as described herein (see Examples). It should also be noted that in these aspects, the EC50 can also be referred to as IC50, although EC50 is the more appropriate term as the peptides of the invention are agonists of human GLP1R and / or human GIPR.

[0153] In another aspect of Formula (I.F), the peptide has an EC50 potency less than 10 micromolar (e.g., see Figs. 1A-1NN, peptides with +, ++, +++, or ++++), less than 1 micromolar (e.g., ++, +++, ++++), less than 100 nM (e.g., +++ or ++++), or less than 10 nM (e.g., ++++) in a human GLP1R HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant GLP1R on their cell surface at low density. Herein, low- density (LD) cell surface receptor expression of human GLP1R is about less than 2,000 receptors / cell.

[0154] In Figs. 1 A-1NN, the GLP1R EC50 values, i.e., ++++, +++, ++, or + are based on data from the cAMP accumulation assay using at least one of the hGLPIR HEK293 high- density (HD) or low-density (LD) cell clones described in the Examples.

[0155] In another aspect of Formula (I.F), the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1 A-1NN, peptides with +, ++, +++, or ++++), less than 1 nM (++, +++, ++++), less than 0.100 nM (+++ or ++++), or less than 0.010 nM (++++) in a human GIPR HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant human GIPR on their cell surface at a density between about 45,000 and 55,000 receptors / cell.

[0156] In another aspect of Formula (I.F), the peptide has a half-life time of stability greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay or an SIF assay, or in both assays. In a related aspect, a peptide of the invention that has a half-life time of stability greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay or an SIF assay, or in both assays, is suitable for oral administration / oral formulation. In one aspect, a peptide of the invention that has a half-life time of stability greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay is suitable for oral administration / oral formulation.

[0157] In another aspect of Formula (I.F), the peptide has a ++++ EC50 potency in a human high density (HD) or low density (LD) GLP1R HEK293 cAMP accumulation assay, and also has a half-life time of stability of greater than 2 hours or 24 hours in both an SGF assay and an SIF assay. As explained herein, a “++++” EC50 potency in a human HD GLP1R HEK293 cAMP assay means that the peptide has an EC50 less than 0.010 nM is said HD assay, and a“++++” EC50 potency in a human LD GLP1R HEK293 cAMP assay means that the peptide has an EC50 less than 10 nM in said LD assay.

[0158] In another aspect, the invention provides a peptide comprising or consisting of a sequence according to any one of SEQ ID NOs: 1-209.

[0159] In another aspect, the present disclosure provides a peptide compound as described by its SMILES formula as listed in Figs. 1 A-1NN.

[0160] In another aspect, the invention provides a peptide comprising or consisting of one of the chemical structures depicted in Figs. 2A-2R.

[0161] In another aspect, the invention provides peptides that are agonists of GLP1R having an EC50 potency less than 1 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 1 micromolar in a human LD GLP1R HEK293 cAMP accumulation assay, wherein the peptide comprises or consist of a sequence according to Formula (II): R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is Ra-C(O)- or hydrogen, wherein Ra is Cl-20 alkyl or C3-8 cycloalkyl; or R1 is acetyl, isovaleric acid, cyclohexanecarboxylic acid, or absent;R2 is NH2 or OH or absent;XI is 2Me3ImidazolePA, 2Pal, 3Pal, aMe His, aOH Imidazole PropanoicAcid, Asn, Cit, dH, His, hHis, His_3Me, Imidazole Propanoic Acid, Lys Dimethyl, NMe His, Phe, Pyrrol e_P A, or Tyr;X2 is Aib, Ala, aMe_Asn, aMe_Gln, aMe_Glu, aMe_Leu, aMe_Pro, aMe_Ser, aMe_Trp, Gly, Iva, or Vai;X3 is aMe Glu, Asp, Cysteate, Gia, Gin, Glu, He, Leu, Tetl, or Tet2;X4 is Ala, Gly, or Ser;X5 is Glu, Gin, Hhc, He, Leu, Lys, NMe_K, 03 S, O3S_Reduced, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 4OH_Val, Asp, Diaminobutanoic acid, Ser, Thr, TThioamide, or Vai;X8 is aMe_Ser, Asp, Gly, Ser, or SThioamide;X9 is aMe_Asp, aMe_Glu, Asp, bMeAsp, Cysteate, diMe_Asp, Gia, Glu, Hhc, Lys, NMe_E, 03 S, O3S_Reduced;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2NC2N, Bip_2pEt4pOC2NDMGN2aeC4, Bip_2pEt4pOC2NDMGN2aeC8, Bip_2pEt4pOC2NDMGN2aeC12,Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm, Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag, Bip_2pEt4pOC2N_Dap_MeOPheTag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm, Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheT ag, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid, Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_C4,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2, Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Arg, Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N, Bip_2pEt4pOC4N_ C0C8N,Bip_2pEt4pOC4N_Dap_lPEG2_lPEG2_C18_diacid,_Bip_2pEt4pOC4N_Dap_Albutag, Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_Dap_Palm, Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC4N_DMG_N_2ae_C 18_diacid, Bip_2pEt4pOC4N_DMG_N_2ae_LysAc, Bip_2pEt4pOC4N_MeOPheTag, Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOC4N_PEG4_NHAc, Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc, Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4N_PEGl 6_NHAc, Bip_2pEt4pOC4N2DMGN2ae, Bip_2pEt4pOC4NDMGN2ae, Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOC4NMe3,_Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, or NMeBip2pMe4pOMe; andXI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphneyl, 35_DimethylPhenyl, 3 chlorophenyl, 3 Methoxy phenyl, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Phe, Phe_2Ad, Pyridin3yl, Quinolin_5_yl, Thr, Tyr, or Vai.(Formula (II).)

[0162] In one aspect of Formula (II), R1 is acetyl and R2 is amine.

[0163] In one aspect of Formula (II), R1 is absent and R2 is amine.

[0164] In another aspect of Formula (II), no additional amino acid residues can be present at the C-terminus after XI 1.

[0165] In another aspect of Formula (II), the peptide of Formula (II) further comprises a dipeptide attached to XI through an amide bond or ester bond, wherein under physiological pH, a nucleophile cleaves the amide or ester bond such that a diketopiperazine or diketomorpholine is formed and released from the peptide of Formula (II). In one aspect, the dipeptide attached to XI through an amide bond is Sar- isoDLys_lPEG2 1PEG2_IsoGlu_C 18_Diacid.

[0166] In another aspect of Formula (II), the peptide has an EC50 potency less than 0.100 nM, or less than 0.010 nM, in a human high-density (HD) GLP1R HEK293 cAMP accumulation assay.

[0167] In another aspect of Formula (II), the peptide has an EC50 potency less than 100 nM, or less than 10 nM, in a human low-density (LD) GLP1R HEK293 cAMP accumulation assay.

[0168] In another aspect of Formula (II), the peptide has a half-life time of stability of greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay or an SIF assay, or in both assays.

[0169] In another aspect of Formula (II), the peptide not only has an EC50 potency less than 1 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 1 micromolar in a human LD GLP1R HEK293 cAMP accumulation assay, but also has a half-life time of stability of greater than 2 hours, greater than 12 hours, greater than 18 hours, 20 hours, or greater than 24 hours in an SGF assay and / or an SIF assay.

[0170] In another aspect, the invention provides a peptide having an EC50 less than 0.100 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 100 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and the peptide comprises or consists of the sequence according to Formula (III): R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is acetyl or absent;R2 is NH2 or OH or absent;XI is 2Me3ImidazolePA, 2Pal, aMe His, aOH Imidazole PropanoicAcid, Asn, Cit, dH, His, hHis, Imidazole Propanoic Acid, NMe His, Phe, Pyrrole PA, or Tyr;X2 is Aib, Ala, aMe_Pro, aMe_Ser, Gly, Iva, or Vai;X3 is Asp, Cysteate, Gia, Gin, Glu, He, Leu, Tetl, or Tet2;X4 is Gly;X5 is Glu, Hhc, He, Lys, Leu, 03 S, or Thr;X6 is aMe_Phe_2F;X7 is 40H_Val, Diaminobutanoic acid, Ser, Thr, or TThioamide;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, Asp, bMe_Asp, Cysteate, diMe_Asp, Glu, Hhc, Lys, or 03 S;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2NC2N, Bip_2pEt4pOC2NDMGN2aeC4,Bip_2pEt4pOC2NDMGN2aeC8, Bip_2pEt4pOC2NDMGN2aeC12,Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm,Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_Dap_MeOPheT ag,Bip_2pEt4pOC2N_DMG_N_2ae_Palm,_Bip_2pEt4pOC2N_IsoGlu_Palm,Bip_2pEt4pOC2N_MeOPheTag,_Bip_2pEt4pOC2N_PEG4_am,Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N,Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_C4,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2,Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag,Bip_2pEt4pOC4N_Arg, Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N,Bip_2pEt4pOC4N_ C0C8N,Bip_2pEt4pOC4N_Dap_lPEG2_lPEG2_C18_diacid,_Bip_2pEt4pOC4N_Dap_Albutag,Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_Dap_Palm,Bip_2pEt4pOC4N_DMG_N_2ae_C 18_diacid, Bip_2pEt4pOC4N_DMG_N_2ae_LysAc,Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC4N_MeOPheT ag,Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOC4N_PEG4_NHAc,Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc,Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4N_PEGl 6_NHAc,Bip_2pEt4pOC4N2DMGN2ae, Bip_2pEt4pOC4NDMGN2ae,Bip_2pEt4pOC4NE)MGN2aeLysAc, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NLys,Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOC4NMe3, Bip_2pEt4pOMe, Bip_2pMe4pOMe, or Bip24_Me; andXI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphenyl, 3choloro4fluorophenyl, 3 chlorophenyl, 3 Methoxy phenyl, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Phe, Quinolin-5-yl, Thr, Tyr, or Vai. (Formula (III).)

[0171] In one aspect of Formula (III), R1 is acetyl and R2 is amine.

[0172] In another aspect of Formula (III), R1 is absent and R2 is amine.

[0173] In another aspect of Formula (III), no additional residues can be present at the C- terminus after XI 1.

[0174] In another aspect of Formula (III), the peptide has an EC50 potency less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay.

[0175] In another aspect of Formula (III), the peptide has a half-life time of stability of greater than 2 hours, 12 hours, 20 hours, or 24 hours in an SGF assay or an SIF assay, or in both assays.

[0176] In another aspect of Formula (III), the peptide not only has an EC50 potency less than 0.100 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 100 nM in a human LD GLP1R HEK293 cAMP accumulation assay, but also has a half-life time of stability of greater than 2 hours, 12 hours, 18 hours, 20 hours, or 24 hours in an SGF assay and / or an SIF assay

[0177] In another aspect, the invention provides a peptide having an EC50 less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and having a half-life greater than 20 hours in both an SGF assay and an SIF assay, and the peptide comprises or consists of the sequence according to Formula (IV):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is absent;R2 is NH2;XI is 2Me3ImidazolePA, aMe_H, aOH Imidazole PropanoicAcid, Asn, dH, His,Imidazole Propanoic Acid, NMe His, Phe, or Tyr;X2 is Aib, aMe_Pro, or Iva;X3 is Glu or Tetl;X4 is Gly;X5 is Thr;X6 is aMe_Phe_2F;X7 is 40H_Val, Ser, or Thr;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, or Asp;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm,Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_DMG_N_2ae_Palm, Bip_2pEt4pOC2NDMGN2aeC4,Bip_2pEt4pOC2NDMGN2aeC8, Bip_2pEt4pOC2NDMGN2aeC12, Bip_2pEt4pOC2NIsoGlu Palm, Bip_2pEt4pOC2N_MeOPheTag, Bip_2pEt4pOC2N_PEG4_am,Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2,Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag,Bip_2pEt4pOC4N_Arg, Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N,Bip_2pEt4pOC4N_ COC8N,Bip_2pEt4pOC4N_Dap_lPEG2_lPEG2_C18_diacid,_Bip_2pEt4pOC4N_Dap_Albutag,Bip_2pEt4pOC4N_ Dap Palm, Bip_2pEt4pOC4N_DMG_N_2ae_C 18_diacid,Bip_2pEt4pOC4N_MeOPheTag, Bip_2pEt4pOC4N_PEG4_am,Bip_2pEt4pOC4N_PEG4_NHAc, Bip_2pEt4pOC4N_PEG8_am,Bip_2pEt4pOC4N_PEG8_NHAc, Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4NAc,Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc,Bip_2pEt4pOC4NMe3,_Bip_2pEt4pOMe, or Bip_2pMe4pOMe; andXI I is 3_pyridylalanine_4_2_methylphenyl, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Ser, Thr, or Vai.(Formula (IV).)

[0178] In another aspect of Formula (IV), no additional residues can be present at the C- terminus after XI 1.

[0179] In another aspect of Formula (IV), a peptide comprises a sequence according to any of the sub-formulas of Formula (IV), i.e., Formula (IV.A) et al., described in the Detailed Description herein.

[0180] In another aspect, the invention provides a peptide having an IC50 less than 0.010 nM in a human GLP1R HEK293 cAMP accumulation assay and having a half-life greater than 24 hours in both an SGF assay and an SIF assay, and the peptide comprises or consists of the sequence according to Formula (IV.A):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is absent;R2 is NH2;XI is dH, His, or Imidazole Propanoic Acid;X2 is Aib or aMe_Pro;X3 is Glu or Tetl;X4 is Gly;X5 is Thr;X6 is aMe_Phe_2F;X7 is Thr;X8 is Ser;X9 is aMe_Asp;X10: Bip_2pEt4pOMe, or Bip_2pMe4pOMe; andXI I is Bip_2pMe, Bip24_Me, or HHPhe_35Me.(Formula (IV.A).)

[0181] In another aspect of Formula (IV.A), no additional residues can be present at the C- terminus after XI 1.

[0182] In another aspect, the invention provides a peptide having an IC50 less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and having a half-life greater than 20 hours in both an SGF assay and an SIF assay, and the peptide comprises or consists of the sequence according to Formula (IV.B):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is absent;R2 is NH2;XI is dH, His, or Imidazole Propanoic Acid;X2 is Aib, aMe_Pro, or Iva;X3 is Glu or Tetl;X4 is Gly;X5 is Thr;X6 is aMe_Phe_2F;X7 is Ser or Thr;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, or Asp;X10: Bip_2pEt4pOMe, or Bip_2pMe4pOMe; andXI I is 3_pyridylalanine_4_2_methylphenyl, Bip_2pMe, Bip24_Me, HHPhe_35Me, or Hph. (Formula (IV.B).).

[0183] In another aspect of Formula (IV.B), no additional residues can be present at the C- terminus after XI 1.

[0184] In another aspect, the invention provides a peptide having an EC50 less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and having a half-life greater than 20 hours in both an SGF assay and an SIF assay, and the peptide comprises or consists of the sequence according to Formula (IV. C):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is absent;R2 is NH2;XI is dH, His, or Imidazole Propanoic Acid;X2 is Aib, aMe_Pro, or Iva;X3 is Glu or Tetl;X4 is Gly;X5 is Thr or 03 S;X6 is aMe_Phe_2F;X7 is 4OH_Val, Ser, or Thr;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, Asp, or 03 S;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N IsoGlu Palm, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOMe, or Bip_2pMe4pOMe; andXI 1 is 3_pyridylalanine_4_2_methylphenyl, Bip_2pMe, Bip24_Me, HHPhe_35Me, or Hph.(Formula (IV.C).)

[0185] In another aspect of Formula (IV.C), no additional residues can be present at the C- terminus after XI 1.

[0186] In another aspect, the invention provides a peptide having an EC50 less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and having a half-life greater than 20 hours in both an SGF assay and an SIF assay, and the peptide comprises or consists of the sequence according to Formula (IV.D):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is absent;R2 is NH2;XI is aOH Imidazole PropanoicAcid, dH, His, Imidazole Propanoic Acid, or NMe His;X2 is Aib, aMe_Pro, or Iva;X3 is Glu or Tetl;X4 is Gly;X5 is Thr or 03 S;X6 is aMe_Phe_2F;X7 is 4OH_Val, Ser, or Thr;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, Asp, or 03 S;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2N_Ahx_Palm, Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_DMG_N_2ae_Palm,_Bip_2pEt4pOC2N _IsoGlu_Palm,Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheTagBip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Dap_Albutag,Bip_2pEt4pOC4N_Dap_Palm, Bip_2pEt4pOC4N_PEG4, Bip_2pEt4pOMe, or Bip_2pMe4pOMe; andXI 1 is 3_pyridylalanine_4_2_methylphenyl, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, or Hph.(Formula (IV.D).)

[0187] In another aspect of Formula (IV.D), no additional residues can be present at the C- terminus after XI 1.

[0188] In another aspect, the invention provides a peptide having an EC50 less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and having a half-life greater than 20 hours in both an SGF assay and an SIF assay, and the peptide comprises or consists of the sequence according to Formula (IV.E):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is absent;R2 is NH2;XI is 2Me3ImidazolePA, aMe_H, aOH Imidazole PropanoicAcid, Asn, dH, His, Imidazole Propanoic Acid, NMe His, Phe, or Tyr;X2 is Aib, aMe_Pro, or Iva;X3 is Glu or Tetl;X4 is Gly;X5 is Thr;X6 is aMe_Phe_2F;X7 is 4OH_Val, Ser, or Thr;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, or Asp;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm, Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm,Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm,_ Bip_2pEt4pOC2N _IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheTag, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2, Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N, Bip_2pEt4pOC4N_ C0C8N, Bip_2pEt4pOC4N Dap Albutag, Bip_2pEt4pOC4N Dap Palm, Bip_2pEt4pOC4N_MeOPheTag, Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOC4N_PEG4_NHAc, Bip_2pEt4pOC4N_PEG8_am,Bip_2pEt4pOC4N_PEG8_NHAc, Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOMe, or Bip_2pMe4pOMe; andXI 1 is 3_pyridylalanine_4_2_methylphenyl, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Ser, Thr, or Vai.(Formula (IV.E).)

[0189] In another aspect of Formula (IV.E), no additional residues can be present at the C- terminus after XI 1.

[0190] In other aspects, a peptide of the invention that exhibits a half-life time of stability in an SGF assay and / or an SIF assay greater than 20 or greater than 24 hours is suitable for oral formulation and administration.

[0191] In another aspect, the invention provides a method for treating T2DM, the method comprising administering to an individual with T2DM an effective amount of a peptide as described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof.

[0192] In other aspects, the disclosure provides a method for treating obesity or inducing weight loss, the method comprising administering to an individual in need of such a treatment an effective amount of a peptide as described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof.

[0193] Additional therapeutic methods include methods for treating a metabolic syndrome, NASH (nonalcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), or moregenerally, any condition or disease where reductions in blood glucose, increase in insulin, reduction in HbAlc, and / or reduction in weight. Further potential uses for GLP1R agonists include cardiovascular disease such as heart attack and stroke, chronic kidney diseases, neurodegenerative disease including Alzheimer’s and Parkinson’s, sleep apnea, addiction (reducing cravings and improving impulse control), anxiety, depression, polycystic ovary syndrome, gastrointestinal disorders (e.g., gastroparesis and dyspepsia), and arthritis.BRIEF DESCRIPTION OF THE FIGURES

[0194] Figs. 1 A-1NN provide a summary table for different peptide based compounds of the invention. These are representative compounds that exhibit potency in activating or agonizing human GLP1R, and in some case, agonizing both human GLP1R and human GIPR biological activity. Representative compounds that are stable in simulated gastric or intestinal assays are also provided, which may indicate suitability for oral administration. The invention contemplates combining the sequence / structural features of the most potent and stable peptides.

[0195] Figs. 1A-1NN provide three rows of information for each peptide compound. Each peptide compound is given a Compound number (C#). The first row provides information per the columns of the Tables. The second row provides the peptide string sequence of the peptide compound, which string sequence includes terminal chemical moieties if present (i.e., R1 at the N-terminus and R2 at the C-terminus of the peptide string sequence). The third row provides the SMILES string sequence of the peptide compound. SMILES stands for Simplified Molecular Input Line Entry System, which is an ASCII string line notation that represents a chemical structure. The SMILES strings for the compounds disclosed herein can be translated to a two-dimensional chemical structure through numerous publicly available sites, including the Smi2Depict tool from the ChemDB Portal: https: / / re.edugen.wiley.com / cgibin / Smi2DepictWeb.py, or through commercial applications such as ChemDraw. For example, the Figure 2 chemical structures were generated by inputting the SMILES code for the peptides (from Figure 1) into ChemDraw. Conversely, SMILES codes can be generated from a two-dimensional structure in ChemDraw.

[0196] The first column provides information as to molecular weight (MW) in Daltons. Currently, the specific peptides of Figs. 1A-1NN are monomer peptide compounds. However, any monomer disclosed herein can be used to form homodimers, heterodimers (i.e., different monomer peptides dimerized together), homotrimers, homotetramers, or other multimers.

[0197] First row information also includes three columns relating to cyclization. If a peptide compound comprises a monomer that is cyclized, the “Cyclization Positions” column will indicate a pair of residues that are cross-linked. For example, the notation “X6Hcy-X12Hcy” indicates that a homocysteine at position 6 and a homocysteine at position 12 are crosslinked, whether directly or indirectly. The next column, “Cyclization Chemical Bond,” indicates the type of covalent bond that is formed between the pair or pairs of cross-linked residues (whether direct or indirect linkage). The third column relating to cyclization is “Cyclization Linker.” If a Cyclization Linker is present, this indicates that the residues at the Cyclization Positions are indirectly linked, as each Cyclization Position residue makes a direct linkage with the Cyclization Linker. The resultant chemical bonds formed between the Cyclization Position residues and the Cyclization Linker or between the Cyclization Position residues directly is indicated under the Cyclization Chemical Bond column. The Cyclization Positions in this Table are not meant to be limiting, and some compounds might comprise an additional cyclic structure.

[0198] The column “Additional Information” relates to structural or functional.

[0199] The next column is titled “Stability Assays (SGF; SIF) .” As described in more detail herein (e.g., Examples), SGF and SIF are assays that can be used to assess the stability of peptides in conditions that simulate gastric (SGF) and intestinal (SIF) conditions. For compounds that have been tested in one or both of these assays, half-life time of stability data is presented, where : >2 hours of stability is indicated by ++++, 1.5-2 hours is +++, 1-1.5 (not including 1.5) is ++, and <1 hour is +.

[0200] The final column presents potency data, i.e., whether the compound exhibits activating or agonist characteristics for human GLP1R and GIPR biological activity or function. The column provides EC50 data for the peptide compounds with respect to increasing cAMP accumulation in human HEK293 cells expressing GLP1R or GIPR at thecell-surface. Herein, human HEK293 cells expressing high-density (HD) or low-density (LD) levels of human GLP1R were used. See Examples. For GIPR EC50, human HEK293 cells expressing about 45,000-55,000 human GIPR at the cell-surface were used. See Examples. The legend for the EC50 data is: GLP1R HD assay or GIPR assay and single digit picomolar (i.e., 0.00X nM) is ++++, GLP1R LD assay and single digit nanomolar (i.e., OOX.O nM) is ++++; GLP1R HD assay or GIPR assay and two digit picomolar (i.e., 0.0XX nM) is +++; GLP1R LD assay and two digit nanomolar (i.e., OXX.O nM) is +++; GLP1R HD assay or GIPR assay and three digit picomolar (i.e., 0.XXX nM) is ++; GLP1R LD assay and three digit nanomolar (i.e., XXX.O nM) is ++; GLP1R HD assay or GIPR assay equal to or greater than 1 nM and less than 20 nM is +; GLP1R LD assay equal to greater than 1 micromolar and less than 10 micromolar is +. All of the exemplary peptides listed in Figs. 1 A-1NN have a potency less than 20 nM in the human GLP1R HD assay or less than 10 micromolar in the human GLP1R LD assay.

[0201] Figs. 2A-2R show the two-dimensional chemical structures for peptide compounds 3, 4, 13, 19, 44, 72, 73, 76, 78, 80, 81, 83, 101, 116, 125, 150, 165, and 181, respectively.

[0202] Figs. 3A-3D shows pcDNA3.1 expression plasmid maps and coding sequences for human GLP1R and human GIPR.

[0203] Figs. 4A-4C show the results of a mouse Glucose Tolerance Test (GTT), which was used to assess the in vivo glycemic control of the peptides of the invention. Shown are the results for C101 (Fig. 4A), Cl 16 (Fig. 4B), and C150 (Fig. 4C) - all peptides significantly reduced blood glucose levels. See Example 4 regarding Figs. 4A-4C.DETAILED DESCRIPTION OF THE INVENTION

[0204] In general, the present disclosure relates to synthetic or recombinant peptides exhibiting GLP1R and / or GIPR agonist activities and methods of using the same. The invention provides a set of compounds that are at least potent agonists of GLP1R which is exhibited by their sub-nanomolar potency in cAMP functional assays. Further, the invention contemplates peptide compounds that are suitable for oral administration, which is reflected by compound stability in assays that simulate gastric and intestinal conditions.Definitions and Nomenclature

[0205] The present disclosure provides peptide compounds that are mono- or dual-agonists of GLP1R and GIPR. These peptide compounds are synthetic incretin peptide hormone analogs having certain chemical features that underly potency and / or stability. The peptide compounds comprise both natural and unnatural amino acids. Herein, the term “amino acid” refers to both natural and unnatural amino acids.

[0206] As used herein, the “X” notation for residue positions is equivalent to the three-letter “Xaa” notation, and both “X” and “Xaa” mean that any amino acid, natural or unnatural, can be at that position, unless specified otherwise.

[0207] Unless otherwise defined herein, scientific and technical terms used in this application shall have meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art.

[0208] As used herein, the following terms have the meanings ascribed to them in the art unless specified otherwise.

[0209] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer (or components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or components).

[0210] The singular forms “a,” “an,” and “the” include the plurals unless the context clearly dictates otherwise.

[0211] The term “including” is used to mean “including but not limited to.” “Including” and “including but not limited to” are used interchangeably.

[0212] The terms “patient,” “subject,” and “individual” may be used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, livestock animals (e.g., bovines, porcines), companion animals (e.g., canines, felines) and rodents (e.g., mice and rats). The term “mammal” refers to anymammalian species such as a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit, livestock, and the like.

[0213] The term “peptide,” as used herein, refers broadly to a sequence of two or more amino acids joined together by peptide bonds, where such amino acids can be natural or unnatural amino acid residues. Further, it should be understood that this term does not connote a specific length of a polymer of amino acids, nor is it intended to imply or distinguish whether the polypeptide is produced using recombinant techniques, chemical or enzymatic synthesis, or is naturally occurring.

[0214] “About” when referring to a value includes the stated value + / - 10% of the stated value. For example, about 50% includes a range of from 45% to 55%, while about 20 molar equivalents includes a range of from 18 to 22 molar equivalents. Accordingly, when referring to a range, “about” refers to each of the stated values + / - 10% of the stated value of each end of the range. For instance, a ratio of from about 1 to about 3 (weight / weight) includes a range of from 0.9 to 3.3.

[0215] The recitations “sequence identity”, “percent identity”, “percent homology”, or, for example, comprising a “sequence 50% identical to,” as used herein, refer to the extent that sequences are identical on a nucleotide-by-nucleotide basis or an amino acid-by-amino acid basis over a window of comparison. Thus, a “percentage of sequence identity” may be calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, I) or the identical amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Vai, Leu, He, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gin, Cys and Met) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity.

[0216] Calculations of sequence similarity or sequence identity between sequences (the terms are used interchangeably herein) can be performed as follows. To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences can be aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a firstand a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In certain embodiments, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position.

[0217] The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0218] The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In some embodiments, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch, (1970, J. Mol. Biol. 48: 444-453) algorithm which has been incorporated into the GAP program in the GCG software package, using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using an NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. Another exemplary set of parameters includes a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5. The percent identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller (1989, Cabios, 4: 11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

[0219] The peptide sequences described herein can be used as a “query sequence” to perform a search against public databases to, for example, identify other family members or relatedsequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al., (1990, J. Mol. Biol, 215: 403-10). BLAST nucleotide searches can be performed with the NBLAST program, score = 100, word length = 12 to obtain nucleotide sequences homologous to nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, word length = 3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al. (Nucleic Acids Res. 25:3389-3402, 1997). When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0220] The term "conservative substitution" as used herein denotes that one or more amino acids are replaced by another, biologically similar residue. Examples include substitution of amino acid residues with similar characteristics, e.g., small amino acids, acidic amino acids, polar amino acids, basic amino acids, hydrophobic amino acids and aromatic amino acids. See, for example, the table below. In some embodiments of the invention, one or more Met residues are substituted with norleucine (Nle) which is a bioisostere for Met, but which, as opposed to Met, is not readily oxidized. Another example of a conservative substitution with a residue normally not found in endogenous, mammalian peptides and proteins, is the conservative substitution of Arg or Lys with, for example, ornithine, canavanine, aminoethylcysteine or another basic amino acid. In some embodiments, one or more cysteines of a peptide analogue of the invention may be substituted with another residue, such as a serine. For further information concerning phenotypically silent substitutions in peptides and proteins, see, for example, Bowie et.al. Science 247, 1306-1310, 1990. In the scheme below, conservative substitutions of amino acids are grouped by physicochemical properties. I: neutral, hydrophilic, II: acids and amides, III: basic, IV: hydrophobic, V: aromatic, bulky amino acids.

[0221] In the scheme below, conservative substitutions of amino acids are grouped by physicochemical properties. VI: neutral or hydrophobic, VII: acidic, VIII: basic, IX: polar, X:modified amino acids, and non-natural amino acids. It includes both D- and L-amino acids.Natural amino acids include those found in nature, such as, e.g., the 23 amino acids that combine into peptide chains to form the building-blocks of a vast array of proteins. These are primarily L stereoisomers, although a few D-amino acids occur in bacterial envelopes and some antibiotics. The 20 “standard,” natural amino acids are listed in the above tables. The “non-standard,” natural amino acids are pyrrolysine (found in methanogenic organisms andother eukaryotes), selenocysteine (present in many non-eukaryotes as well as most eukaryotes), and N-formylmethionine (encoded by the start codon AUG in bacteria, mitochondria and chloroplasts). “Unnatural” or “non-natural” amino acids are non- proteinogenic amino acids (i.e., those not naturally encoded or found in the genetic code) that either occur naturally or are chemically synthesized. Over 140 unnatural amino acids are known and thousands of more combinations are possible. Examples of “unnatural” amino acids include P-amino acids (P3and p2), homo-amino acids, proline and pyruvic acid derivatives, 3-substituted alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear core amino acids, diamino acids, D-amino acids, alpha-methyl amino acids and N-methyl amino acids. Unnatural or non-natural amino acids also include modified amino acids. “Modified” amino acids include amino acids (e.g., natural amino acids) that have been chemically modified to include a group, groups, or chemical moiety not naturally present on the amino acid.

[0223] All amino acids have a central carbon atom surrounded by a hydrogen atom, a carboxyl group (COOH), an amino group (NH2) and an R-group (also referred to as the sidechain). Amino acids are often modified by attaching chemical moieties to the central carbon atom (also referred to as the a-carbon), side-chain, amino group, or the carboxyl group. For example, a-methyl variants of an amino acids have a methyl group attached to the central carbon, replacing the hydrogen that is normally attached. N-methyl variants have a methyl group attached to the nitrogen of the amino group, replacing a hydrogen. N-methylation (left) vs. alpha-methylation (right) is shown below.

[0224] The names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions suggested by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC -IUB Commission on Biochemical Nomenclature as set out in “Nomenclature of a- Amino Acids (Recommendations, 1974)”Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues employed in this specification and appended claims differ from those suggestions, they will be made clear to the reader.

[0225] Throughout the present specification, unless naturally occurring amino acids are referred to by their full name (e.g., alanine, arginine, etc.), they are designated by their conventional three-letter or single-letter abbreviations (e.g., Ala or A for alanine, Arg or R for arginine, etc.). Unless otherwise indicated, three-letter and single-letter abbreviations of amino acids refer to the L-isomeric form of the amino acid in question. The term “L-amino acid,” as used herein, refers to the “L” isomeric form of a peptide, and conversely the term “D-amino acid” refers to the “D” isomeric form of a peptide (e.g., (D)Asp or D-Asp or dAsp or dD; (D)Phe or D-Phe or dPhe or dF). Amino acid residues in the D isomeric form can be substituted for any L-amino acid residue, whether natural or unnatural, as long as the desired function is retained by the peptide. D-amino acids may be indicated as customary in lower case prefix letter “d ” For example, L-arginine can be represented as “Arg” or “R,” while D- arginine can be represented as “dArg” or “dR .” Similarly, L-lysine can be represented as “Lys” or “K,” while D-lysine can be represented as “dLys” or “dK.” The D-amino acid nomenclature can also be used with unnatural amino acids, e.g., see Table 1.

[0226] The term “linker moiety” or “linker” or “linking moiety” as used herein, refers broadly to a doubly functionalized chemical structure that is capable of linking or joining together at least two chemical groups.

[0227] The term “disulfide bond” or “disulfide linkage” has its conventional meaning, e.g., a R1-S-S-R2 bond. The linkage is also called a disulfide bridge and is usually derived by the coupling of two thiol groups. Amino acids with free thiol groups include Cys, Hey, Hhc, Pen, HhPen, dCys, dPen, dHcy, dHhc, dHhPen, and the like.

[0228] The term “thioether bond” or “thioether linkage” has its conventional meaning, e.g., a R1-S-R2 bond. Thioethers are also called sulfides, and thioethers are typically prepared by alkylation of thiols.

[0229] The term “amide bond” or “amide linkage” has its conventional meaning, e.g., an -NH-C(O)- or a -C(O)-NH- bond. A common preparation is to couple a carboxylic acid with an amine.

[0230] The term “solvate” in the context of the present invention refers to a complex of defined stoichiometry formed between a solute (e.g., a peptide of the invention or pharmaceutically acceptable salt thereof according to the invention) and a solvent. The solvent in this connection may, for example, be water, ethanol or another pharmaceutically acceptable, typically small-molecular organic species, such as, but not limited to, acetic acid or lactic acid. When the solvent in question is water, such a solvate is normally referred to as a hydrate.

[0231] The term “alkyl” includes a straight chain or branched, noncyclic or cyclic, saturated aliphatic hydrocarbon containing from 1 to 24 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, methyl, ethyl, w-propyl, / / -butyl, w-pentyl, w-hexyl, and the like, while saturated branched alkyls include, without limitation, isopropyl, ec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, while unsaturated cyclic alkyls include, without limitation, cyclopentenyl, cyclohexenyl, and the like.

[0232] The term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include Ci-4, Ci-6, C1-20 and the like.

[0233] The term “alkyl” includes a straight chain or branched, noncyclic or cyclic, saturated aliphatic hydrocarbon containing from 1 to 24 carbon atoms. The term “Cn-m alkyl,” refers to an alkyl group having n to m carbon atoms. For example, “C1-6 alkyl” refers to a hydrocarbon radical straight or branched, containing from 1 to 6 carbon atoms that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Representative saturated straight chain alkyls include, but are not limited to, methyl, ethyl, w-propyl, w-butyl, w-pentyl, w-hexyl, and the like, while saturated branched alkyls include, without limitation, isopropyl, ec-butyl, isobutyl, tert-butyl, isopentyl, and the like.

[0234] The term “alkylene” refers to a divalent alkyl group, particularly having from 1 to 24 carbon atoms. The term is exemplified by groups such as methylene (-CH2-), ethylene (- CH2CH2-), the propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-) and the like.

[0235] The term “alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

[0236] The term “alkenyl” alone or in combination with other terms, means a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with one C-H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound. The term "Cn-m alkenyl" refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 16, 2 to 14, or 2 to 8 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, ^-propenyl, isopropenyl, n- butenyl, ec-butenyl, 5-pentenyl, 8-octenyl, and the like.

[0237] The term “alkenylene” means a straight or branched bivalent hydrocarbon chain containing at least one carbon-carbon double bond. Representative alkenylene include - CH=CH-, -CH2 CH=CH-, -C(CH3)=CH-, -CH2 CH=CHCH2-, and the like.

[0238] The term “cycloalkyl” or “carbocycle” by themselves or in combination with other terms means cyclic versions of "alkyl" in which all ring atoms are carbon. "Cycloalkyl" or "carbocycle" refers to a mono- or polycyclic group. When used in connection with cycloalkyl substituents, the term "polycyclic" refers herein to fused and non-fused alkyl cyclic structures. "Cycloalkyl" or "carbocycle" may form a bridged ring or a spiro ring. In some embodiments, the cycloalkyl group may have one or more double or triple bond(s) in the cycloalkyl ring. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0239] The term “halo” or “halogen” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo or iodo.

[0240] The term “haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen.For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moi eties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like.

[0241] The term “alkanoyl” means an alkyl-C(O)- group, wherein the alkyl group is as defined herein. Representative alkanoyl groups include methanoyl, ethanoyl, 3- methylbutanoyl, and the like.

[0242] “Benzyl” means a phenyl-CEk - group. Representative benzyl include 4-bromobenzyl, 4-methoxybenzyl, 4-aminobenzyl, and the like.

[0243] “Carbamoyl” means a group of formula R^^NCO- wherein Rxand Ryare independently hydrogen or alkyl. Representative carbamoyl groups include carbamoyl (H2NCO-), methylcarbamoyl (MeNHCO-), and the like.

[0244] “ Thiol”, “mercapto” or “sulfanyl” means an -SH group.

[0245] The term “alkylthio” means an alkyl-S- group, wherein the alkyl group is defined herein. Representative alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, and the like.

[0246] As used herein, “functional group” on the side chain of an amino acid means -COOH, -NH2, -NH-, -SH, -SCH3, -OH, -C(O)NH2, guanidinyl, imidazoyl, pyrrolidinyl, phenyl, indolyl, and the like.

[0247] The term “NH2,” as used herein, refers to the free amino group that is often present at the amino terminus of a peptide. The term “OH,” as used herein, refers to a free carboxy group, often present at the carboxy terminus of a peptide. Further, the term “Ac,” as used herein, refers to acetyl group, wherein acetyl protection of a NH2 terminus of a peptide can be achieved through acylation.

[0248] The term “carboxy,” as used herein, refers to -CO2H.

[0249] In the case of less common or non-naturally occurring amino acids, unless they are referred to by their full name (e.g., sarcosine, ornithine, etc.), frequently employed three- orfour-character codes are employed for residues thereof, including, Sar or Sarc (sarcosine, i.e. N-methylglycine), Aib (a-aminoisobutyric acid), Daba (2,4-diaminobutanoic acid), Dapa (2,3 -diaminopropanoic acid), y-Glu (y-glutamic acid), pGlu (pyroglutamic acid), Gaba (y- aminobutanoic acid), P-Pro (pyrrolidine-3 -carboxylic acid), 8 Ado (8-amino-3,6- dioxaoctanoic acid), Abu (2-aminobutyric acid), bhPro (P-homo-proline), bhPhe (P-homo-L- phenylalanine), bhAsp (P-homo-aspartic acid]), Dpa (P,P diphenylalanine), Ida (Iminodiacetic acid), hCys (homocysteine), bhDpa (P-homo-P,P -diphenylalanine). Additional unnatural amino acids are listed in Table 1.

[0250] As is clear to the skilled artisan, the peptide sequences disclosed herein are shown proceeding from left to right, with the left end of the sequence being the N-terminus of the peptide and the right end of the sequence being the C-terminus of the peptide. In many embodiments, peptide sequences disclosed herein comprise an “Ac” (acetyl) moiety at the amino terminus (N-terminus) and an “Am” moiety (amine; see Table 1, “am” = H2N-R1) (which covers amide moi eties when Ri of H2N-R1 comprises a carbonyl) as well at the carboxy terminus (C-terminus) of the sequence. In some cases, a “H” moiety at the N- terminus indicates a hydrogen atom, corresponding to the presence of a free primary or secondary amino group at the N-terminus, while an “-OH” or an “-NH2” moiety at the C- terminus of the sequence indicates a hydroxy group or an amino group, corresponding to the presence of an amido (CONH2) group at the C-terminus, respectively. In each sequence of the invention, a C-terminal “-OH” moiety may be substituted for a C-terminal “-NH2” moiety, and vice-versa. Peptide Formulas of the invention refer to N-terminal moieties as an “RI” (or Ri) group and C-terminal moieties as an “R2” (or R2) group.

[0251] As used herein, the term "cycle” or “cyclic” and the like, refers to a molecule having a chemical structure that includes a ring or cycle formed by at least eight covalently bonded ring atoms. In some embodiments, a cyclic peptide means the peptide comprises a ring or cycle formed by at least 9 covalently bonded ring atoms. The term “cyclized” or “cyclization,” as used herein, refers to a reaction in which one part of a peptide molecule becomes linked to another part of the peptide molecule to form a closed ring, such as by forming a disulfide bridge or other similar bond. Herein, a “cyclic peptide,” is a peptide thathas been cyclized or “cross-linked” (an intramolecular cross-link) by covalently bonding two amino acids together, whether directly or indirectly through a cyclization linker.

[0252] One of skill in the art will appreciate that certain amino acids and other chemical moieties are modified when bound to another molecule. For example, an amino acid side chain may be modified when it forms an intramolecular bridge with another amino acid side chain, e.g., one or more hydrogen may be removed or replaced by the bond. As conventionally understood, each amino acid has a specific side chain, known as an R group, that is attached to the a carbon. Unnatural amino acids often differ from natural amino acids by side chain substitution. Amino acid side chains, natural or unnatural, can comprise “reactive” or “free” substituent chemical moieties that can form chemical bonds with other molecules. For example, the side-chain of cysteine comprises a free thiol (sulfhydryl) group that can react with another free thiol group to form a disulfide bond or with a free alkyl group to form a thioether bond.

[0253] “Pharmaceutically effective amount” refers to an amount of a compound of the invention in a composition or combination thereof that provides the desired therapeutic or pharmaceutical result.

[0254] “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0255] Provided are also pharmaceutically acceptable salts and tautomeric forms of the compounds described herein. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0256] The term “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the peptides or compounds of the present invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity,irritation, and allergic response; which are commensurate with a reasonable benefit / risk ratio, and which are effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, di gluconate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, tri chloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Also, amino groups in the compounds of the present invention can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. A pharmaceutically acceptable salt may suitably be a salt chosen, e.g., among acid addition salts and basic salts. Examples of acid addition salts include chloride salts, citrate salts and acetate salts. Examples of basic salts include salts where the cation is selected among alkali metal cations, such as sodium or potassium ions, alkaline earth metal cations, such as calcium or magnesium ions, as well as substituted ammonium ions, such as ions of the type NX4+(wherein X is Ci-Ce alkyl). Also included are base addition salts, such as sodium or potassium salts. Other examples of pharmaceutically acceptable salts are described in “Remington’s Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), in the “Encyclopaedia of Pharmaceutical Technology”, 3rd edition, James Swarbrick (Ed.), InformaHealthcare USA (Inc.), NY, USA, 2007, and in J. Pharm. Sci. 66: 2 (1977). Also, for a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, andUse by Stahl and Wermuth (Wiley-VCH, 2002). Other suitable base salts are formed from bases which form non-toxic salts. Representative examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases may also be formed, e.g., hemisulphate and hemicalcium salts.

[0257] Compounds described herein may include isotopically labeled compounds, which are identical to those recited in the various formulas and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as2H,3H,X3C,14C,15N,18O,170,35S,18F,36C1, respectively. Certain isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Further, substitution with isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In particular embodiments, the compounds disclosed herein are isotopically substituted with deuterium. In more particular embodiments, one or more hydrogen atoms in the compounds disclosed herein can be replaced by a deuterium atom or D.

[0258] The compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where compounds are represented in their chiral form, it is understood that the aspect encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the aspect is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s). As used herein, “scalemic mixture” is a mixture of stereoisomers at a ratio other than 1 : 1.

[0259] “ Stereoisomer” and “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0260] “ Tautomer” refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- and a ring =N- such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0261] “Therapeutically effective amount” or “effective amount” as used herein refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to affect such treatment for the disease. The effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. As is understood in the art, aneffective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any coadministered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0262] “ Treatment” or “treat” or “treating” as used herein refers to an approach for obtaining beneficial or desired results. For purposes of the present invention, beneficial or desired results include, but are not limited to, alleviation of a symptom and / or diminishment of the extent of a symptom and / or preventing a worsening of a symptom associated with a disease or condition. In one aspect, “treatment” or “treating” includes one or more of the following: (a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); (b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); (c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival; and (d) preventing the disease, condition or disorder in a subject who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease. In some embodiments, treating refers to inhibiting or ameliorating the disease. In some embodiments, treating is preventing the disease.

[0263] “ Co-administration” as used herein refers to administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some aspects, a unit dose of a compound of the invention is administered first, followed within seconds or minutes by administration of a unit dose of oneor more additional therapeutic agents. Alternatively, in other aspects, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes. In some aspects, a unit dose of a compound of the invention is administered first, followed, after a period of hours (e.g., 1- 12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other aspects, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the invention. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient.

[0264] The term “Polyethylene glycol” or “PEG” is a polyether compound of general formula H-(O-CH2-CH2)n-OH. PEGs are also known as polyethylene oxides (PEOs) or polyoxyethylenes (POEs), depending on their molecular weight PEO, PEE, or POG, as used herein, refers to an oligomer or polymer of ethylene oxide. The three names are chemically synonymous, but PEG has tended to refer to oligomers and polymers with a molecular mass below 20,000 g / mol, PEO to polymers with a molecular mass above 20,000 g / mol, and POE to a polymer of any molecular mass. PEG and PEO are liquids or low-melting solids, depending on their molecular weights. Throughout this disclosure, the three names may be used indistinguishably. PEGs are prepared by polymerization of ethylene oxide and are commercially available over a wide range of molecular weights from 300 g / mol to 10,000,000 g / mol. While PEG and PEO with different molecular weights find use in different applications, and have different physical properties (e.g., viscosity) due to chain length effects, their chemical properties are nearly identical. The polymeric moiety is preferably water-soluble (amphiphilic or hydrophilic), non-toxic, and pharmaceutically inert. Suitable polymeric moi eties include polyethylene glycols (PEG), homo- or co-polymers of PEG, a monomethyl-substituted polymer of PEG (mPEG), or polyoxyethylene glycerol (POG). See, for example, Int. J. Hematology 68: 1 (1998); Bioconjugate Chem. 6: 150 (1995); and Crit.Rev. Therap. Drug Carrier Sys. 9:249 (1992). Also encompassed are PEGs that are prepared for purpose of half-life extension, for example, mono-activated, alkoxy -terminated polyalkylene oxides (POA’s) such as mono-methoxy -terminated polyethyelene glycols (mPEG’s); bis activated polyethylene oxides (glycols) or other PEG derivatives are also contemplated. Suitable polymers will vary substantially by weights ranging from about 200 to about 40,000 are usually selected for the purposes of the present invention. In certain embodiments, PEGs having molecular weights from 200 to 2,000 daltons or from 200 to 500 daltons are used. Different forms of PEG may also be used, depending on the initiator used for the polymerization process, e.g., a common initiator is a monofunctional methyl ether PEG, or methoxypoly(ethylene glycol), abbreviated mPEG. Other suitable initiators are known in the art and are suitable for use in the present invention.

[0265] Lower-molecular-weight PEGs are also available as pure oligomers, referred to as monodisperse, uniform, or discrete. These are used in certain embodiments of the present invention.

[0266] PEGs are also available with different geometries: branched PEGs have three to ten PEG chains emanating from a central core group; star PEGs have 10 to 100 PEG chains emanating from a central core group; and comb PEGs have multiple PEG chains normally grafted onto a polymer backbone. PEGs can also be linear. The numbers that are often included in the names of PEGs indicate their average molecular weights (e.g. a PEG with n = 9 would have an average molecular weight of approximately 400 daltons, and would be labeled PEG 400.

[0267] As used herein, “PEGylation” is the act of coupling (e.g., covalently) a PEG structure to a desired molecule forming a PEGylated molecule. Herein, in some embodiments, a linker molecule comprising a PEG structure connects two peptides of the invention thereby forming a dimeric molecule (e.g., a homodimer comprising two identical peptide monomers or a heterodimer comprising two different peptide monomers). Herein, PEG comprising linkers can be used as dimerization linkers and / or to improve the in vivo half-life of the peptide compounds of the invention.

[0268] The skilled worker will be well aware of suitable techniques which can be used to perform the coupling reaction. As discussed herein, PEG linkers can comprise one or more reactive groups (and for dimerization, at least two separate functional groups), including an amine, carboxylic acid, and acrylate groups. Further, a PEG moiety bearing a methoxy group can be coupled to a Cys thiol group by a maleimido linkage using reagents commercially available from Nektar Therapeutics AL.

[0269] For the most part, the names of naturally occurring and non-naturally occurring aminoacyl residues used herein follow the naming conventions suggested by the IUPAC Commission on the Nomenclature of Organic Chemistry and the IUPAC -IUB Commission on Biochemical Nomenclature as set out in “Nomenclature of a-Amino Acids (Recommendations, 1974)” Biochemistry, 14(2), (1975). To the extent that the names and abbreviations of amino acids and aminoacyl residues employed in this specification and appended claims differ from those suggestions, they will be made clear to the reader. Some abbreviations useful in describing the invention are defined below in the following Table 1. Table 1 does not usually include D-forms of amino acids (natural or unnatural) - the POSA understands that the stereogenic carbon alpha to the amino group simply has the D- configuration rather than the L-configuration.Table 1. Abbreviations of Non-Natural Amino Acids and Chemical MoietiesIllPeptide Structures

[0270] The peptide compounds of the invention are synthetic or recombinant peptide-based compounds that bind to and agonize / activate human GLP1R, and in some case, also human GIPR. The peptide compounds of the invention are potent agonists, which is reflected by nanomolar and sub-nanomolar EC50 values for the peptides in inducing cAMP accumulation in HEK-293 cells that stably express human GLP1R or GIPR. In other embodiments, the peptide compounds exhibit stability in a simulated gastrointestinal degradation assays (SGF and SIF assays). The peptide compounds may exhibit potential for oral administration as reflected by time of stability in the SGF and SIF assays. However, peptide compounds that do not exhibit stability in such assays are still suitable for other modes of administration, e.g., subcutaneous injection or intravenous injection. In certain instances, the peptide compounds will have both nanomolar (or less) potency and stability. As explained hereinbelow, the peptide compounds of the invention can be categorized into various groupings based on one or more structural or functional features.

[0271] In most embodiments, the main subunit of the peptide compounds of the invention is a string of natural and / or unnatural amino acids mostly having a length of 11 amino acids. This main subunit can be referred to as a monomer, monomer peptide, a monomeric unit or subunit, a monomeric peptide, and the like. Sometimes the monomer includes a chemical moiety, that is not a natural or unnatural amino acid, interspersed within the carbon backbone of the string of amino acids (natural and / or unnatural. In other words - a chemical moiety that is not an amino acid will only be given an X position within a sequence formula if is not at the terminal ends of the peptide string (as such non-amino acid moieties present at a terminal end of a peptide string are identified as R1 or R2 within a sequence formula). A monomer ofthe invention can have a linear structure or comprise a cyclic structure. A monomer of the invention can also be part of a multimeric molecule, whether a homodimeric molecule, a heterodimeric molecule, or other multimers such as homotrimers and homotetramers. Multimeric molecules can be formed by joining monomer subunits by any conventional means. In some embodiments, dimeric molecules can be formed by covalently linking monomers directly, or indirectly through a dimerization linker molecule.

[0272] For all Formulas (including SEQ ID NOs) of the invention, the sequence can comprise natural and unnatural amino acids, as well as chemical moieties that are not natural or unnatural amino acids. Abbreviations for unnatural amino acids and chemical moieties are provided in Table 1. The sequences reflect a linear monomer peptide sequence and do not necessarily reflect the secondary structure of the peptide compound. Figs. 1A-1NN provide information for when the linear monomer peptide sequence underlies a cyclic peptide structure. When the peptide-based compounds comprise a cyclic structure, at least two positions in the linear peptide sequence will be connected or cross-linked, whether through a direct covalent linkage or through an indirect covalent linkage (where at least two positions in the peptide sequence each make an independent covalent linkage with a cyclization linker).

[0273] For the Formulas, including the SEQ ID NO formulas, the R1(or Rl) and R2(or R2) positions represent non-amino acid (natural or unnatural) chemical moieties that are present on the terminal ends of the linear amino acid sequence.

[0274] To the extent that a Formula is described differently between different parts of the application, the Formulas should be reconciled by over-inclusion. For example, if a Formula in one part of the application states that a particular X position can have a residue not described for the same Formula in another part of the application, then the Formula should include the residue.

[0275] In some embodiments, the invention provides peptides that are agonists of at least human GLP1R comprising an amino acid sequence according to Formula (I): Rkxi-x -xs-xd-xs-xe^-xs-X -xio-xii-xi -xis-xid-xis-xie-xn-xis-xi - X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2is NH2 , OH, Palm, or absent;XI is 2Me3ImidazolePA, 2Pal, 3Pal, 4Pal, aMe His, aOH Imidazole PropanoicAcid, Asn, Cit, dH, hHis, His, His lMe, His_3Me, His Bzl, Imidazole Propanoic Acid, Lys Dimethyl, Lys_Me3, NMe His, Om, Phe, Pyrrole PA, Quin_3, or Tyr;X2 is Aib, Ala, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe_Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Cys, dHcy, Gly, Hey, Hhc, Iva, Pen, HhPen, or Vai;X3 is aMe Glu, Asp, Cysteate, Glu, Gia, Gin, He, Leu, Tetl, or Tet2;X4 is Ala, Aib, Asn, Gly, Lys, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Glu, Hey, Hhc, HhPen, He, Leu, Lys, NMe_K, 03 S,03 S Reduced, Pen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 40H_Val, Asn, Asp, Dap, Diaminobutanoic Acid, Ser, Thr, Thr Ac, Thr Me, TThioamide, or Vai;X8 is Aad, Ala, Abu, aMe_Ser, Asp, Dap, dS, Fur, Gin, Gly, hSer, Ser, Ser_Bz, orS Thioamide;X9 is Aad, aMe_Asp, aMe_Glu, Api, Arg, Asp, Asp_OMe, bE, bMeAsp, Cysteate, dD, diMe Asp, Gia, Glu, Hhc, Lys, Lys_PEG2_IsoGlu_Palm, NMe_E, 03 S, 03S_Reduced, Tetl, Tet2, or Tyr;X10: aMeBip2pMe4pOMe, Bip_2pEt4pOC2N, Bip_2pEt4pOC2NC2N,Bip_2pEt4pOC2NDMGN2aeC4, Bip_2pEt4pOC2NDMGN2aeC8,Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm,Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_Dap_MeOPheTag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm, Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheT ag, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_C4,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2, Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm,Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Arg, Bip_2pEt4pOC4N_COC 12N,Bip_2pEt4pOC4N_COC4N, Bip_2pEt4pOC4N_ C0C8N, Bip_2pEt4pOC4N_Dap_Albutag,Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_Dap_Palm,Bip_2pEt4pOC4N_DMG_N_2ae_C 18_diacid, Bip_2pEt4pOC4N_DMG_N_2ae_LysAc,Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC4N_MeOPheT ag,Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOC4N_PEG4_NHAc,Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc,Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4N_PEGl 6_NHAc,Bip_2pEt4pOC4N2DMGN2ae, Bip_2pEt4pOC4NDMGN2ae,Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NLys,Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOC4NMe3,_Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, NMeBip2pMe4pOMe, or Tyr;XI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl,34Dimethyoxyphenyl, 35_DiemthylPhenyl, 3choloro4fluorophenyl, 3 chlorophenyl,3 Methoxy phenyl, aMe Ser, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me,Hph, Phe, Phe_2Ad, Pyridin3yl, Quinolin_5_yl, Ser, Thr, Tyr, or Vai;X12 is Gly or absent;XI 3 is Glu, Gly, or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Val or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent.(Formula (I).)

[0276] In other embodiments, the invention provides a peptide comprising or consisting of a sequence according to any of the following sub-formulas of Formula (I), i.e., Formula (I. A) et al., laid out below.

[0277] In one embodiment, the invention provides peptides that are mono- or dual- agonists of GLP1R and GIPR, wherein the peptide comprises or consist of a sequence according to Formula (I. A):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is Ra-C(O)- or hydrogen, wherein Ra is Cl-20 alkyl or C3-8 cycloalkyl; or R1 is acetyl, isovaleric acid, cyclohexanecarboxylic acid, or absent;R2 is NH2 or OH or absent;XI is 2Pal, 3Pal, 4Pal, His, Imidazole Propanoic Acid, NMe His, or Tyr;X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_Ile, aMe_Leu, aMe_Pro, aMe Ser, aMe Val, Cap, Cys, dHcy, Hey, Hhc, Pen, or HhPen;X3 is aMe Glu, Glu, Gla, Gin, or Tetl;X4 is Ala, Aib, Asn, Gly, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Hey, Hhc, Pen, HhPen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Thr or Thr Ac;X8 is Abu, aMe_Ser, hSer, or Ser;X9 is aMe_Asp, aMe_Glu, Asp, Gla, Glu, or Tetl;XI 0: Bip_2pEt4pOMe, Bip_2pMe4pOMe, or Tyr;XI I is Bip_2pMe, HHPhe_35Me, Hph, or Ser;X12 is Gly or absent;XI 3 is Gly or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Vai or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent; wherein the peptide optionally comprises a cyclic structure wherein X2 and X5 are individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen, which are directly covalently linked or indirectly covalently linked through a cyclization linker.(Formula (I. A).)

[0278] In one embodiment, the invention provides peptides that are at least agonists of human GLP1R, wherein the peptide comprises or consist of a sequence according to Formula (I B):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is Ra-C(O)- or hydrogen, wherein Ra is Cl-20 alkyl or C3-8 cycloalkyl; or R1 is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2 is NH2 , OH, Palm, or absent;XI is 2Pal, 3Pal, 4Pal, aMe His, Asn, Cit, dH, His, His lMe, His_3Me, His Bzl, Imidazole Propanoic Acid, Lys Dimethyl, Lys_Me3, NMe His, Om, Quin_3, or Tyr;X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe_Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Cys, dHcy, Hey, Hhc, Iva, Pen, or HhPen;X3 is aMe_Glu, Asp, Cysteate, Glu, Gia, Gin, Tetl, or Tet2;X4 is Ala, Aib, Asn, Gly, Lys, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Glu, Hey, Hhc, HhPen, Lys, Pen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Asn, Asp, Dap, Ser, Thr, Thr Ac, Thr Me, TThioamide, or Vai;X8 is Aad, Ala, Abu, aMe_Ser, Asp, Dap, dS, Fur, Gin, Gly, hSer, Ser, Ser_Bz, orS Thioamide;X9 is Aad, aMe_Asp, aMe_Glu, Api, Arg, Asp, Asp_OMe, bE, bMeAsp, Cysteate, dD, Gia, Glu, Lys, Lys_PEG2_IsoGlu_Palm, Tetl, Tet2, or Tyr;X10: aMeBip2pMe4pOMe, Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, NMeBip2pMe4pOMe, or Tyr;XI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, aMe_Ser, Bip_2pMe, Bip24_Me, HHPhe_35Me, Hph, Phe, Phe_2Ad, or Ser;X12 is Gly or absent;XI 3 is Glu, Gly, or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Val or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent; wherein the peptide optionally comprises a cyclic structure wherein: (i) X2 and X5 are individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen, which are directly covalently linked or indirectly covalently linked through a cyclization linker, or (ii) X5 is Lys and XI 3 is Glu which are directly covalently linked through an amide bond (i.e., a cyclic amide, or lactam bond).(Formula (LB).)

[0279] In one embodiment, the invention provides peptides that are at least agonists of human GLP1R, wherein the peptide comprises or consist of a sequence according to Formula (I Q:R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is Ra-C(O)- or hydrogen, wherein Ra is Cl-20 alkyl or C3-8 cycloalkyl; or R1 is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2 is NH2, OH, Palm, or absent;XI is 2Pal, 3Pal, 4Pal, aMe His, Asn, Cit, dH, His, His lMe, His_3Me, His Bzl, Imidazole Propanoic Acid, Lys Dimethyl, Lys_Me3, NMe His, Om, Quin_3, or Tyr; X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe_Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Cys, dHcy, Hey, Hhc, Iva, Pen, or HhPen;X3 is aMe_Glu, Asp, Cysteate, Glu, Gia, Gin, Tetl, or Tet2;X4 is Ala, Aib, Asn, Gly, Lys, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Glu, Hey, Hhc, HhPen, Lys, Pen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 40H_Val, Asn, Asp, Dap, Ser, Thr, Thr Ac, Thr Me, TThioamide, or Vai;X8 is Aad, Ala, Abu, aMe_Ser, Asp, Dap, dS, Fur, Gin, Gly, hSer, Ser, Ser_Bz, orS Thioamide;X9 is Aad, aMe_Asp, aMe_Glu, Api, Arg, Asp, Asp_OMe, bE, bMeAsp, Cysteate, dD, Gia, Glu, Lys, Lys_PEG2_IsoGlu_Palm, Tetl, Tet2, or Tyr;X10: aMeBip2pMe4pOMe, Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, NMeBip2pMe4pOMe, or Tyr;XI I is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphenyl, 3choloro4fluorophenyl, 3 chlorophenyl, 3 Methoxy phenyl, aMe_Ser, Bip_2pMe, Bip24_Me, HHPhe_35Me, Hph, Phe, Phe_2Ad, or Ser;X12 is Gly or absent;XI 3 is Glu, Gly, or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Val or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent;(Formula (I.C).)

[0280] In another embodiment, the invention provides peptides that are at least agonists of human GLP1R, wherein the peptide comprises or consist of a sequence according to Formula (I D):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is Ra-C(O)- or hydrogen, wherein Ra is Cl-20 alkyl or C3-8 cycloalkyl; or R1 is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2 is NH2, OH, Palm, or absent;XI is 2Pal, 3Pal, 4Pal, aMe His, Asn, Cit, dH, hHis, His, His lMe, His_3Me, His Bzl, Imidazole Propanoic Acid, Lys Dimethyl, Lys_Me3, NMe His, Om, Phe, Pyrrole PA, Quin_3, or Tyr;X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe_Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Cys, dHcy, Hey, Hhc, Iva, Pen, or HhPen;X3 is aMe Glu, Asp, Cysteate, Glu, Gia, Gin, He, Leu, Tetl, or Tet2;X4 is Ala, Aib, Asn, Gly, Lys, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Glu, Hey, Hhc, HhPen, He, Leu, Lys, NMe_K, 03 S,03 S Reduced, Pen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 40H_Val, Asn, Asp, Dap, Diaminobutanoic Acid, Ser, Thr, Thr Ac, Thr Me, TThioamide, or Vai;X8 is Aad, Ala, Abu, aMe_Ser, Asp, Dap, dS, Fur, Gin, Gly, hSer, Ser, Ser_Bz, orS Thioamide;X9 is Aad, aMe_Asp, aMe_Glu, Api, Arg, Asp, Asp_OMe, bE, bMeAsp, Cysteate, dD, diMe Asp, Gia, Glu, Hhc, Lys, Lys_PEG2_IsoGlu_Palm, NMe_E, 03 S, O3S_Reduced, Tetl, Tet2, or Tyr;X10: aMeBip2pMe4pOMe, Bip_2pEt4pOC2N,Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid, Bip_2pEt4pOC2N_Albutag,Bip_2pEt4pOC2N_Dap_Albutag, Bip_2pEt4pOC2N_Dap_MeOPheT ag, Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC4N,Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Dap_Albutag, Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, NMeBip2pMe4pOMe, or Tyr;XI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphenyl, 35_DiemthylPhenyl, 3choloro4fluorophenyl, 3 chlorophenyl, 3 Methoxy phenyl, aMe Ser, Bip_2pMe, Bip24_Me, HHPhe_35Me, Hph, Phe, Phe_2Ad, Pyridin3yl, Quinolin_5_yl, or Ser;X12 is Gly or absent;XI 3 is Glu, Gly, or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Val or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent;(Formula (LD).)

[0281] In one embodiment, the invention provides peptides that are at least agonists of human GLP1R, wherein the peptide comprises or consist of a sequence according to Formula (I E):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is Ra-C(O)- or hydrogen, wherein Ra is Cl-20 alkyl or C3-8 cycloalkyl; or R1 is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2 is NH2, OH, Palm, or absent;XI is 2Pal, 3Pal, 4Pal, aMe His, aOH Imidazole PropanoicAcid, Asn, Cit, dH, hHis, His, His lMe, His_3Me, His Bzl, Imidazole Propanoic Acid, Lys Dimethyl, Lys_Me3, NMe His, Orn, Phe, Pyrrole PA, Quin_3, or Tyr;X2 is Aib, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe_Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Cys, dHcy, Hey, Hhc, Iva, Pen, or HhPen;X3 is aMe Glu, Asp, Cysteate, Glu, Gia, Gin, He, Leu, Tetl, or Tet2;X4 is Ala, Aib, Asn, Gly, Lys, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Glu, Hey, Hhc, HhPen, He, Leu, Lys, NMe_K, 03 S, 03 S Reduced, Pen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 40H_Val, Asn, Asp, Dap, Diaminobutanoic Acid, Ser, Thr, Thr Ac, Thr Me, TThioamide, or Vai;X8 is Aad, Ala, Abu, aMe_Ser, Asp, Dap, dS, Fur, Gin, Gly, hSer, Ser, Ser_Bz, orS Thioamide;X9 is Aad, aMe_Asp, aMe_Glu, Api, Arg, Asp, Asp_OMe, bE, bMeAsp, Cysteate, dD, diMe Asp, Gia, Glu, Hhc, Lys, Lys_PEG2_IsoGlu_Palm, NMe_E, 03 S, 03S_Reduced, Tetl, Tet2, or Tyr;X10: aMeBip2pMe4pOMe, Bip_2pEt4pOC2N,Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid, Bip_2pEt4pOC2N_Ahx_Palm, Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_Dap_MeOPheTag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm, Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheT ag, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC4N,Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid, Bip_2pEt4pOC4N_Ahx_Palm,Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Dap_Albutag,Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_Dap_Palm, Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, NMeBip2pMe4pOMe, or Tyr;XI I is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphenyl, 35_DiemthylPhenyl, 3choloro4fluorophenyl, 3 chlorophenyl,3 Methoxy phenyl, aMe Ser, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Phe, Phe_2Ad, Pyridin3yl, Quinolin_5_yl, or Ser;X12 is Gly or absent;XI 3 is Glu, Gly, or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Vai or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent;(Formula (I E).)

[0282] In one embodiment, the invention provides peptides that are at least agonists of human GLP1R, wherein the peptide comprises or consist of a sequence according to Formula (I F):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is Ra-C(O)- or hydrogen, wherein Ra is Cl-20 alkyl or C3-8 cycloalkyl; or R1 is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2 is NH2 , OH, Palm, or absent;XI is 2Me3ImidazolePA, 2Pal, 3Pal, 4Pal, aMe His, aOH Imidazole PropanoicAcid, Asn, Cit, dH, hHis, His, His lMe, His_3Me, His Bzl, Imidazole Propanoic Acid, Lys Dimethyl, Lys_Me3, NMe His, Om, Phe, Pyrrole PA, Quin_3, or Tyr;X2 is Aib, Ala, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe_Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Cys, dHcy, Gly, Hey, Hhc, Iva, Pen, or HhPen;X3 is aMe Glu, Asp, Cysteate, Glu, Gia, Gin, He, Leu, Tetl, or Tet2;X4 is Ala, Aib, Asn, Gly, Lys, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Glu, Hey, Hhc, HhPen, He, Leu, Lys, NMe_K, 03 S, 03 S Reduced, Pen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 40H_Val, Asn, Asp, Dap, Diaminobutanoic Acid, Ser, Thr, Thr Ac, Thr Me, TThioamide, or Vai;X8 is Aad, Ala, Abu, aMe_Ser, Asp, Dap, dS, Fur, Gin, Gly, hSer, Ser, Ser_Bz, orS Thioamide;X9 is Aad, aMe_Asp, aMe_Glu, Api, Arg, Asp, Asp_OMe, bE, bMeAsp, Cysteate, dD, diMe Asp, Gia, Glu, Hhc, Lys, Lys_PEG2_IsoGlu_Palm, NMe_E, 03 S, 03S_Reduced, Tetl, Tet2, or Tyr;X10: aMeBip2pMe4pOMe, Bip_2pEt4pOC2N,Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm,Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_Dap_MeOPheTag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm, Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheT ag, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12,_Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2,Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N, Bip_2pEt4pOC4N_ C0C8N, Bip_2pEt4pOC4N_Dap_Albutag, Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_Dap_Palm, Bip_2pEt4pOC4N_IsoGlu_Palm,Bip_2pEt4pOC4N_MeOPheTag, Bip_2pEt4pOC4N_PEG4_am,Bip_2pEt4pOC4N_PEG4_NHAc, Bip_2pEt4pOC4N_PEG8_am,Bip_2pEt4pOC4N_PEG8_NHAc, Bip_2pEt4pOC4N_PEGl 6_am,Bip_2pEt4pOC4N_PEGl 6_NHAc, Bip_2pEt4pOC4N2DMGN2ae,Bip_2pEt4pOC4NDMGN2ae, Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, NMeBip2pMe4pOMe, or Tyr;XI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphenyl, 35_DiemthylPhenyl, 3choloro4fluorophenyl, 3 chlorophenyl,3 Methoxy phenyl, aMe Ser, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Phe, Phe_2Ad, Pyridin3yl, Quinolin_5_yl, Ser, Thr, Tyr, or Vai;X12 is Gly or absent;XI 3 is Glu, Gly, or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Val or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent;(Formula (I F).)

[0283] In one embodiment, a peptide of Formula (I), (I. A), (LB), (I.C), (I D), (I.E), or (I.F) comprises a cyclic structure wherein: (i) X2 and X5 are individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen, which are directly covalently linked or indirectly covalently linked through a cyclization linker, or (ii) X5 is Lys (or another residue with a side-chain comprising a free NH2 group) and XI 3 is Glu (or another residue with a side-chain comprising a free - COOH group) which are directly covalently linked through an amide bond (i.e., a cyclic amide, or lactam bond).

[0284] In another embodiment, the peptide of Formula (I), (LA), (LB), (I.C), (I.D), (I.E), or (I.F) comprises an intramolecular cross-link between X5 and X9, wherein the two crosslinked residues are connected by a lactam bond. In one aspect, X5 is Lys or NMe Lys and X9 is Glu or NMe_Glu. In another aspect, X5 is Glu or NMe_Glu and X9 is Lys or NMe_Lys.

[0285] In one embodiment of Formula (I), (LA), (LB), (I.C), (I.D), (I.E), or (I.F), R1is acetyl.

[0286] In one embodiment of Formula (I), (I. A), (LB), (I.C), (I D), (I.E), or (I.F), R1is absent.

[0287] In one embodiment of Formula (I), (I. A), (LB), (I.C), (I.D), (I.E), or (I.F), R2is amine.

[0288] In one embodiment of Formula (I), (LA), (LB), (I.C), (I.D), (I.E), or (I.F), X12 through X26 are absent.

[0289] In another embodiment of Formula (I), (LA), (LB), (I.C), (I.D), (I.E), or (I.F), the peptide does not comprise a cyclic structure.

[0290] In one embodiment of Formula (I), (LA), (LB), (I.C), (I.D), (I.E), or (I.F), X2 and X5 are directly cross-linked via a disulfide bond. In this case, the two cross-linked residues are individually or both a residue with a side chain comprising a free / reactive thiol group, such that the two thiol groups can form a disulfide bond. Such residues include, but are not limited to, Cys, dC, Hey, dHcy, Hhc, dHhc, Pen, dPen, HhPen, and dHhPen.

[0291] In another embodiment of Formula (I), (LA), (LB), (I.C), (I.D), (I.E), or (I.F), X2 and X5 are indirectly cross-linked via a cyclization linker to form a cyclic structure, wherein the two residues comprise a thiol moiety in their side chains such that they can each form a thioether bond with a cyclization linker. The cyclization linker can be, for example, a Butane Linker, a Carbonyl Linker, a Dimethylcyclopropane Linker, a Ebutene Linker, a Hexane Linker, an Oxetane Linker a Pentane Linker, a Propane Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker. The two residues that each comprise a free / reactive thiol moiety in their side-chains are, for example, Cys, dC, Hey, dHcy, Hhc, dHhc, Pen, dPen, HhPen, and dHhPen.

[0292] In another embodiment, besides cyclization between two residues of X2-X5, a peptide can be cyclized by covalently linking, i.e., “cross-linking,” any two positions of a peptide monomer (i.e., Ri, XI through X26, and R2, of a peptide of Formula I), directly or indirectly through a cyclization linker to form a cyclic peptide. This can be done in different ways depending on the type of chemical moieties or amino acids to be cross-linked: head-to-tail cyclization, head-to-side chain cyclization, side-chain-to-tail cyclization, and side-chain-to- side-chain cyclization.

[0293] In some embodiments, a peptide is cyclized by (a) directly linking the side chains of two amino acid residues to form an amide bond, (e.g., -NHC(O)- or -C(O)NH-), a disulfide bond (e.g., -S-S-), a thioether bond (e.g., -C-S-C-), a carbon-carbon single bond (e.g., -CH2- CH2-), or a carbon-carbon double bond (e.g., -CH=CH-); or (b) linking the side chains of two amino acids through a cyclization linker to form two thioether bonds, one between the side chain of one of the amino acids with a chemical group of the linker and one between the side chain of the other amino acid with a different chemical group of the linker. In other embodiments, a peptide has a cyclic structure comprising an intramolecular cross-link between two amino acid residues (or between two amino acid residues via a cyclization linker) that comprises a lactam, an olefin, a triazole (e.g., click chemistry), a selenoether, or a diselenide bond.

[0294] Whether the cyclization is direct or indirect, representative pairs of chemical moieties for cross-linking are: an amine group and a carboxylic acid group to form an amide bond; two thiols groups to form a disulfide bond; a thiol group and an alkyl group to form a thioether bond; two alkenyl groups to form a carbon-carbon double bond; and carbon-carbon double bond can be reduced to a carbon-carbon single bond.

[0295] In addition to Figs. 1 A-1NN, which indicates the type of cyclization chemistry (if cyclized) for each peptide, the person of ordinary skill can determine the structure and therefore type of bond(s) of the intramolecular cross-link through the conversion of the provided SMILES code of the peptide compound into two-dimensional structure.

[0296] Representative cross-linked structures are shown below:

[0297] In one embodiment, for any one of the peptides comprising a sequence of SEQ ID NO: 1-209, any of the amino acids, natural or unnatural, can be substituted with its corresponding D-amino acid, or vice versa. Up to all, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid(s) can be substituted with its corresponding D-amino acid, or vice versa.

[0298] In another embodiment, for any one of the peptides comprising a sequence of SEQ ID NO: 1-209, up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid(s) can be replaced with a conservative substitution and / or a corresponding analog (e.g., if the peptide has a lysine analog at a particular position, then other lysine analogs can provide the corresponding analog substitution, see Table 1). A corresponding analog can be, for example, an alphamethyl or N-methyl variant of the amino acid.

[0299] In another embodiment, for any one of the peptides comprising a sequence of SEQ ID NO: 1-209, up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 unnatural amino acid(s) can be replaced with its corresponding natural amino acid (e.g., if the peptide has a lysine analog at a particular position, then it can be substituted with lysine, see Table 1 for analog information).

[0300] In one aspect, any one of the peptides of the invention may be in the form of a pharmaceutically acceptable salt.

[0301] In one embodiment, a peptide of the invention can be a monomer (i.e., a monomeric subunit) of a homodimer or heterodimer or other multimeric peptide molecule. Each monomer of a multimer can have a direct covalent attachment to a dimerization linker, regardless of whether the monomer comprises a cyclic structure or a linear structure. For example, each monomer of a dimer compound can comprise a Lys or dK (or another residue with a free amine in its side-chain) that is directly covalently linked to a PEGDA linker, wherein the PEGDA linker is a diacid such that the amine in the side chains of Lys or dK form an amide bond with the terminal acidic groups of the linker.

[0302] In one aspect, a PEG linker comprises -(OCH2CH2)n-, wherein n is between 5 and 25.

[0303] In one aspect for the dimers of the invention, each monomer is directly covalently linked to a PEG linker through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker. The PEG linker can be, for example, a molecule with repeating PEG units with an acidic moiety at the terminal ends of the molecule, such as PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA. Alternatively, the peptide monomer can comprise a residue with a side chain comprising one or more PEG units and a free NH moiety that canform an amide bond with a cyclization linker that is a diacid - for example, Lys_PEG4_PEG4_NH2 can form an amide bond with one end of a DIG linker.

[0304] In another embodiment of Formula (I), (LA), (LB), (LC), (LD), (LE), or (LF), the peptide has an EC50 potency less than 1 nM (e.g., see Figs. 1A-1NN peptides with ++, +++, or ++++), less than 0.100 nM (e.g., see Figs. 1 A- INN peptides with +++ or ++++), or less than 0.010 nM (e.g., see Figs. 1 A-1NN peptides with ++++) in a human GLP1R HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant human GLP1R on their cell surface at high density. Herein, high density cell surface receptor expression of human GLP1R is greater than about 200,000 receptors / cell. (See Examples for the cAMP accumulation assay and cell surface receptor density determination).

[0305] In another embodiment of Formula (I), (LA), (LB), (LC), (LD), (LE), or (LF), the peptide has an EC50 potency less than 1 micromolar (e.g., see Figs. 1 A-1NN peptides with ++, +++, or ++++), less than 100 nM (e.g., see Figs. 1 A-1NN peptides with +++ or ++++), or less than 10 nM (e.g., see Figs. 1 A-1NN peptides with ++++) in a human GLP1R HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant GLP1R on their cell surface at low density. Herein, low density cell surface receptor expression of human GLP1R is about less than 2,000 receptors / cell.

[0306] In another embodiment of Formula (I), (LA), (LB), (LC), (LD), (LE), or (LF), the peptide has an EC50 potency less than 1 nM, less than 0.100 nM, or less than 0.010 nM in a human GIPR HEK293 cAMP accumulation assay. EC50

[0307] In other embodiments of Formula (I), (LA), (LB), (LC), (LD), (LE), or (LF), the peptide has a half-life time of stability greater than 2 hours, greater than 12 hours, or greater than 24 hours in an SGF assay or an SIF assay, or in both assays. In a related embodiment, a peptide of the invention that has a half-life time of stability greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay or an SIF assay, or in both assays, is suitable for oral administration / oral formulation. In one embodiment, a peptide of the invention that has a half-life time of stability greater than 2 hours or greater than 24 hours in an SGF assay is suitable for oral administration / oral formulation.

[0308] In another embodiment of Formula (I), (LA), (LB), (LC), (LD), (LE), or (LF), the peptide not only has an EC50 potency less than 1 nM, less than 0.100 nM, or less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay, and / or a human GIPR HEK293 cAMP accumulation assay, but also has a half-life time of stability of greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay and / or an SIF assay.

[0309] In another embodiment of Formula (I), (LA), (LB), (LC), (LD), (LE), or (LF), the peptide not only has an EC50 potency less than 1 micromolar, less than 100 nM, or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and / or a human GIPR HEK293 cAMP accumulation assay, but also has a half-life time of stability of greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay and / or an SIF assay.

[0310] In another embodiment, the invention provides a peptide comprising or consisting of a sequence according to any one of SEQ ID NOs: 1-209.

[0311] In another embodiment, the present disclosure provides a peptide compound as described by its SMILES formula as listed in Figs. 1 A-1NN.

[0312] In another embodiment, the invention provides a peptide comprising or consisting of one of the chemical structures depicted in Figs. 2A-2R.

[0313] In another embodiment, the invention provides peptides that are agonists of GLP1R having an EC50 potency less than 1 nM in a human high-density (HD) GLP1R HEK293 cAMP accumulation assay or less than 1 micromolar in a human low-density (LD) GLP1R HEK293 cAMP accumulation assay, wherein the peptide comprises or consist of a sequence according to Formula (II):R1-Xl-X2-X3-X4-X5-X6-X7-X8-X9-X10-Xl 1-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, or absent;R2is NH2 or OH or absent;XI is 2Me3ImidazolePA, 2Pal, 3Pal, aMe His, aOH Imidazole PropanoicAcid, Asn, Cit, dH, His, hHis, His_3Me, Imidazole Propanoic Acid, Lys Dimethyl, NMe His, Phe, Pyrrol e_P A, or Tyr;X2 is Aib, Ala, aMe_Asn, aMe_Gln, aMe_Glu, aMe_Leu, aMe_Pro, aMe_Ser, aMe_Trp, Gly, Iva, or Vai;X3 is aMe Glu, Asp, Cysteate, Gia, Gin, Glu, He, Leu, Tetl, or Tet2;X4 is Ala, Gly, or Ser;X5 is Glu, Gin, Hhc, He, Leu, Lys, NMe_K, 03 S, 03S_Reduced, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 40H_Val, Asp, Diaminobutanoic acid, Ser, Thr, TThioamide, or Vai;X8 is aMe_Ser, Asp, Gly, Ser, or SThioamide;X9 is aMe_Asp, aMe_Glu, Asp, bMeAsp, Cysteate, diMe_Asp, Gia, Glu, Hhc, Lys, NMe_E, 03 S, 03S_Reduced;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2NC2N, Bip_2pEt4pOC2NDMGN2aeC4,Bip_2pEt4pOC2NDMGN2aeC8, Bip_2pEt4pOC2NDMGN2aeC12,Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm,Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_Dap_MeOPheTag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm, Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheT ag, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid, Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_C4,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2,Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Arg, Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N, Bip_2pEt4pOC4N_ C0C8N,Bip_2pEt4pOC4N_Dap_lPEG2_lPEG2_C18_diacid,_Bip_2pEt4pOC4N_Dap_Albutag,Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_Dap_Palm, Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC4N_DMG_N_2ae_C 18_diacid, Bip_2pEt4pOC4N_DMG_N_2ae_LysAc, Bip_2pEt4pOC4N_MeOPheTag, Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOC4N_PEG4_NHAc, Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc,Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4N_PEGl 6_NHAc, Bip_2pEt4pOC4N2DMGN2ae, Bip_2pEt4pOC4NDMGN2ae, Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOC4NMe3,_Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, or NMeBip2pMe4pOMe; andXI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphneyl, 35_DimethylPhenyl, 3 chlorophenyl, 3 Methoxy phenyl, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Phe, Phe_2Ad, Pyridin3yl, Quinolin_5_yl, Thr, Tyr, or Vai.(Formula (II).)

[0314] In one embodiment of Formula (II), R1is absent and R2is amine

[0315] In one embodiment of Formula (II), R1is acetyl and R2is amine.

[0316] In another embodiment of Formula (II), no additional amino acid residues can be present at the C-terminus after XI 1.

[0317] In another embodiment of Formula (II), the peptide of Formula (II) further comprises a dipeptide attached to XI through an amide bond or ester bond, wherein under physiological pH, a nucleophile cleaves the amide or ester bond such that a diketopiperazine or diketomorpholine is formed and released from the peptide of Formula (II). In one embodiment, the dipeptide attached to XI through an amide bond is Sar- isoDLys_lPEG2 1PEG2_IsoGlu_C 18_Diacid.

[0318] In another embodiment of Formula (II), the peptide has an EC50 potency less than 0.100 nM, or less than 0.010 nM, in a human high-density (HD) GLP1R HEK293 cAMP accumulation assay.

[0319] In another embodiment of Formula (II), the peptide has an EC50 potency less than 100 nM, or less than 10 nM, in a human low-density (LD) GLP1R HEK293 cAMP accumulation assay.

[0320] In another embodiment of Formula (II), the peptide has a half-life time of stability of greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay or an SIF assay, or in both assays.

[0321] In another embodiment of Formula (II), the peptide not only has an EC50 potency less than 1 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 1micromolar in a human LD GLP1R HEK293 cAMP accumulation assay, but also has a halflife time of stability of greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay and / or an SIF assay.

[0322] In another embodiment, the invention provides a peptide having an EC50 less than0.100 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 100 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and the peptide comprises or consists of the sequence according to Formula (III):R1-Xl-X2-X3-X4-X5-X6-X7-X8-X9-X10-Xl 1-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is acetyl or absent;R2is NH2 or OH or absent;XI is 2Me3ImidazolePA, 2Pal, aMe His, aOH Imidazole PropanoicAcid, Asn, Cit, dH, His, hHis, Imidazole Propanoic Acid, NMe His, Phe, Pyrrole PA, or Tyr;X2 is Aib, Ala, aMe_Pro, aMe_Ser, Gly, Iva, or Val;X3 is Asp, Cysteate, Gla, Gin, Glu, He, Leu, Tetl, or Tet2;X4 is Gly;X5 is Glu, Hhc, He, Lys, Leu, 03 S, or Thr;X6 is aMe_Phe_2F;X7 is 4OH-Val, Diaminobutanoic acid, Ser, Thr, or TThioamide;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, Asp, bMe_Asp, Cysteate, diMe_Asp, Glu, Hhc, Lys, or 03 S;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2NC2N, Bip_2pEt4pOC2NDMGN2aeC4, Bip_2pEt4pOC2NDMGN2aeC8, Bip_2pEt4pOC2NDMGN2aeC12, Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm, Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid, Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm, Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag, Bip_2pEt4pOC2N_Dap_MeOPheTag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm, Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheT ag, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12,_Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid, Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_C4,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2, Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm,Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Arg, Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N, Bip_2pEt4pOC4N_ C0C8N, Bip_2pEt4pOC4N_Dap_Albutag, Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_Dap_Palm, Bip_2pEt4pOC4N_DMG_N_2ae_C 18_diacid, Bip_2pEt4pOC4N_DMG_N_2ae_LysAc, Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC4N_MeOPheT ag, Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOC4N_PEG4_NHAc, Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc, Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4N_PEGl 6_NHAc, Bip_2pEt4pOC4N2DMGN2ae, Bip_2pEt4pOC4NDMGN2ae, Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOC4NMe3, Bip_2pEt4pOMe, Bip_2pMe4pOMe, or Bip24_Me; andXI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, , 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphenyl, 3choloro4fluorophenyl, 3 chlorophenyl, 3 Methoxy phenyl, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Phe, Quinolin-5-yl, Thr, Tyr, or Vai. (Formula (III).)

[0323] In one embodiment of Formula (III), R1is acetyl and R2is amine.

[0324] In another embodiment of Formula (III), R1is absent and R2is amine.

[0325] In another embodiment of Formula (III), no additional amino acid residues can be present at the C-terminus after XI 1.

[0326] In another embodiment of Formula (III), the peptide does not comprise a cyclic structure.

[0327] In another embodiment of Formula (III), the peptide has a half-life time of stability of greater than 2 hours, 12 hours, 20 hours, or 24 hours in an SGF assay or an SIF assay, or in both assays.

[0328] In another embodiment of Formula (III), the peptide not only has an EC50 potency less than 0.100 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 100 nM in a human LD GLP1R HEK293 cAMP accumulation assay, but also has a half-life time of stability of greater than 2 hours, greater than 12 hours, greater than 20 hours, or greater than 24 hours in an SGF assay and / or an SIF assay.

[0329] In another embodiment, the invention provides a peptide having an EC50 less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and having a half-life greater than 20 hours in both an SGF assay and an SIF assay, and the peptide comprises or consists of the sequence according to Formula (IV):R1-Xl-X2-X3-X4-X5-X6-X7-X8-X9-X10-Xl 1-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is absent;R2is NH2;XI is 2Me3ImidazolePA, aMe_H, aOH Imidazole PropanoicAcid, Asn, dH, His, Imidazole Propanoic Acid, NMe His, Phe, or Tyr;X2 is Aib, aMe_Pro, or Iva;X3 is Glu or Tetl;X4 is Gly;X5 is Thr;X6 is aMe_Phe_2F;X7 is 4OH_Val, Ser, or Thr;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, or Asp;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm, Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_DMG_N_2ae_Palm, Bip_2pEt4pOC2NDMGN2aeC4, Bip_2pEt4pOC2NDMGN2aeC8, Bip_2pEt4pOC2NDMGN2aeC12, Bip_2pEt4pOC2NIsoGlu Palm, Bip_2pEt4pOC2N_MeOPheTag, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12,_Bip_2pEt4pOC4N,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2, Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Arg, Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N, Bip_2pEt4pOC4N_ COC8N,Bip_2pEt4pOC4N_Dap_lPEG2_lPEG2_C18_diacid,_Bip_2pEt4pOC4N_Dap_Albutag, Bip_2pEt4pOC4N_ Dap Palm, Bip_2pEt4pOC4N_DMG_N_2ae_C 18_diacid, Bip_2pEt4pOC4N_MeOPheTag, Bip_2pEt4pOC4N_PEG4_am,Bip_2pEt4pOC4N_PEG4_NHAc, Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc, Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NMe3,_Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOMe, or Bip_2pMe4pOMe; andXI 1 is 3_pyridylalanine_4_2_methylphenyl, Bip_2pMe, Bip24_Me, HHPhe_35Me, or Hph. (Formula (IV).)

[0330] In other embodiments of Formula (IV), the invention provides a peptide comprising a sequence according to any one of the sub-formulas of Formula (IV) described below, i.e., Formula (IV. A) et al.

[0331] In one embodiment, the invention provides a peptide having an IC50 less than 0.010 nM in a human GLP1R (high density) HEK293 cAMP accumulation assay and having a halflife greater than 24 hours in both an SGF assay and an SIF assay, and the peptide comprises or consists of the sequence according to Formula (IV. A):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is absent;R2 is NH2;XI is dH, His, or Imidazole Propanoic Acid;X2 is Aib or aMe_Pro;X3 is Glu or Tetl;X4 is Gly;X5 is Thr;X6 is aMe_Phe_2F;X7 is Thr;X8 is Ser;X9 is aMe_Asp;X10: Bip_2pEt4pOMe, or Bip_2pMe4pOMe; andXI I is Bip_2pMe, Bip24_Me, or HHPhe_35Me.(Formula (IV. A).)

[0332] In another embodiment, the invention provides a peptide having an IC50 less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and having a half-life greater than20 hours in both an SGF assay and an SIF assay, and the peptide comprises or consists of the sequence according to Formula (IV.B):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is absent;R2 is NH2;XI is dH, His, or Imidazole Propanoic Acid;X2 is Aib, aMe_Pro, or Iva;X3 is Glu or Tetl;X4 is Gly;X5 is Thr;X6 is aMe_Phe_2F;X7 is Ser or Thr;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, or Asp;X10: Bip_2pEt4pOMe, or Bip_2pMe4pOMe; andXI I is 3_pyridylalanine_4_2_methylphenyl, Bip_2pMe, Bip24_Me, HHPhe_35Me, or Hph.(Formula (IV.B).)

[0333] In another embodiment, the invention provides a peptide having an EC50 less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and having a half-life greater than 20 hours in both an SGF assay and an SIF assay, and the peptide comprises or consists of the sequence according to Formula (IV. C):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is absent;R2 is NH2;XI is dH, His, or Imidazole Propanoic Acid;X2 is Aib, aMe_Pro, or Iva;X3 is Glu or Tetl;X4 is Gly;X5 is Thr or 03 S;X6 is aMe_Phe_2F;X7 is 40H_Val, Ser, or Thr;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, Asp, or 03 S;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N IsoGlu Palm, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOMe, or Bip_2pMe4pOMe; andXI 1 is 3_pyridylalanine_4_2_methylphenyl, Bip_2pMe, Bip24_Me, HHPhe_35Me, or Hph. (Formula (IV.C).)

[0334] In another embodiment, the invention provides a peptide having an EC50 less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and having a half-life greater than 20 hours in both an SGF assay and an SIF assay, and the peptide comprises or consists of the sequence according to Formula (IV.D):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is absent;R2 is NH2;XI is aOH Imidazole PropanoicAcid, dH, His, Imidazole Propanoic Acid, or NMe His;X2 is Aib, aMe_Pro, or Iva;X3 is Glu or Tetl;X4 is Gly;X5 is Thr or 03 S;X6 is aMe_Phe_2F;X7 is 4OH_Val, Ser, or Thr;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, Asp, or 03 S;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2N_Ahx_Palm, Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_DMG_N_2ae_Palm,_Bip_2pEt4pOC2N _IsoGlu_Palm, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheTagBip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_Ahx_Palm,Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Dap_Albutag, Bip_2pEt4pOC4N_Dap_Palm, Bip_2pEt4pOC4N_PEG4, Bip_2pEt4pOMe, or Bip_2pMe4pOMe; andXI 1 is 3_pyridylalanine_4_2_methylphenyl, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, or Hph.(Formula (IV.D).)

[0335] In another embodiment, the invention provides a peptide having an EC50 less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and having a half-life greater than 20 hours in both an SGF assay and an SIF assay, and the peptide comprises or consists of the sequence according to Formula (IV.E):R1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is absent;R2 is NH2;XI is 2Me3ImidazolePA, aMe_H, aOH Imidazole PropanoicAcid, Asn, dH, His, Imidazole Propanoic Acid, NMe His, Phe, or Tyr;X2 is Aib, aMe_Pro, or Iva;X3 is Glu or Tetl;X4 is Gly;X5 is Thr;X6 is aMe_Phe_2F;X7 is 4OH_Val, Ser, or Thr;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, or Asp;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm, Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_DMG_N_2ae_Palm,_ Bip_2pEt4pOC2N _IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheTag, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2, Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag,Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N, Bip_2pEt4pOC4N_ C0C8N, Bip_2pEt4pOC4N Dap Albutag, Bip_2pEt4pOC4N Dap Palm, Bip_2pEt4pOC4N_MeOPheTag, Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOC4N_PEG4_NHAc, Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc, Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOMe, or Bip_2pMe4pOMe; andXI 1 is 3_pyridylalanine_4_2_methylphenyl, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Ser, Thr, or Vai.(Formula (IV.E).)

[0336] In another embodiment of Formula (IV), (IV. A), (IV.B), (IV. C), (IV.D), or (IV.E), no additional residues can be present at the C-terminus after XI 1.

[0337] In other embodiments, a peptide of the invention that exhibits a half-life time of stability in an SGF assay and / or an SIF assay greater than 20 hours or greater than 24 hours is suitable for oral formulation and administration.

[0338] In one embodiment, for any of the Formula herein, the Formula may be modified to specifically exclude any peptide that comprises the following sequence at X1-X9: H-Aib-E- G-T-aMe_Phe_2F-T-S-D (SEQ ID NO: 210).

[0339] In one embodiment, for any one of the peptides comprising a sequence of SEQ ID NO: 1-209, any of the amino acids, natural or unnatural, can be substituted with its corresponding D-amino acid, or vice versa. Up to all, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid(s) can be substituted with its corresponding D-amino acid, or vice versa.

[0340] In another embodiment, for any one of the peptides comprising a sequence of SEQ ID NO: 1-209, up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid(s) can be replaced with a conservative substitution and / or a corresponding analog (e.g., if the peptide has a lysine analog at a particular position, then other lysine analogs can provide the corresponding analog substitution, see Table 1).

[0341] In another embodiment, for any one of the peptides comprising a sequence of SEQ ID NO: 1-209, up to 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 unnatural amino acid(s) can be replaced with its corresponding natural amino acid (e.g., if the peptide has a lysine analog at a particular position, then it can be substituted with lysine, see Table 1 for analog information).

[0342] In one embodiment, a peptide of the invention can be a monomer (i.e., a monomeric subunit) of a homodimer or heterodimer or other multimeric peptide molecules. Each monomer of a multimer can have a direct covalent attachment to a dimerization linker, regardless of whether the monomer comprises a cyclic structure or a linear structure. For example, each monomer of a dimer compound can comprise a Lys or dK that is directly covalently linked to a PEGDA linker, wherein the PEGDA linker is a diacid such that the side chains of Lys or dK form an amide bond with the terminal acidic groups of the linker.

[0343] In one embodiment, a PEG linker comprises -(OCH2CH2)n-, wherein n is between 5 and 25.

[0344] In one embodiment for the dimers of the invention, each monomer is directly covalently linked to a PEG linker through an amide bond, wherein one monomer is linked to one terminal end of the PEG linker and the other monomer is linked to the other terminal end of the PEG linker. The PEG linker can be, for example, a molecule with repeating PEG units with an acidic moiety at the terminal ends of the molecule, such as PEG5DA, PEG9DA, PEG13DA, PEG21DA, or PEG25DA. Alternatively, the peptide monomer can comprise a residue with a side chain comprising one or more PEG units and a free NH moiety that can form an amide bond with a cyclization linker that is a diacid - for example, Lys_PEG4_PEG4_NH2 can form an amide bond with one end of a DIG linker.Prodrug

[0345] A prodrug is a compound that undergoes chemical conversion by an enzymatic or non-enzymatic chemical process in vivo resulting in liberation of the parent drug. Herein, the parent drug is a peptide of the invention. An intact prodrug is not substantially pharmacologically active. Rather, herein, a terminal dipeptide-based amide or ester extension is attached to the N-terminus, C-terminus, or side-chain, of a peptide of the invention, whereupon in vivo, the extension is cleaved from the peptide of the invention, resulting in the liberation of the peptide in its free form.

[0346] Dipeptides are known in the art for prodrug development for targeting or targeted transport as they are substrates for enzymes or biotransport systems or for the non-enzymatic route for dipeptide prodrug formation, namely the ability to undergo intramolecularcyclization to form the corresponding diketopiperazine (DKP) or diketomorpholine (DKM) and release the active drug. See, e.g., US20110237493A1 and US20130137849A1, both of which are hereby incorporated-by-reference for their teachings on suitable dipeptide moieties that can be attached to the GLP1R agonist peptides described herein. Potential susceptibility of dipeptide-based prodrugs to peptidases may be addressed by incorporating at least one non-natural amino acid in the dipeptide motif.

[0347] Such dipeptides may be attached to a drug via ester bonds. In this case, the cyclization reaction consists of a nucleophilic attack of the N-terminal amine of the peptide on the ester carbon atom to form a tetrahedral intermediate. This is followed by a proton transfer from the amine to the leaving group oxyanion with simultaneous formation of a peptide bond to give the cyclic DKP product and free drug. The reaction has been described for ester prodrugs for example for cyclosporin A (Hamel, A R; Hubler, F; Carrupt, A; Wenger, R M; Mutter, M, J. Pept. Res., vol. 63, num. 2 (2004), p. 147-154). WO-A 2009 / 99763 describes ester based dipeptide prodrugs of bioactive peptides such as GLP-1 capable of releasing the peptide through diketopiperazine formation of the dipeptidic extension.

[0348] DKP formation reaction also results from amide prodrugs. U.S. Pat. No. 5,952,294 details prodrug activation using diketopiperazine formation for dipeptidyl amide prodrugs of cytarabine. In this case, the temporary linkage was formed between the carbonyl of a dipeptide and the aromatic amino group of cytarabine. In another study, the utility of diketopiperazine activation was demonstrated for even more stable aliphatic amide prodrugs (Suaifan et al., Tetrahedron 62 (2006) 11245-11266).

[0349] Thus, in one embodiment, the invention provides DKP-forming or DKM-forming prodrugs of the peptides of the invention, wherein a DKP-forming moiety or a DKM-forming moiety, i.e., a dipeptide, is attached to the N-terminus, C-terminus, or a side-chain of the peptides of the invention. The dipeptide can be attached through an ester bond or an amide bond.

[0350] In one embodiment, the dipeptide can be attached via an amide bond between the dipeptide and an aliphatic amino group of a peptide of the invention (e.g., a primary amine such as the N-terminal amine or the amino group of an amino acid side chain or via a linkingmoiety that comprises a primary amine bearing an acyl group or alkyl group). In a related embodiment, the R1 or R2 group of a peptide of the invention can be absent or modified to comprise an acyl or alkyl group with a free amine moiety.

[0351] The prodrug dipeptides can also have one or more biocompatible polymers attached to a side chain of one of the residues of the dipeptide. Polymers can have, for example, a size selected from a range of about 20,000 to 120,000 Daltons. In one embodiment the polymer has a size selected from a range of about 40,000 to 100,000 or about 40,000 to 80,000 Daltons. In one embodiment the polymer has a size of about 40,000, 50,000, 60,000, 70,000 or 80,000 Daltons. Suitable polymers include but are not limited to dextrans, polylactides, polyglycolides, caprolactone-based polymers, poly(caprolactone), polyanhydrides, polyamines, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyesters, polybutylene terephthalate, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polysaccharides, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers and mixtures thereof, and biodegradable polymers and their copolymers including caprolactone-based polymers, polycaprolactones and copolymers which include polybutylene terephthalate. In one embodiment the polymer is selected from the group consisting of polyethylene glycol, dextran, polylactic acid, polygly colic acid and a copolymer of lactic acid and glycolic acid. In one embodiment, the polymer is polyethylene glycol, and the polymer can comprise one or more polyethylene glycol chains linked to the dipeptide element wherein the combined molecular weight of polymer(s) is 40,000 to 80,000 Daltons.

[0352] In one embodiment, the attachment between the dipeptide and a peptide of the invention comprises an amide bond and the dipeptide can comprise a structure according to Dipeptide Formula (I):wherein Rl, R2, R4 and R8 are independently selected from the group consisting of H, Cl- CIS alkyl, C2-C18 alkenyl, (C1-C18 alkyl)OH, (C1-C18 alkyl)SH, (C2-C3 alkyl)SCH3, (Cl- C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and Cl -Cl 2 alkyl(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or Rl and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl or aryl; or R4 and R8 together with the atoms to which they are attached form a C3-C6 cycloalkyl; R3 is selected from the group consisting of Cl -Cl 8 alkyl, (Cl -Cl 8 alkyl)OH, (Cl -Cl 8 alkyl)NH2, (Cl -Cl 8 alkyl)SH, (C0-C4 alkyl)(C3-C6)cycloalkyl, (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, and (C1-C4 alkyl)(C3-C9 heteroaryl) or R4 and R3 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R5 is NHR6 or OH; R6 is H, C1-C8 alkyl or R6 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; and R7 is selected from the group consisting of H and OH, with the proviso that when R4 and R3 together with the atoms to which they are attached form a 5 or 6 member heterocyclic ring, then at least one of Rl and R2 are other than hydrogen.(Dipeptide Formula (I).)

[0353] In another embodiment, the dipeptide structure that is attached to a peptide of the invention through an amide bond comprises a structure according to Dipeptide Formula (II):wherein(I) R1 and R2 are independently selected from the group consisting of H, Cl -Cl 8 alkyl, C2- C18 alkenyl, (Cl -Cl 8 alkyl)OH, (Cl -Cl 8 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0- C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and Cl -Cl 2 alkyl(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; R3 is C1-C18 alkyl; R4 and R8 are each H; R5 is NHR6, or R5 and R2 together with the atoms to which they are attachedform a 4, 5 or 6 member heterocyclic ring; R6 is H or C1-C4 alkyl; and, R7 is selected from the group consisting of H and OH; wherein the dipeptide is linked to a peptide of the invention through an amide bond between the dipeptide and an aliphatic amino group (e.g., a primary amine such as the N-terminal amine or the amino group of an amino acid side chain or via a linking moiety that comprises a primary amine bearing acyl group or alkyl group) of the peptide; with the proviso that when both R1 and R2 are H, R3 is C5-C18 alkyl;(II) R1 and R2 are independently selected from the group consisting of H, Cl -Cl 8 alkyl, C2- C18 alkenyl, (Cl -Cl 8 alkyl)OH, (Cl -Cl 8 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0- C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and Cl -Cl 2 alkyl(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; R3 is C1-C18 alkyl; R4 is selected from the group consisting of CH3, CH2(C1-C1O alkyl), CH2(C2-C10 alkenyl), CH2(C0-C10 alkyl)OH, CH2(C0-C10 alkyl)SH, CH2(C0-C3 alkyl)SCH3, CH2(C0-C3 alkyl)CONH2CH2(C0-C3 alkyl)COOH, CH2(C0-C3 alkyl)NH2, CH2(C0-C3 alkyl)NHC(NH2+)NH2CH2(C0-C3 alkyl)(C3-C6 cycloalkyl), CH2(C0-C3 alkyl)(C2-C5 heterocyclic), CH2(C0-C3 alkyl)(C6-C10 aryl)R7, CH2(C1-C3 alkyl)(C3-C9 heteroaryl), and CH2(C0-C12 alkyl)(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R4 and R3 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R8 is H; R5 is NHR6, or R5 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R6 is H or C1-C4 alkyl; and, R7 is selected from the group consisting of H and OH; wherein the dipeptide is linked to a peptide of the invention through an amide bond between the dipeptide and an aliphatic amino group (e.g., a primary amine such as the N-terminal amine or the amino group of an amino acid side chain or via a linking moiety that comprises a primary amine bearing acyl group or alkyl group) of the peptide; with the proviso that when either R1 or R2 are H, then R4 and R3 together with the atoms to which they are attached do not form a 4, 5 or 6 member heterocyclic ring;(III) R1 and R2 are independently selected from the group consisting of H, Cl -Cl 8 alkyl, C2- C18 alkenyl, (Cl -Cl 8 alkyl)OH, (Cl -Cl 8 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0- C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and Cl -Cl 2 alkyl(Wl)Cl-C12 alkyl, wherein W1is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; R3 is C1-C18 alkyl; R4 is independently selected from the group consisting of CH(C1-C8 alkyl)2, CH(C2-C8 alkenyl)?, CH(C1-C8 alkyl)(OH), CH(C1-C8 alkyl)((Cl-C8 alkyl)SH), and CH(C1-C3 alkyl)((Cl-C8 alkyl)(NH2); R8 is H; R5 is NHR6, or R5 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R6 is H or C1-C4 alkyl; and, R7 is selected from the group consisting of H and OH; wherein the dipeptide is linked to a peptide of the invention through an amide bond between the dipeptide and an aliphatic amino group of the peptide;(IV) R1 and R2 are independently selected from the group consisting of H, Cl -Cl 8 alkyl, C2-C18 alkenyl, (Cl -Cl 8 alkyl)OH, (Cl -Cl 8 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, alkyl)(C3-C9 heteroaryl), and C12 alkyl(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; R3 is C1-C18 alkyl; R4 and R8 are each H; R5 is NHR6, or R5 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R6 is H or C1-C4 alkyl; and, R7 is selected from the group consisting of H and OH; wherein A-B is linked to a peptide of the invention through an amide bond between A-B and an aromatic amino group on an amino acid side chain of the peptide;(V) R1 and R2 are independently selected from the group consisting of H, Cl -Cl 8 alkyl, C2- C18 alkenyl, (C1-C18 alkyl)OH, (C1-C18 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, alkyl)COOH, alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3- C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and Cl -Cl 2 alkyl(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; R3 is C1-C18 alkyl; R4 is selected from the group consisting of CH3, CH2(C1-C1O alkyl), CH2(C2-C10 alkenyl), CH2(C0-C10 alkyl)OH, CH2(C0-C10 alkyl)SH, CH2(C0-C3 alkyl)SCH3, CH2(C0-C3 alkyl)CONH2, CH2(C0-C3 alkyl)COOH, CH2(C0-C3 alkyl)NH2, CH2(C0-C3 alkyl)NHC(NH2+)NH2, CH2(C0-C3 alkyl)(C3-C6 cycloalkyl), CH2(C0-C3 alkyl)(C2-C5 heterocyclic), CH2(C0-C3 alkyl)(C6-C10 aryl)R7, CH2(C1-C3 alkyl)(C3-C9 heteroaryl), and CH2(C0-C12alkyl)(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R4 and R3 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R8 is H; R5 is NHR6, or R5 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R6 is H or C1-C4 alkyl; and, R7 is selected from the group consisting of H and OH. wherein the dipeptide is linked to a peptide of the invention through an amide bond between the dipeptide and an aromatic amino group on an amino acid side chain of the peptide of the invention;(VI) R1 and R2 are independently selected from the group consisting of H, Cl -Cl 8 alkyl, C2-C18 alkenyl, (Cl -Cl 8 alkyl)OH, (Cl -Cl 8 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2 +)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and Cl -Cl 2 alkyl(Wl)Cl-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl; R3 is C1-C18 alkyl; R4 is independently selected from the group consisting of CH(C1-C8 alkyl)2, CH(C2-C8 alkenyl)2, CH(C1-C8 alkyl)(OH), CH(C1-C8 alkyl)((Cl-C8 alkyl)SH), and CH(C1-C3 alkyl)((Cl-C8 alkyl)(NH2); R8 is H; R5 is NHR6, or R5 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring; R6 is H or C1-C4 alkyl; and, R7 is selected from the group consisting of H and OH; wherein the dipeptide is linked to a peptide of the invention through an amide bond between the dipeptide and an aromatic amino group on an amino acid side chain of the peptide of the invention.

[0354] Suitable amino acids for the dipeptide (which can be referred to herein as “ A-B”) include, but are not limited to:(1) for the first residue of the dipeptide (N-terminal residue of the dipeptide), or the “A” residue: Aib, Gly, Ala, Leu, Met, Asn, Glu, Asp, Gin, His, Lys, Arg, Ser, Cys, Pro, Phe, Tyr, Trp, He, Vai, Thr, their corresponding D-forms, their N-methyl variant forms (N-methyl amino acids have a methyl group attached to the nitrogen), and D-forms of the N-methyl variants;(2) for the second residue of the dipeptide, or the “B” residue, modified amino acids are contemplated, where the modification comprises attaching an alkyl group to the amino group of the core amino acid structure, for example: Gly(N — Cl-C8alkyl), Gly(N — Cl-C8alkyl), Ala(N— Cl-C8alkyl), Leu(N— Cl-C8alkyl), Met(N— Cl-C8alkyl), Asn(N— Cl-C8alkyl),Glu(N— Cl-C8alkyl), Asp(N— Cl-C8alkyl), Gln(N— Cl-C8alkyl), His(N— Cl-C8alkyl), Lys(N— Cl-C8alkyl), Arg(N— Cl-C8alkyl), Ser(N— Cl-C8alkyl), Cys(N— Cl-C8alkyl), Pro, Phe(N— Cl-C8alkyl), Tyr(N— Cl-C8alkyl), Trp(N— Cl-C8alkyl), Val(N— Cl- C8alkyl), Thr(N — Cl-C8alkyl), Gly(N-methyl), Ala(N-methyl), Leu(N-m ethyl), Met(N- methyl), Asn(N-methyl), Glu(N-methyl), Asp(N-methyl), Gln(N-methyl), His(N-methyl), Lys(N-methyl), Arg(N-methyl), Ser(N-methyl), Cys(N-methyl), Phe(N-methyl), Tyr(N- methyl), Trp(N-methyl), Ile(N-methyl), Val(N-methyl), Thr(N-methyl), Gly(N-hexyl), Ala(N-hexyl), Leu(N-hexyl), Met(N-hexyl), Asn(N-hexyl), Glu(N-hexyl), Asp(N-hexyl), Gln(N-hexyl), His(N-hexyl), Lys(N-hexyl), Arg(N-hexyl), Ser(N-hexyl), Cys(N-hexyl), Phe(N-hexyl), Tyr(N-hexyl), Trp(N-hexyl), Ile(N-hexyl), Val(N-hexyl), Thr(N-hexyl), and their corresponding D-isoforms.

[0355] In some embodiments, the half-life of the prodrug, e.g., the chemical cleavage halflife (t 1 / 2) of A-B from a peptide of the invention under physiological conditions, is dependent on the presence and length of the N-alkyl substituent on the B amino acid. For example, a prodrug that has a shorter N-alkyl substituent on the B amino acid (e.g. Gly(N- methyl)), will undergo a slower rate of cleavage of A-B, and have a longer half-life, than a prodrug that has a longer N-alkyl substituent on the B amino acid (e.g., Gly(N-hexyl)).

[0356] In some embodiments, the half-life of the prodrug is dependent on the presence or absence of an alkyl side chain, and the degree of substitution at the beta position of the alkyl side chain, of the B amino acid of the dipeptide prodrug element. For example, a prodrug that has an N-alkylated B amino acid that is disubstituted at the beta position (e.g., N-alkylated isoleucine) will undergo slower cleavage of A-B, and have a longer half-life, than a prodrug that has an N-alkylated B amino acid that is monosubstituted at the beta position (e.g., N- alkylated leucine). Further, a prodrug that has an N-alkylated B amino acid that is monosubstituted at the beta position (e.g., N-alkylated leucine) will undergo slower cleavage of A-B, and have a longer half-life, than a prodrug that has an N-alkylated B amino acid that is unsubstituted at the beta position (e.g., N-alkylated alanine). Further still, a prodrug with an N-alkylated B amino acid that has an unsubstituted beta position (e.g., N-alkylated alanine) will undergo slower cleavage of A-B, and have a longer half-life, than a prodrug that has glycine or N-alkylated glycine as the B amino acid.

[0357] In some embodiments, the half-life of the prodrug is dependent on the bulkiness of the side chain of the B amino acid. For example, a prodrug that has a bulkier side chain on the B amino acid (e.g., N-alkylated phenylalanine), will undergo slower cleavage of A-B, and have a longer half-life, than a prodrug that has a less bulky side chain on the B amino acid (e.g., N- alkylated alanine). Cleavage rates of dipeptides can be further differentiated by the amine of the peptide to which they are attached. More particularly the same dipeptide will cleave at a faster rate when linked to an aromatic amine relative to an N-terminal amine, where the dipeptide linked to an N-terminal amine will cleave at a faster rate relative to when the dipeptide is linked to the side chain amine of a lysine residue.

[0358] In other embodiments, a dipeptide that is attached to a peptide of Figs. 1 A-1NN comprises Sar-isoDLys_lPEG2_lPEG2_IsoGlu_C18_Diacid, Thz- dIsoLys_lPEG2_IsoGlu_C20_Diacid, Thz-dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Sar- dIsoLys_lPEG2_IsoGlu_C20_Diacid, or Sar- dIsoLys_lPEG2_IsoGlu_C18_Diacid. As discussed above, the dipeptide can be attached through an amide bond or an ester bond at the N-terminus, C-terminus, or to a side-chain of an amino acid in said peptide of Figs. 1 A-1NN. In one embodiment, the dipeptide is attached to the side chain of a Lys or dK residue.

[0359] In one embodiment, an amino acid residue is present at X0 (X0 is immediately N- terminal to XI), and a dipeptide is attached to X0 via an amide bond.

[0360] In one embodiment, XI of a peptide of the invention is changed from Tyr to His, wherein His is attached to a dipeptide via an amide bond. In another embodiment, a half-life extension conjugate (see below) is attached to a side chain of the first or second amino acid of the dipeptide.

[0361] In another embodiment, a peptide of the invention further comprises a dipeptide attached to XI through an amide bond or ester bond, wherein under physiological pH, a nucleophile cleaves the amide or ester bond such that a diketopiperazine or diketomorpholine is formed and released from the peptide of Formula (I). In one embodiment, the dipeptide attached to XI through an amide bond is Sar-isoDLys_lPEG2_lPEG2_IsoGlu_C18_Diacid.

[0362] In one embodiment, XI is His, which is attached to a dipeptide via an amide bond. In another embodiment, a half-life extension conjugate (see below) is attached to a side chain of the first or second amino acid of the dipeptide.Peptide-Half-Life Extension Conjugates

[0363] In certain embodiments, peptides of the present invention comprise one or more conjugated chemical substituents, such as lipophilic substituents and polymeric moieties, collectively referred to herein as half-life extension moieties. Without wishing to be bound by any particular theory, it is believed that the lipophilic substituent binds to albumin in the bloodstream, thereby shielding the peptide compound from enzymatic degradation, and thus enhancing its half-life. In addition, it is believed that polymeric moieties enhance half-life and reduce clearance in the bloodstream, and in some cases enhance permeability through the epithelium and retention in the lamina propria. The skilled person will be well aware of suitable techniques for preparing the compounds employed in the context of the invention. For examples of non-limiting suitable chemistry, see, e.g., WO98 / 08871, WOOO / 55184, WOOO / 55119, Madsen et al (J. Med. Chem. 2007, 50, 6126-32), and Knudsen et al. 2000 (J. Med Chem. 43, 1664-1669).

[0364] In some embodiments, the side chains of one or more amino acid residues in a peptide of the invention is further conjugated (e.g., covalently attached) to a lipophilic substituent or other half-life extension moiety. The lipophilic substituent may be covalently bonded to an atom in the amino acid side chain, or alternatively may be conjugated to the amino acid side chain via one or more spacers or linker moieties. The spacer or linker moiety, when present, may provide spacing between the peptide compound and the lipophilic substituent.

[0365] In certain embodiments, the lipophilic substituent or half-life extension moiety comprises a hydrocarbon chain having from 4 to 30 C atoms, for example at least 8 or 12 C atoms, and preferably 24 C atoms or fewer, or 20 C atoms or fewer. The hydrocarbon chain may be linear or branched and may be saturated or unsaturated. In certain embodiments, the hydrocarbon chain is substituted with a moiety which forms part of the attachment to the amino acid side chain or the spacer, for example an acyl group, a sulfonyl group, an N atom, an O atom or an S atom. In some embodiments, the hydrocarbon chain is substituted with anacyl group, and accordingly the hydrocarbon chain may form part of an alkanoyl group, for example palmitoyl, caproyl, lauroyl, myristoyl or stearoyl.

[0366] A lipophilic substituent may be conjugated to any amino acid side chain in a peptide compound of the invention. In one embodiment, a lipophilic substituent is conjugated to an N-terminus amino acid side chain. In certain embodiments, the amino acid side chain includes a carboxy, hydroxyl, thiol, amide or amine group, for forming an ester, a sulphonyl ester, a thioester, an amide or a sulphonamide with the spacer or lipophilic substituent. For example, the lipophilic substituent may be conjugated to Asn, Asp, Glu, Gin, His, Lys, Arg, Ser, Thr, Tyr, Trp, Cys or Dbu, Dpr or Om. Representative examples are the thiol group of Cys residues and the epsilon amino group of Lys residues, and the carboxyl groups of Asp and Glu residues may also be involved. In certain embodiments, the lipophilic substituent is conjugated to Lys, if Lys is not already conjugated to a dimerization linker. An amino acid shown as Lys in any of the Formulas provided herein may be replaced by, e.g., Dbu, Dpr or Orn where a lipophilic substituent is added.

[0367] In further embodiments of the present invention, alternatively or additionally, the side-chains of one or more amino acid residues in a peptide compound of the invention may be conjugated to a polymeric moiety or other half-life extension moiety, for example, in order to increase solubility and / or half-life in vivo (e.g., in plasma) and / or bioavailability. Such modifications are also known to reduce clearance (e.g. renal clearance) of therapeutic proteins and peptides. In one embodiment, a polymeric moiety or other half-life extension moiety is conjugated to an N-terminus amino acid side chain.

[0368] In some embodiments, suitable methods known in the art for determining solubility include incubating the peptide compound in various buffers (Acetate pH4.0, Acetate pH5.0, Phos / Citrate pH5.0, Phos Citrate pH6.0, Phos pH 6.0, Phos pH 7.0, Phos pH7.5, Strong PBS pH 7.5, Tris pH7.5, Tris pH 8.0, Glycine pH 9.0, Water, Acetic acid (pH 5.0 and other known in the art) and testing for aggregation or solubility using standard techniques. These include, but are not limited to, visual precipitation, dynamic light scattering, Circular Dichroism and fluorescent dyes to measure surface hydrophobicity, and detect aggregation or fibrillation, for example.

[0369] In some embodiments, the present disclosure includes a peptide compound conjugated with a PEG linker (in cases where there is already a PEG dimerization linker, an additional PEG linker may be added for half-life extension, solubility, and / or bioavailability) that is attached covalently, e.g., through an amide, a thiol, via click chemistry, or via any other suitable means known in the art.

[0370] Other suitable polymeric moieties include poly-amino acids such as poly-lysine, polyaspartic acid and poly-glutamic acid (see for example Gombotz, et al. (1995), Bioconjugate Chem., vol. 6: 332-351; Hudecz, et al. (1992), Bioconjugate Chem., vol. 3, 49-57 and Tsukada, et al. (1984), J. Natl. Cancer Inst., vol. 73, : 721-729. The polymeric moiety may be straight-chain or branched. In some embodiments, it has a molecular weight of 500- 40,000 Da, for example 500-10,000 Da, 1000-5000 Da, 10,000-20,000 Da, or 20,000-40,000 Da.

[0371] As used herein, disulfide bond oxidation can occur within a single step or is a two- step process. As used herein, for a single oxidation step, the trityl protecting group is often employed during assembly, allowing deprotection during cleavage, followed by solution oxidation. When a second disulfide bond is required, one has the option of native or selective oxidation. For selective oxidation requiring orthogonal protecting groups, Acm and Trityl is used as the protecting groups for cysteine. Cleavage results in the removal of one protecting pair of cysteine allowing oxidation of this pair. The second oxidative deprotection step of the cysteine protected Acm group is then performed. For native oxidation, the trityl protecting group is used for all cysteines, allowing for natural folding of the peptide.

[0372] A skilled worker will be well aware of suitable techniques which can be used to perform the oxidation step.

[0373] In certain embodiments, a peptide compound of the present disclosure comprises or further comprises a half-life extension moiety, which may be selected from but is not limited to the following: Ahx-Palm, PEG2-Palm, PEGl l-Palm, isoGlu-Palm, dapa-Palm, isoGlu- Lauric acid, isoGlu-Mysteric acid, and isoGlu-Isovaleric acid.

[0374] In certain embodiments, a peptide compound comprises a half-life extension moiety having the structure shown below, wherein n=0 to 24 or n=14 to 24:n=0 to 24X=CH3, CO2H, NH2, OH

[0375] In certain embodiments, a peptide of the present invention comprises a conjugated half-life extension moiety shown in Table 2.Table 2. Illustrative Half-Life Extension Moieties

[0376] In certain embodiments, a half-life extension moiety is conjugated directly to a peptide compound, while in other embodiments, a half-life extension moiety is conjugated to a peptide compound via a linker moiety, e.g., any of those depicted in Table 3.Table 3. Illustrative Half-Life Extension Linker Moieties*(Peg) is -(OCH2CH2)-

[0377] In some embodiments, a peptide of the present invention comprises any of the linker moi eties shown in Table 3 and any of the half-life extension moi eties shown in Table 2, including any of the following combinations shown in Table 4.Table 4 - Illustrative Combinations of Linkers and Half-Life Extension Moieties

[0378] In some embodiments, a peptide of the present invention exhibits increased stability (e.g., as measured by half-life, rate of protein degradation) as compared to the same peptide without having an additional half-life extension moiety (i.e., the “reference compound”). In certain embodiments, the stability of a peptide of the present invention is increased at least about 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, or 200-fold greater or at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, or 500% greater than the reference compound.

[0379] In certain embodiments, a peptide of the present invention, comprising a conjugated half-life extension moiety, has an increased serum half-life following oral, intravenous or subcutaneous administration as compared to the same analogue but lacking the conjugated half-life extension moiety. In some embodiments, the serum half-life of a peptide of the present invention following any of oral, intravenous or subcutaneous administration is at least 12 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 48 hours, at least 72 hours or at least 168 h. In some embodiments, it is between 12 and 168 hours, between 24 and 168 hours, between 36 and 168 hours, or between 48 and 168 hours.

[0380] In some embodiments, the half-life is measured in vitro using any suitable method known in the art, e.g., the SGF and / or SIF assays described in the Examples, or in some embodiments, the stability of a peptide of the present invention is determined by incubating the peptide with pre-warmed human serum (Sigma) at 370C. Samples are taken at various time points, typically up to 24 hours, and the stability of the sample is analyzed by separating the peptide compound from the serum proteins and then analyzing for the presence of the peptide of interest using LC-MS.

[0381] In some embodiments, the stability of the peptide compound is measured in vivo using any suitable method known in the art, e.g., in some embodiments, the stability of a peptide compound is determined in vivo by administering the peptide to a subject such as a human or any mammal (e.g., mouse, canine, monkey) and then samples are taken from the subject via blood draw at various time points, typically up to 24 hours. Samples are then analyzed as described above in regard to the in vitro method of measuring half-life.Methods Based on Activation of GLP1R and / or GIPR

[0382] The peptide compounds of the invention are potent agonists of GLP1R and / or GIPR. As discussed, representative peptide compounds include sub nanomolar EC50 values in human cAMP accumulation assays with HEK293 cells expressing human GLP1R or human GIPR.

[0383] In one embodiment, the disclosure provides a method for treating T2DM, the method comprising administering to an individual with T2DM an effective amount of a peptide asdescribed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof.

[0384] In other embodiments, the disclosure provides a method for treating obesity or inducing weight loss, the method comprising administering to an individual in need of such a treatment an effective amount of a peptide as described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof.

[0385] Additional therapeutic methods include methods for treating a metabolic syndrome, NASH (nonalcoholic steatohepatitis), NAFLD (non-alcoholic fatty liver disease), or more generally, any condition or disease where reductions in blood glucose, increase in insulin, reduction in HbAlc, and / or reduction in blood weight is desired.

[0386] In some embodiments, the disclosure provides a method for treating a disease or disorder as disclosed herein in a subject. The method comprises administering to the subject in need thereof a peptide compound of the present invention in combination with one or more therapeutic agents or therapies. In certain embodiments, one or more therapeutic agents or therapies are provided to the subject before and / or simultaneously with and / or after the pharmaceutical composition is administered to the subject.

[0387] The pharmaceutical compositions of the invention comprise a peptide compound per one of the Formulas (including SEQ ID NO formulas), which compositions can be administered to a subject with a condition as described above. In some embodiments, when administration is by injection or by oral ingestion, the pharmaceutical composition comprises a peptide compound of the invention that exhibits an EC50 of 1 nM or less, 0.099 nM or less (i.e., double digit picomolar or less), or 0.009 nM or less (i.e., single digit picomolar) in a human high-density (HD) GLP1R HEK293 cAMP accumulation assay as described herein or as known in the art. In some embodiments, when administration is by injection or by oral ingestion, the pharmaceutical composition comprises a peptide compound of the invention that exhibits an EC50 of 1 micromolar or less, 100 nM or less, or 10 nM or less in a human high-density (LD) GLP1R HEK293 cAMP accumulation assay as described herein or as known in the art. In some embodiments, when administration is by oral ingestion, the pharmaceutical composition comprises a peptide compound of the invention that exhibits oneof the said EC50 values and also exhibits a half-life of at least 0.5, at least 1, at least 1.5, or at least 2 hours in an SGF and / or SIF assay. In one embodiment, the pharmaceutical composition is suitable for oral administration, and comprises a peptide compound of the invention that exhibits a single digit picomolar potency in a human cAMP HD GLP1R assay or less than 10 nM potency in a human cAMP LD GLP1R assay, and a half-life of greater than 20 hours or greater than 24 hours in an SGF assay. In another embodiment, the pharmaceutical composition is suitable for oral administration, and comprises a peptide compound of the invention that exhibits a single digit picomolar potency in a human cAMP HD GLP1R assay or less than 10 nM in a human cAMP LD GLP1R assay, and a half-life of greater than 20 hours or greater than 24 hours in an SGF assay and in an SIF assay.Pharmaceutical Compositions

[0388] The peptides of the present invention may be formulated as pharmaceutical compositions which are suited for administration with or without storage, and which typically comprise a therapeutically effective amount of at least one peptide of the invention, together with a pharmaceutically acceptable carrier, excipient or vehicle.

[0389] The present invention provides compositions (for example pharmaceutical compositions) comprising one or more peptides of the present invention and a pharmaceutically acceptable carrier, excipient or diluent. A pharmaceutically acceptable carrier, diluent or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like.

[0390] The term “pharmaceutically acceptable carrier” includes any of the standard pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical art and are described, for example, in “Remington's Pharmaceutical Sciences”, 17th edition, Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985. For example, sterile saline and phosphate-buffered saline at slightly acidic or physiological pH may be used. Suitable pH-buffering agents may, e.g.,be phosphate, citrate, acetate, tri s(hydroxymethyl)aminom ethane (TRIS), N- tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), ammonium bicarbonate, diethanolamine, histidine, arginine, lysine or acetate (e.g. as sodium acetate), or mixtures thereof. The term further encompasses any carrier agents listed in the US Pharmacopeia for use in animals, including humans.

[0391] In certain embodiments, the compositions comprise two or more peptides disclosed herein.

[0392] In some embodiments, the pharmaceutical compositions of the invention are in unit dosage form. In such forms, the composition is divided into unit doses containing appropriate quantities of the active component or components. The unit dosage form may be presented as a packaged preparation, the package containing discrete quantities of the preparation, for example, packaged tablets, capsules or powders in vials or ampoules. The unit dosage form may also be, e.g., a capsule, cachet or tablet in itself, or it may be an appropriate number of any of these packaged forms. A unit dosage form may also be provided in single-dose injectable form, for example in the form of a pen device containing a liquid-phase (typically aqueous) composition. Compositions may be formulated for any suitable route and means of administration, e.g., any one of the routes and means of administration disclosed herein.

[0393] In some embodiments, the peptide, or the pharmaceutical composition comprising a peptide, is suspended in a sustained-release matrix. A sustained-release matrix, as used herein, is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid-base hydrolysis or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids. A sustained-release matrix desirably is chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid) polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone. One embodiment of a biodegradablematrix is a matrix of one of either polylactide, polyglycolide, or polylactide co-glycolide (copolymers of lactic acid and glycolic acid).

[0394] In certain embodiments, the compositions are administered parenterally, subcutaneously or orally. In particular embodiments, the compositions are administered orally, intraci sternally, intravaginally, intraperitoneally, intrarectally, topically (as by powders, ointments, drops, suppository, or transdermal patch, including delivery intravitreally, intranasally, and via inhalation) or buccally. The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intradermal and intra-articular injection and infusion. Accordingly, in certain embodiments, the compositions are formulated for delivery by any of these routes of administration.

[0395] In certain embodiments, pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders, for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, beta-cyclodextrin, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prolonged absorption of an injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.

[0396] Injectable depot forms include those made by forming microencapsule matrices of the peptide in one or more biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters), poly(anhydrides), and (poly)glycols, such as PEG. Depending upon the ratio of peptide to polymer and the nature of the particular polymer employed, the rate ofrelease of the peptide can be controlled. Depot injectable formulations are also prepared by entrapping the peptide in liposomes or microemulsions compatible with body tissues.

[0397] The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

[0398] Peptides of the present invention may also be administered in liposomes or other lipid-based carriers. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a peptide of the present invention, stabilizers, preservatives, excipients, and the like. In certain embodiments, the lipids comprise phospholipids, including the phosphatidyl cholines (lecithins) and serines, both natural and synthetic. Methods to form liposomes are known in the art.

[0399] Pharmaceutical compositions to be used in the invention suitable for parenteral administration may comprise sterile aqueous solutions and / or suspensions of the peptide inhibitors made isotonic with the blood of the recipient, generally using sodium chloride, glycerin, glucose, mannitol, sorbitol, and the like.

[0400] Compositions with a peptide of the instant invention can be prepared for oral administration according to any of the methods, techniques, and / or delivery vehicles described herein. Further, one having skill in the art will appreciate that the peptides of the invention can be modified or integrated into a system or delivery vehicle that is not disclosed herein yet is well known in the art and compatible for use in oral delivery of peptides.

[0401] In certain embodiments, formulations for oral administration may comprise adjuvants (e.g. resorcinols and / or nonionic surfactants such as polyoxyethylene oleyl ether and n- hexadecylpolyethylene ether) to artificially increase the permeability of the intestinal walls, and / or enzymatic inhibitors (e.g. pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) or trasylol) to inhibit enzymatic degradation. In certain embodiments, the peptide of asolid-type dosage form for oral administration can be mixed with at least one additive, such as sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymer, or glyceride. These dosage forms can also contain other type(s) of additives, e.g., inactive diluting agent, lubricant such as magnesium stearate, paraben, preserving agent such as sorbic acid, ascorbic acid, alpha-tocopherol, antioxidants such as cysteine, disintegrators, binders, thickeners, buffering agents, pH adjusting agents, sweetening agents, flavoring agents or perfuming agents.

[0402] In particular embodiments, oral dosage forms or unit doses compatible for use with the peptides of the present invention may include a mixture of a peptide and nondrug components or excipients, as well as other non-reusable materials that may be considered either as an ingredient or packaging. Oral compositions may include at least one of a liquid, a solid, and a semi-solid dosage forms. In some embodiments, an oral dosage form is provided comprising an effective amount of a peptide of the invention, wherein the dosage form comprises at least one of a pill, a tablet, a capsule, a gel, a paste, a drink, a syrup, ointment, and suppository. In some instances, an oral dosage form is provided that is designed and configured to achieve delayed release of the peptide in the subject’s small intestine and / or colon.

[0403] In one embodiment, an oral pharmaceutical composition comprising a peptide of the present invention comprises an enteric coating that is designed to delay release of the peptide inhibitor in the small intestine. In at least some embodiments, a pharmaceutical composition is provided which comprises a peptide of the present invention and a protease inhibitor, such as aprotinin, in a delayed release pharmaceutical formulation. In some instances, pharmaceutical compositions of the instant invention comprise an enteric coat that is soluble in gastric juice at a pH of about 5.0 or higher. In at least one embodiment, a pharmaceutical composition is provided comprising an enteric coating comprising a polymer having dissociable carboxylic groups, such as derivatives of cellulose, including hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate and cellulose acetate trimellitate and similar derivatives of cellulose and other carbohydrate polymers.

[0404] In one embodiment, a pharmaceutical composition comprising a peptide of the present invention is provided in an enteric coating, the enteric coating being designed to protect and release the pharmaceutical composition in a controlled manner within the subject’s lower gastrointestinal system, and to avoid systemic side effects. In addition to enteric coatings, the peptides of the instant invention may be encapsulated, coated, engaged or otherwise associated within any compatible oral drug delivery system or component. For example, in some embodiments a peptide of the present invention is provided in a lipid carrier system comprising at least one of polymeric hydrogels, nanoparticles, microspheres, micelles, and other lipid systems.

[0405] In some embodiments, the pharmaceutical compositions comprise a hydrogel polymer carrier system in which a peptide of the present invention is contained, whereby the hydrogel polymer protects the peptide from proteolysis or degradation in the small intestine and / or colon. The peptides of the present invention may further be formulated for compatible use with a carrier system that is designed to increase the dissolution kinetics and enhance intestinal absorption of the peptide. These methods include the use of liposomes, micelles and nanoparticles to increase GI tract permeation of peptides.

[0406] Various bioresponsive systems may also be combined with one or more peptides of the present invention to provide a pharmaceutical agent for oral delivery. In some embodiments, a peptide of the instant invention is used in combination with a bioresponsive system, such as hydrogels and mucoadhesive polymers with hydrogen bonding groups (e.g., PEG, poly(methacrylic) acid [PMAA], cellulose, Eudragit®, chitosan and alginate) to provide a therapeutic agent for oral administration. Other embodiments include a method for optimizing or prolonging drug residence time for a peptide disclosed herein, wherein the surface of the peptide is modified to comprise mucoadhesive properties through hydrogen bonds, polymers with linked mucins or / and hydrophobic interactions. These modified peptide molecules may demonstrate increase drug residence time within the subject, in accordance with a desired feature of the invention. Moreover, targeted mucoadhesive systems may specifically bind to receptors at the enterocytes and M-cell surfaces, thereby further increasing the uptake of particles containing a peptide of the invention.

[0407] In other embodiments, the disclosure provides a method for oral delivery of a peptide of the present invention, wherein the peptide is provided to a subject in combination with permeation enhancers that promote the transport of the peptides across the intestinal mucosa by increasing paracellular or transcellular permeation. For example, a permeation enhancer is combined with a peptide of the invention, wherein the permeation enhancer comprises at least one of a long-chain fatty acid, a bile salt, an amphiphilic surfactant, and a chelating agent. In one embodiment, a permeation enhancer comprising sodium N-[hydroxybenzoyl)amino] caprylate is used to form a weak noncovalent association with a peptide of the instant invention, wherein the permeation enhancer favors membrane transport and further dissociation once reaching the blood circulation. In another embodiment, a peptide of the present invention is conjugated to oligoarginine, thereby increasing cellular penetration of the peptide into various cell types. Further, in at least one embodiment a noncovalent bond is provided between a peptide inhibitor of the present invention and a permeation enhancer selected from the group consisting of a cyclodextrin (CD) and a dendrimers, wherein the permeation enhancer reduces peptide aggregation and increasing stability and solubility for the peptide.Dosages and administrations

[0408] The total daily usage of the peptides and compositions of the present invention can be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including: a) the disorder being treated and the severity of the disorder; b) activity of the specific compound employed; c) the specific composition employed, the age, body weight, general health, sex and diet of the patient; d) the time of administration, route of administration, and rate of excretion of the specific peptide employed; e) the duration of the treatment; f) drugs used in combination or coincidental with the specific peptide employed, and like factors well known in the medical arts.

[0409] In some embodiments, the total daily dose of the peptides of the invention to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.0001 to 300 mg / kg body weight daily or 1 to 300 mg / kg body weightdaily. In certain embodiments, a dosage of a peptide of the present invention is in the range from about 0.0001 to about 100 mg / kg body weight per day, such as from about 0.0005 to about 50 mg / kg body weight per day, such as from about 0.001 to about 10 mg / kg body weight per day, e.g. from about 0.01 to about 1 mg / kg body weight per day, administered in one or more doses, such as from one to three doses. In certain embodiments, a total dosage is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg about once or twice weekly, e.g., for a human patient. In certain embodiments, the total dosage is in the range of about 1 mg to about 5 mg, or about 1 mg to about 3 mg, or about 2 mg to about 3 mg per human patient, e.g., about once weekly.

[0410] In various embodiments, a peptide of the invention may be administered continuously (e.g. by intravenous administration or another continuous drug administration method), or may be administered to a subject at intervals, typically at regular time intervals, depending on the desired dosage and the pharmaceutical composition selected by the skilled practitioner for the particular subject. Regular administration dosing intervals include, e.g., once daily, twice daily, once every two, three, four, five or six days, once or twice weekly, once or twice monthly, and the like.

[0411] Such regular administration regimens of the invention may, in certain circumstances such as, e.g., during chronic long-term administration, be advantageously interrupted for a period of time so that the medicated subject reduces the level of or stops taking the medication, often referred to as taking a “drug holiday.” Drug holidays are useful for, e.g., maintaining or regaining sensitivity to a drug especially during long-term chronic treatment, or to reduce unwanted side-effects of long-term chronic treatment of the subject with the drug. The timing of a drug holiday depends on the timing of the regular dosing regimen and the purpose for taking the drug holiday (e.g., to regain drug sensitivity and / or to reduce unwanted side effects of continuous, long- term administration). In some embodiments, the drug holiday may be a reduction in the dosage of the drug (e.g. to below the therapeutically effective amount for a certain interval of time). In other embodiments, administration of the drug is stopped for a certain interval of time before administration is started again using the same or a different dosing regimen (e.g. at a lower or higher dose and / or frequency ofadministration). A drug holiday of the invention may thus be selected from a wide range of time-periods and dosage regimens. An exemplary drug holiday is two or more days, one or more weeks, or one or more months, up to about 24 months of drug holiday. So, for example, a regular daily dosing regimen with a peptide, a peptide analogue, or a dimer of the invention may, for example, be interrupted by a drug holiday of a week, or two weeks, or four weeks, after which time the preceding, regular dosage regimen (e.g. a daily or a weekly dosing regimen) is resumed. A variety of other drug holiday regimens are envisioned to be useful for administering the peptides of the invention.

[0412] Thus, the peptides of the invention may be delivered via an administration regime which comprises two or more administration phases separated by respective drug holiday phases.

[0413] During each administration phase, the peptide is administered to the recipient subject in a therapeutically effective amount according to a pre-determined administration pattern. The administration pattern may comprise continuous administration of the drug to the recipient subject over the duration of the administration phase. Alternatively, the administration pattern may comprise administration of a plurality of doses of the peptide to the recipient subject, wherein said doses are spaced by dosing intervals.

[0414] A dosing pattern may comprise at least two doses per administration phase, at least five doses per administration phase, at least 10 doses per administration phase, at least 20 doses per administration phase, at least 30 doses per administration phase, or more.

[0415] Said dosing intervals may be regular dosing intervals, which may be as set out above, including once daily, twice daily, once every two, three, four, five or six days, once or twice weekly, once or twice monthly, or a regular and even less frequent dosing interval, depending on the particular dosage formulation, bioavailability, and pharmacokinetic profile of the peptide of the present invention.

[0416] An administration phase may have a duration of at least two days, at least a week, at least 2 weeks, at least 4 weeks, at least a month, at least 2 months, at least 3 months, at least 6 months, or more.

[0417] Where an administration pattern comprises a plurality of doses, the duration of the following drug holiday phase is longer than the dosing interval used in that administration pattern. Where the dosing interval is irregular, the duration of the drug holiday phase may be greater than the mean interval between doses over the course of the administration phase. Alternatively, the duration of the drug holiday may be longer than the longest interval between consecutive doses during the administration phase.

[0418] The duration of the drug holiday phase may be at least twice that of the relevant dosing interval (or mean thereof), at least 3 times, at least 4 times, at least 5 times, at least 10 times, or at least 20 times that of the relevant dosing interval or mean thereof.

[0419] Within these constraints, a drug holiday phase may have a duration of at least two days, at least a week, at least 2 weeks, at least 4 weeks, at least a month, at least 2 months, at least 3 months, at least 6 months, or more, depending on the administration pattern during the previous administration phase.

[0420] An administration regime comprises at least 2 administration phases. Consecutive administration phases are separated by respective drug holiday phases. Thus, the administration regime may comprise at least 3, at least 4, at least 5, at least 10, at least 15, at least 20, at least 25, or at least 30 administration phases, or more, each separated by respective drug holiday phases.

[0421] Consecutive administration phases may utilise the same administration pattern, although this may not always be desirable or necessary. However, if other drugs or active agents are administered in combination with a peptide of the invention, then typically the same combination of drugs or active agents is given in consecutive administration phases. In certain embodiments, the recipient subject is human.

[0422] In some embodiments, the invention provides a device comprising at least one peptide of the present invention, or pharmaceutically acceptable salt or solvate thereof for delivery of the peptide to a subject.

[0423] In some embodiments, the present invention provides kits comprising at least one peptide of the invention, or a composition (e.g., pharmaceutical composition) as disclosedherein packaged together with a reagent, a device, instructional material, or a combination thereof.

[0424] In some embodiments, the present invention provides a method of administering a peptide or a composition (e.g., pharmaceutical composition) comprising a peptide of the invention to a subject via implant or osmotic pump, by cartridge or micro pump, or by other means appreciated by the skilled artisan, as well-known in the art.

[0425] In addition to the methods described in the Examples herein, the peptides of the present invention may be produced using methods known in the art including chemical synthesis, biosynthesis or in vitro synthesis using recombinant DNA methods, and solid phase synthesis. See e.g. Kelly & Winkler (1990) Genetic Engineering Principles and Methods, vol. 12, J. K. Setlow ed., Plenum Press, NY, pp. 1-19; Merrifield (1964) J Amer Chem Soc 85:2149; Houghten (1985) PNAS USA 82:5131-5135; and Stewart & Young (1984) Solid Phase Peptide Synthesis, 2ed. Pierce, Rockford, IL, which are herein incorporated by reference. The peptides of the present invention may be purified using protein purification techniques known in the art such as reverse phase high-performance liquid chromatography (HPLC), ion-exchange or immunoaffinity chromatography, filtration or size exclusion, or electrophoresis. See Olsnes, S. and A. Pihl (1973) Biochem.12(16):3121-3126; and Scopes (1982) Protein Purification, Springer- Verlag, NY, which are herein incorporated by reference.EXAMPLES

[0426] The following examples demonstrate certain specific embodiments of the present invention. The following examples were carried out using standard techniques that are well known and routine to those of skill in the art, except where otherwise described in detail. It is to be understood that these examples are for illustrative purposes only and do not purport to be wholly definitive as to conditions or scope of the invention. As such, they should not be construed in any way as limiting the scope of the present invention.ABBREVIATIONS:DCM: dichloromethaneDMF: N,N-dimethylformamide NMP: N-methylpyrolidoneHBTU: O-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HATU : 2-(7-aza- IH-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphateDCC: DicyclohexylcarbodiimideNHS: N-hydoxysuccinimideDIPEA: diisopropyl ethylamineEtOH: ethanolEt2O: diethyl etherHy: hydrogenTFA: trifluoroacetic acidTIS: triisopropyl silaneACN: acetonitrileHPLC: high performance liquid chromatography ESI-MS: electron spray ionization mass spectrometry PBS: phosphate-buffered salineBoc: t-butoxycarbonylFmoc: FluorenylmethyloxycarbonylAcm: acetamidomethylIVA: Isovaleric acid (or Isovaleryl)Palm: Indicates conjugation of a palmitic acid (palmitoyl).

[0427] In the peptide sequences provided herein, wherein a compound or chemical group is connected by an underscore to an amino acid residue or a chemical moiety, it is to be understood that the compound or chemical group is a side chain or group bonded to the amino acid residue or the chemical moiety but is not connected to any other adjacent amino acid residue. For example, Leu-Trp_5F-Asp indicates the 5F substituent is only bonded to Trp but is not connected to Asp. The dash line between 5F and Asp denotes the bonding between Trp and Asp. Lys Ac indicates the Ac group is conjugated to a side chain of the lysine residue.General procedure for purification of peptides

[0428] Purification of the peptides of the invention was carried out using reverse-phase high performance liquid chromatography (RP-HPLC). A semi-preparative column - Gemini 5 pm Cl 8 column (21.2 mm x 250 mm) (Phenomenex®) was applied at the flow rate of 20mL / min. The separation was achieved using linear gradients with mobile phase A (MPA = 0.1% TFA in water) and mobile phase B (MPB = 0.1% TFA in acetonitrile).

[0429] One of skill in the art will appreciate that standard methods of peptide synthesis may be used to generate the compounds of the invention.

[0430] The peptides disclosed herein were prepared in accordance with procedures and synthetic sequences similar to those set forth in the representative Examples that follow. The molecular weights of the peptides were determined by LC / MS.Example 1 SYNTHESIS OF PEPTIDE ANALOGUES

[0431] Unless otherwise specified, reagents and solvents employed in the following were available commercially in standard laboratory reagent or analytical grade and were used without further purification. Additional teachings for peptide synthesis and isolation, including cyclization and dimerization chemistry, can be found in prior Protagonist patent publications, which are hereby incorporated-by-reference for such teachings - for example: US 10,030,061; US 10,059,744; US 11,807,674; US 9,624,268; US 11,840,581; US 11,845,808; US 10,407,468; and US 11,041,000.General procedure for Fmoc solid-phase peptide synthesis (SPPS)

[0432] Peptides were synthesized utilizing the CEM liberty Blue Microwave assisted peptide synthesizer. Using the Liberty Blue, Fmoc-deprotection was carried out by addition of 20% piperidine in A A-di methyl form am ide (DMF) and then heating to 90° C using microwave irradiation for 80 sec. After DMF washes the Fmoc-protected amino acids were coupled by addition of 0.2 M amino acid (5 eq), 0.5 M N,N" -Diisopropylcarbodiimide (DIC; 5 eq) and 1.0 M ethyl cyanohydroxyiminoacetate (Oxyma; 5 eq) all dissolved in DMF. The coupling solution is heated using microwave radiation to 90° C for 160 sec. A second coupling was employed when coupling Arg or other sterically hindered amino acids. When coupling with histidine, the reaction was heated to 50° C for 10 min, double coupling. The cycles were repeated until the desired peptide was obtained.General procedure for cleavage of peptides off resin and side chain deprotection

[0433] Side chain deprotection and cleavage off the resin for peptide analogues of the invention was achieved by stirring dry resin in a solution containing trifluoroacetic acid(TFA), water, 2,2’-(ethylenedioxy)diethanethiol (DODT) and triisopropylsilane (TIPS) (90:5:2.5:2.5) for 2 h. Following TFA removal, peptide was precipitated using ice-cold diethyl ether. The solution was centrifuged (5,000 rpm, 4° C, 5 min), and the ether was decanted. The peptide was dissolved in an acetonitrile (MeCN) / water solution (1 : 1) and the resulting solution was filtered. The linear peptide quality was assessed using electrospray ionization mass spectrometry (ESI-MS).General procedure for purification of peptides and final lyophilization

[0434] Purification of the peptides of the invention was carried out using reverse-phase high performance liquid chromatography (RP-HPLC). A semi-preparative column - Gemini 5 pm Cl 8 column (21.2 mm x 250 mm) (Phenomenex®) was applied at the flow rate of 20 mL / min. The separation was achieved using linear gradients with mobile phase A (MPA = 0.1% TFA in water) and mobile phase B (MPB = 0.1% TFA in acetonitrile). The collected fractions were analyzed by analytical RP-HPLC, and all fractions >95% purity were combined and freeze-dried under lyophilizer.General Procedure for Intramolecular Disulfide Bond Formation (Disulfide Bond Cyclization) via Oxidation

[0435] A peptide containing a free thiol at the desired cyclization positions can be assembled on a Rink Amide-MBHA resin following general Fmoc-SPPS procedure. The peptide is cleaved from the resin by treatment with cleavage reagent 90% trifluoroacetic acid, 5% water, 2.5% 1,2-ethanedithiol, 2.5% tri-isopropylsilane). The cleaved peptides are precipitated in cold diethyl ether followed by two washings with ethyl ether. The filtrate was poured off and a second aliquot of cold ether was added, and the procedure repeated. The crude peptide is dissolved in a solution of acetonitrile:water (7:3 with 1% TFA) and filtered giving the wanted unoxidized peptide crude peptide

[0436] The crude, cleaved peptide is dissolved in 20 ml of water: acetonitrile. Saturated Iodine in acetic acid is then added drop wise with stirring until yellow color persisted. The solution is stirred for 15 minutes, and the reaction is monitored with analytic HPLC and LCMS. When the reaction is complete, solid ascorbic acid is added until the solution becomes clear. The solvent mixture is then purified by first being diluted with water and then loaded onto a reverse phase HPLC machine (Luna C18 support, 10 u, 100 A, Mobile phaseA: water containing 0.1% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA, gradient began with 5% B, and changed to 50% B over 60 minutes at a flow rate of 15 ml / min). Fractions containing pure product are then freeze-dried on a lyophilyzer.General Procedure for Intramolecular Thioether Bond Formation (Thioether Bond Cyclization)

[0437] A peptide containing a free thiol at the desired position and a free alkyl at the other desired residue position for cyclization is assembled on a Rink Amide-MBHA resin following general Fmoc-SPPS procedure. Chlorination is carried out by treating the resin with PPh3 (10 equiv.) and C13CCN (10 equiv.) in DCM for 2 h. The peptide is cleaved from the resin by treatment with cleavage reagent 90% trifluoroacetic acid, 5% water, 2.5% 1,2- ethanedithiol, 2.5% tri-isopropylsilane). The cleaved peptides are precipitated in cold diethyl ether followed by two washings with ethyl ether. The filtrate was poured off and a second aliquot of cold ether is added, and the procedure repeated. The crude peptide is dissolved in a solution of acetonitrile:water (7:3 with 1% TFA) and filtered giving the wanted uncyclized crude peptide.

[0438] The crude peptide possessing a free thiol and an alkyl halide intermediate at the desired cyclization positions is dissolved in 0.1 M TRIS buffer pH 8.5. Cyclization is allowed to take place overnight at RT. The solvent mixture is then purified by first being diluted twofold with water and then loaded onto a reverse phase HPLC machine (Luna C18 support, 10 u, 100 A, Mobile phase A: water containing 0.1% TFA, mobile phase B: Acetonitrile (ACN) containing 0.1% TFA, gradient began with 5% B, and changed to 50% B over 60 minutes at a flow rate of 15 ml / min). Fractions containing pure product are then freeze-dried on a lyophilyzer.General Procedure for Intramolecular Bis-thioether Bond Formation (Cyclization Linker Mediated Cross-Linking)

[0439] After crude linear peptides purification, combine the desired fractions (-200 mL for 1.5 mmol scale). To this, 1 eq. of TCEP was added, then 15-20 eq. of base K2CO3 was added to adjust the pH to 10-11. Diiodide alkane (2-4 eq.) was then added batchwise over an hour to minimize the formation of double alkylated side products. Cyclization was generally completed within 1-2 hr, and can be monitored by LC-MS. Upon completion, the reactionmixture was then diluted to containing 30% ACN / H20, acidified by TFA, followed by purification using RP-HPLC.General Procedure for Hydrocarbon Ring Close Metathesis (RCM) (Carbon-carbon single or double bond cross-linking)

[0440] After the coupling of second olefin residue, the resin was washed with DCM and dried under high vacuum. The dry resin was then placed in the round bottom flask and swollen in toluene (1 g resin per 20 mL toluene). To the reaction mixture was added Grubbs catalyst 1stgeneration (0.35 eq.). The resulting solution was bubbled with N2 for 5 mins and capped with a small nitrogen balloon. It was heated to 60 °C overnight (O / N). Microcleavage test confirmed reaction completion. After cooling down to room temperature resin was filtered and washed with DMF x2, DMSO xl, DCM x3.General Procedures for Olefin Reduction

[0441] After the RCM reaction, the dry resin was swollen in MeCN (1 g resin per 20 mL solvent). It was cooled by ice bath and charged with 2-nitrobenzenesulfonyl chloride (10 eq.). Hydrazine hydrate (25 eq.) was slowly added to the reaction mixture. After addition, it was allowed to warm up to room temperature and continued stirred overnight. Micro-cleavage test to confirm the reaction completion. Second round of treatment can be applied if the reaction was not yet completed.

[0442] Once the reaction was completed, the reaction mixture was filtered and washed with DMF x2, DMF / H2O (1 : 1) xl, THF xl, DMF xl, DCM x2; then dried under vacuum and transferred back to the reaction vessel to continue the amino acid assembly using Fmoc SPPS until completion.General Procedures for Linker Activation and Dimerization

[0443] Peptide monomer subunits are linked to form peptide dimers as described below.

[0444] Small Scale DIG Linker Activation Procedure: 5 mL of NMP is added to a glass vial containing IDA diacid (304.2 mg, 1 mmol), N-hydroxysuccinimide (NHS, 253.2 mg, 2.2 eq.2.2 mmol) and a stirring bar. The mixture is stirred at room temperature to completely dissolve the solid starting materials. N, N'-Dicyclohexylcarbodiimide (DCC, 453.9 mg, 2.2 eq., 2.2 mmol) is then added to the mixture. Precipitation appears within 10 min and the reaction mixture is further stirred at room temperature overnight. The reaction mixture is thenfiltered to remove the precipitated dicyclohexylurea (DCU). The activated linker is kept in a closed vial prior to use for dimerization. The nominal concentration of the activated linker is approximately 0.20 M.

[0445] For dimerization using PEG linkers, there is no pre-activation step involved. Commercially available pre-activated bi-functional PEG linkers are used.

[0446] Dimerization Procedure: 2 mL of anhydrous -DMF or DMSO is added to a vial containing peptide monomer (0.1 mmol). The pH of the peptide was the adjusted to 8-9 with DIEA. Activated linker (0.48 eq relative to monomer, 0.048 mmol) is then added to the monomer solution. The reaction mixture is stirred at room temperature for one hour.Completion of the dimerization reaction is monitored using analytical HPLC. The time for completion of dimerization reaction varies depending upon the linker. After the completion, the reaction mixture is diluted with MeCN by 20-100x fold and loaded on to RP-HPLC for purification.Example 2POTENCY ASSAYS

[0447] To assess the potency of peptides at the human GLP1 and GIP receptors, HEK-293 clonal cell lines expressing either the human GLP1R or GIPR were used to measure 3’, 5’- cyclic adenosine monophosphate (cAMP) accumulation, which is a second messenger downstream of receptor activation.Materials

[0448] Reagent information is provided in the Table below:

[0449] Plasmid DNA constructs. All plasmids (GLP1R, GIPR, GCGR) were constructed and verified by Azenta. The plasmids are pCDNA3.1 expression vectors encoding human GIPR, human GLP1R, or human GCGR. The human GIPR and GLP1R coding sequences (i.e., open reading frames) and the pcDNA3.1 expression vector maps are presented in Figs. 3A-3D.Construction of HEK293 cell lines stably expressing human GLP1R or GIPR

[0450] 1. Transfection.

[0451] Day 1. HEK293 cells were detached with 0.25% Trypsin when the cell confluence was about 80%. Detached cells were resuspended in 3 ml fresh cell culture medium. Cell number was counted and cells diluted to proper density. Cells were seeded at 0.5 x 10A6 cells into 6-well plates in 2 ml per well so that they were 80-85% confluent at the time of transfection.

[0452] Day 2. For huGLP-lR, Ipg huGLPIR expression plasmid (i.e., Fig. 3A) and Ipg CRE plasmid were added in 200pl of Opti-MEM® Medium without serum. For huGIPR and huGCGR, 2pg of expression plasmid were added in 200 pl of Opti-MEM® Medium without serum. FuGENE®HD was added at 6ul to 200pl Opti-MEM® Medium with the expressionplasmid, and incubated for 20 minutes at room temperature. lOOpl of DNA-FuGENE complexes were added to each well containing cells and medium. Cells were incubated at 37°C in a CO2 incubator for 24 hours until they are ready to assay for transgene expression.Two 6-well plates were used per below.

[0453] 2. Clone Selection

[0454] Cells were passaged to 10 cm dishes 24 hours after transfection. Selective medium were added to select for transfectants. (For huGLP-lR: 300 pg / ml Hygromycin B, 1000pg / ml G418; for huGIPR: 300 pg / ml Hygromycin B; for huGCGR: 300 pg / ml Hygromycin B).

[0455] Medium was exchanged every 3 days. Once all cells died in the negative control dish (non-transfected or transfected empty vector), cell colonies were digested and reseeded to 96- well plates (0.5 cell / well).

[0456] After about a week, cells with only a single clone group were selected under a microscope and marked. After waiting for a single colony to grow to full size, it was transferred from the 96-well plate to a 12-well plate, and then to a 6-well plate, a 6 cm dish, and a 10 cm dish in sequence. After the cells in the 6cm dish were full, 1 / 2 of the cells were transferred to the 10cm dish, and the remaining cells were tested for cAMP.

[0457] 3. Receptor Density Determination Using Fluorescence Quantitation

[0458] Fluorescence quantitation was used to determine the cell-surface receptor density of cell clones for use with cAMP testing of the peptides of the invention. Specifically, Becton Dickinson (BD) Quantibrite Phycoerythrin (PE) tubes were used, which are designed for use with PE-labeled monoclonal antibodies for the purpose of estimating the quantity of cellsurface proteins (i.e., proteins that are recognized by the monoclonal antibodies; in this case, hGLPIR or hGIPR).Materials:

[0459] Cell collection: Cells from 15cm should be near 80% confluency before collection.Culture medium was removed and dishes were gently rinsed using PBS. 0.05% trypsin (0.25% trypsin-EDTA was diluted 5-fold by PBS) was added and cells incubated at 37 °C and 5% CO2 until cells were dislodged. 5 ml of medium was added to a final volume of 10 mL and cells were pipetted up and down until cells were homogeneously dispersed in the solution. The cell suspension was centrifuged at 1000 rpm for 5 min. After centrifugation, supernatant was discarded. Cell pellets were resuspended with 5 mL cell culture medium. 20uL of the resuspended cells were removed to count cells, which was done by adding the 20 pL of resuspended cells to 20 pL dye with Cell Counter Star. Live cell number was recorded.

[0460] Fluorescence Quantitation Assay and Flow Cytometric Analysis: BD Quantibrite PE tubes were reconstituted with 500ul buffer (PBS with 0.5% bovine serum albumin) and then vortexed. Cells were collected as described above, and aliquoted at 1 x 106cells / 100 uL into FACS tubes. PE-conjugated primary antibody was added (either anti-hGLPIR, anti-hGIPR, or anti-hGCGR) at 10 uL / 106cells) and vortexed. Cells were incubated for 30 minutes at room temperature in the dark. Unbound antibody was removed by washing the cells in 2 mL staining buffer. Cells were then centrifuged at 300g for 5 minutes and buffer was decanted. Cells were resuspended by adding 2 mL of staining buffer. Wash step was repeated and cells resuspended in 300 uL of staining buffer for flow cytometric analysis. For flow cytometric analysis, a BD Quantibrite PE tube was first analyzed, with thresholding on FSC or SSC, and 10,000 events were collected. Using the same instrument settings, cellular samples were analyzed. The Log 10 for the FL2 geometric means and for the PE molecules per bead were calculated. A linear regression of Log 10 PE molecules per bead was plotted against LoglO fluorescence, using the following equation: y = mx + c (y equals LoglO fluorescence and x equals LoglO PE molecules per bead). Receptor density was determinedby substituting Log FL2 geometric means in the equation and solving for Log receptor. AntiLog was determined to estimate receptor density. Thus, with the BD Quantibrite PE tubes, the FL2 axis of the flow cytometer is converted into the number of PE molecules bound per cell. By using known ratios of PE to antibodies, the PE molecules per cell is converted to antibodies per cell, and therefore the number of receptors / proteins per cell that are recognized by the antibodies. Herein, human high-density (HD) GLP1R HEK 293 cell clones expressed on their cell surface about greater than 200,000 receptors / cell, and human low-density (LD) GLP1R HEK 293 cell clones expressed on the cell-surface about less than 2,000 receptors / cell (per flow cytometry and BD Quantibrite). Herein, HEK 293 cell clones express human GIPR on the cell surface at a density between about 45,000 and 55,000 receptors / cell.

[0461] Alternatively, radioligand binding can be performed as described in the art. For example, Willard et al., JCI Insight, 2020; 5(17):el40532, at p. 9, which states in part: “Membranes from HEK293 cells expressing the cloned human GLP-1R or human GIPR were prepared as described previously (50). Receptor expression density was determined using homologous competition, and Ki values were determined using competition binding. Incubations were performed in a total volume of 200 pL in a 96-well plate (Coming). [125I]GLP-1(7-36)NH2 or [125I]GIP(1-42)OH (2200 Ci / mmol, > 95 % purity, final assay concentrations ~0.12-0.20 nM, PerkinElmer) in assay buffer (2.5 mM MgC12[Millipore Sigma], 1.0 mM CaC12 [MilliporeSigma], 0.1% w / v fraction V fatty acid free bovine serum albumin [82-002-4, MilliporeSigma], 0.1% w / v bacitracin [11805, Affymetrix] in 25 mM HEPES [Thermo Fisher Scientific], pH 7.4, final concentrations) was added to peptide in assay buffer (concentration-response curves in DMSO, 3 -fold acoustic direct dilution [Echo555, Labcyte], final DMSO concentration in the assay was 0.96%). Assay buffer (100 pL) containing GLP-1R or GIPR membranes that had been preincubated at room temperature with WGA-PVT SPA beads (PerkinElmer) for 2 hours was added. The amount of membrane protein and WGA-SPA bead depended on the expression density and was 0.5- 1.0 pg protein with 0.25 mg bead for the high-, 1.5-7.5 pg protein with 0.25-0.5 mg bead for the medium-, and 5.0-20 pg protein with 0.25-0.75 mg bead for the low-expressing cell lines. The plates were covered with sealing tape, mixed, and incubated for an additional 18hours at room temperature. The plates were centrifuged at ~200g for 5 minutes at room temperature. Bound ligand was determined using a MicroBeta Trilux Scintillation Counter (PerkinElmer). Using GraphPad Prism 7 software, Bmax values for [125I]GLP-1(7-36)NH2 or [125I]GIP(l-42) binding to GLP-1R and GIPR membranes were determined by nonlinear regression analysis using the amount bound versus the concentration of competing homologous peptide added. The Bmax was used to calculate the number of receptors per cell. For competing peptides, Ki values were determined by nonlinear regression analysis using the amount of [125I]GLP-1(7-36)NH2 or

[1251] GIP( 1-42) bound versus the concentration of peptide added.” Thus, membranes from HEK293 clones can be isolated and competition binding assays conducted with radiolabeled and unlabeled ligand, i.e., radiolabeled and unlabeled hGLP-1 ligand (7-36) for hGLPIR; radiolabeled and unlabeled hGIP ligand (1-42) for hGIPR. Nonlinear regression analysis can be conducted using the amount bound of radiolabeled ligand to its receptor (using the membrane fractions) versus the concentration of competing unlabeled ligand. The Bmax can be used to calculate the number of receptor per cell. cAMP assay

[0462] Peptide compounds were diluted from stock concentration to source concentration by DMSO (1000X), then 3 -fold diluted in DMSO with a total of 10 dose. 10 nL diluted compound was added to assay plate by ECHO. The assay plate was centrifuged at 1000 rpm for 1 minute.

[0463] Stable cell lines ~ 80% confluence was acceptable for experiments of 2-3 days duration. The cells were dissociated from the dish and centrifuged at 1000 rpm for 5 minutes. Cells were washed with DPBS once and resuspended with DPBS which contained 0.1% BSA and 500uM IB MX. Cells were seeded to 384-well plate which was pre-transferred with 10 nL of peptide compound to be tested. 1000 cells / well for GLP1R expressing cells (HD or LD) or 3000 cells / well for GIPR expressing cells. The assay plate was covered and incubated for 30 minutes at room temperature (RT). 5 pL / well of diluted (25 uL of cAMP d2 reagent in 475 ul of lx detection buffer) d2 -labeled cAMP conjugate was dispensed followed by 5 pL / well of cryptate-labeled anti-cAMP antibody (from a mixture of 25 uL of antibody in 475 uL ofdetection buffer) to the cell plate. Fluorescence intensity was measured at emission of 665 nm and 615 nm (Em665 and Em615), with excitation at 320 nm after Ih at room temperature.Statistical analysis

[0464] The percent (%) activation of the compound in each well was calculated based on the HTRF ratio recorded from the well (test value) and the mean HTRF ratios in the positive control and negative control wells contained within each assay plate. The positive control wells were 100% activation. The negative control wells were 0% activation.

[0465] The concentrations and % activation values for tested compounds were plotted, and the concentration of compound required for 50% activation (EC50) was determined by fitting the data with a four-parameter logistic dose response equation. The EC50 values for the reference compounds were evaluated in each experiment as a quality control measure. Assay window was the ratio of negative control and positive control.Example 3STABILITY ASSAYSSimulated Gastric Fluid (SGF) Assay

[0466] Blank SGF was prepared by adding 2 g sodium chloride, 7 mL hydrochloric acid (37%) in a final volume of 1 L water, and adjusted pH to 1.2.

[0467] SGF was prepared by dissolving 320 mg Pepsin (Sigma®, P6887, from Porcine Stomach Mucosa) in 100 mL Blank SGF and stirred at room temperature for 30 minutes. The solution was filtered through 0.45 pm membrane and aliquot and stored at -20 °C.

[0468] Experimental: peptides of interest (20 uM) were incubated with pre-warmed SGF at 37°C. Aliquots were taken at various time points up to 24 hours (e.g. 0, 0.25, 1, 3, 6 and 24 hr), and immediately quenched with 4 volumes of organic solvent (acetonitrile / methanol (1 : 1) and 0.1% formic acid, containing 1 pM internal standard). Quenched samples were stored at 4 °C until the end of the experiment and centrifuged at 4,000 rpm for 10 minutes. The supernatant were diluted 1 : 1 with deionized water and analyzed using LC-MS. Percentage remaining at each time point was calculated based on the peak area ratio (analyte over internal standard) relative to the initial level at time zero. Half-lives were calculated by fitting to a first-order exponential decay equation using GraphPad.Simulated Intestinal Fluid (SIF) Stability Assay

[0469] Blank FaSSIF (Fasted State Simulated Intestinal Fluid) was prepared by dissolving 0.348 g NaOH, 3.954 g sodium phosphate monobasic monohydrate and 6.186 g NaCl in a final volume of 1 liter water (pH adjusted to 6.5).

[0470] FaSSIF was prepared by dissolving 1.2 g porcine pancreatin (Chem-supply, PL378) in 100 mL Blank FaSSIF and stirred at room temperature for 30 minutes. The solution was filtered through 0.45 pm membrane and aliquot and stored at -20 °C.

[0471] Experimental: peptides of interest (20 uM) were incubated with pre-warmed FaSSIF (1% pancreatin in final incubation mixture) at 37°C. Aliquots were taken at various time points up to 24 hours (e.g. 0, 0.25, 1, 3, 6 and 24 hr), and immediately quenched with 4 volumes of organic solvent (acetonitrile / methanol (1 : 1) and 0.1% formic acid, containing 1 pM internal standard). Quenched samples were stored at 4 °C until the end of the experiment and centrifuged at 4,000 rpm for 10 minutes. The supernatant were diluted 1 : 1 with deionized water and analyzed using LC-MS. Percentage remaining at each time point was calculated based on the peak area ratio (analyte over internal standard) relative to the initial level at time zero. Half-lives were calculated by fitting to a first-order exponential decay equation using GraphPad.Plasma Stability Assay

[0472] Peptides of interest (20 uM) were incubated with pre-warmed plasma (BioreclamationIVT) at 37°C. Aliquots were taken at various time points up to 24 hours (e.g. 0, 0.25, 1, 3, 6 and 24 hr), and immediately quenched with 4 volumes of organic solvent (acetonitrile / methanol (1 : 1) and 0.1% formic acid, containing 1 pM internal standard). Quenched samples were stored at 4 °C until the end of the experiment and centrifuged at 17,000 g for 15 minutes. The supernatant were diluted 1 : 1 with deionized water and analyzed using LC-MS. Percentage remaining at each time point was calculated based on the peak area ratio (analyte over internal standard) relative to the initial level at time zero. Half-lives were calculated by fitting to a first-order exponential decay equation using GraphPad.Example 4 GLUCOSE TOLERANCE TESTS

[0473] Adult, female C57BL / 6 mice aged 8-10 weeks were purchased from the Charles River Laboratories (Hollister, CA). The animals were housed under the conditions of constant temperature (18-22°C), humidity (40-55%), and a light / dark cycle of 12 h with free access to food and water. Animal care procedures followed the National Institute of Health Guidelines on the Care and Use of Animals and were approved by the Institutional Animal Care and Utilization Committee (IACUC) at Protagonist Therapeutics.

[0474] Peptides were synthesized in house. C57BL / 6 mice were divided into groups of five according to body weight. Mice were fasted in new cages overnight for 12 h. One hour before oral glucose challenge (Fig. 4A and 4B) or 24 hours before oral glucose challenge (Fig. 4C), the mice received a single dose by oral delivery with vehicle (10% cyclodextrin) as control, or peptide compounds at different doses (e.g., 10, 30, 60 mg / kg oral (PO)). For the oral glucose challenge, a bolus of 20% glucose solution was delivered orally at 1.5 g / kg body weight one hour post compound dosing. Blood was drawn from the tail vein and the glucose levels were measured using a Clarity BG1000 Glucose Monitoring System (Boca Raton, FL) at 0, 15, 30, 60, and 120 min after glucose administration. Control mice were bled at the same timepoints. AUC was calculated from TO through T120 minutes. Terminal blood was collected to measure systemic compound concentrations. Fig. 4A shows the blood glucose AUC levels for mice orally and subcutaneously dosed with Compound 101 - Compound 101 significantly reduced blood glucose levels with all doses. Fig. 4B shows the blood glucose AUC levels for mice orally dosed with Compound 116 - Compound 116 significantly reduced blood glucose levels even with a low oral dose of 10 mg / kg. Fig. 4C shows the blood glucose AUC levels for mice orally dosed with Compound 150 - Compound 150 significantly reduced blood glucose levels with a low oral dose of 10 mg / kg.

[0475] All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety.

[0476] At least some of the chemical names or sequences of compounds of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. In the instance where the indicated chemical name or sequence and the depicted structure differ, the depicted structure will control. In the chemical structures where a chiral center exists in a structure, but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure. Similarly, for the peptides where E / Z isomers exist but are not specifically mentioned, both isomers are specifically disclosed and covered.

[0477] From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention.

Claims

What is Claimed:

1. A peptide that is an agonist of human GLP1R, wherein the peptide comprises a sequence according to Formula (I):RCxi-x -xs-xd-xs-xe-x -xs^-xio-xi i-xi -xis-xid-xis-xie-xn-xis-x^-X20-X21-X22-X23-X24-X25-X26-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2is NH2, OH, Palm, or absent;XI is 2Me3ImidazolePA, 2Pal, 3Pal, 4Pal, aMe His, aOH Imidazole PropanoicAcid, Asn, Cit, dH, hHis, His, His lMe, His_3Me, His Bzl, Imidazole Propanoic Acid, Lys Dimethyl, Lys_Me3, NMe His, Om, Phe, Pyrrole PA, Quin_3, or Tyr;X2 is Aib, Ala, aMe_Asn, aMe_Asp, aMe_Gln, aMe_Glu, aMe_His, aMe_Ile, aMe_Leu, aMe_Phe, aMe_Phe_2F, aMe_Pro, aMe_Ser, aMe_Trp, aMe_Tyr, aMe_Val, Cap, Cys, dHcy, Gly, Hey, Hhc, Iva, Pen, HhPen, or Vai;X3 is aMe Glu, Asp, Cysteate, Glu, Gia, Gin, He, Leu, Tetl, or Tet2;X4 is Ala, Aib, Asn, Gly, Lys, Ser, or Thr;X5 is Asn, Asp, Cys, dHcy, Gin, Glu, Hey, Hhc, HhPen, He, Leu, Lys, NMe_K, 03 S, 03 S Reduced, Pen, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 40H_Val, Asn, Asp, Dap, Diaminobutanoic Acid, Ser, Thr, Thr Ac, Thr Me, TThioamide, or Vai;X8 is Aad, Ala, Abu, aMe_Ser, Asp, Dap, dS, Fur, Gin, Gly, hSer, Ser, Ser_Bz, orS Thioamide;X9 is Aad, aMe_Asp, aMe_Glu, Api, Arg, Asp, Asp_OMe, bE, bMeAsp, Cysteate, dD, diMe Asp, Gia, Glu, Hhc, Lys, Lys_PEG2_IsoGlu_Palm, NMe_E, 03 S, 03S_Reduced, Tetl, Tet2, or Tyr;X10: aMeBip2pMe4pOMe, Bip_2pEt4pOC2N, Bip_2pEt4pOC2NC2N,Bip_2pEt4pOC2NDMGN2aeC4, Bip_2pEt4pOC2NDMGN2aeC8,Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm,Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_Dap_MeOPheTag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm,Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheT ag, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid, Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_C4,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2, Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Arg, Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N, Bip_2pEt4pOC4N_ COC8N, Bip_2pEt4pOC4N_Dap_lPEG2_lPEG2_C 18_diacid,_Bip_2pEt4pOC4N_Dap_Albutag, Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_Dap_Palm, Bip_2pEt4pOC4N_DMG_N_2ae_C 18_diacid, Bip_2pEt4pOC4N_DMG_N_2ae_LysAc, Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC4N_MeOPheTag, Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOC4N_PEG4_NHAc, Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc, Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4N_PEGl 6_NHAc, Bip_2pEt4pOC4N2DMGN2ae,Bip_2pEt4pOC4NDMGN2ae, Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOC4NMe3,_Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, NMeBip2pMe4pOMe, or Tyr;XI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphenyl, 35_DiemthylPhenyl, 3choloro4fluorophenyl, 3 chlorophenyl,3 Methoxy phenyl, aMe Ser, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Phe, Phe_2Ad, Pyridin3yl, Quinolin_5_yl, Ser, Thr, Tyr, or Vai;X12 is Gly or absent;XI 3 is Glu, Gly, or absent;XI 4 is Pro or absent;XI 5 is Ser or absent;XI 6 is Arg or absent;XI 7 is His or absent;XI 8 is Leu or absent;XI 9 is Asn or absent;X20 is Leu or absent;X21 is Val or absent;X22 is Thr or absent;X23 is Arg or absent;X24 is Gin or absent;X25 is Arg or absent; andX26 is Tyr or absent. (Formula (I).)2. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein the peptide is linear or does not comprise a cyclic structure.

3. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X12-X26 are absent.

4. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein the peptide comprises a cyclic structure comprising two cross-linked amino acid residues at X2 and X5.

5. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X2 and X5 are indirectly cross-linked through a thioether bond with a cyclization linker, wherein X2 and X5 are individually or both Cys, dHcy, Hey, Hhc, Pen, or HhPen, and wherein the cyclization linker is a Butane Linker, a Carbonyl Linker, a Dimethylcyclopropane Linker, a Ebutene Linker, a Hexane Linker, an Oxetane Linker a Pentane Linker, a Propane Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker.

6. A peptide that is an agonist of human GLP1R having an EC50 less than 1 nM in a human high-density (HD) GLP1R HEK293 cAMP accumulation assay or less than 1 micromolar in a human low-density (LD) GLP1R HEK293 cAMP accumulation assay, wherein the peptide comprises or consists of a sequence according to Formula (II):R1-Xl-X2-X3-X4-X5-X6-X7-X8-X9-X10-Xl 1-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is Ra-C(O)- or hydrogen, wherein Ra is C1-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, or absent;R2is NH2 or OH or absent;XI is 2Me3ImidazolePA, 2Pal, 3Pal, aMe His, aOH Imidazole PropanoicAcid, Asn, Cit, dH, His, hHis, His_3Me, Imidazole Propanoic Acid, Lys Dimethyl, NMe His, Phe, Pyrrol e_P A, or Tyr;X2 is Aib, aMe_Asn, aMe_Gln, aMe_Glu, aMe_Leu, aMe_Pro, aMe_Ser, aMe_Trp, Gly, Iva, or Vai;X3 is aMe Glu, Asp, Cysteate, Gia, Gin, Glu, He, Leu, Tetl, or Tet2;X4 is Ala, Gly, or Ser;X5 is Glu, Gin, Hhc, He, Leu, Lys, NMe_K, 03 S, O3S_Reduced, or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is 40H_Val, Asp, Diaminobutanoic acid, Ser, Thr, TThioamide, or Vai;X8 is aMe_Ser, Asp, Gly, Ser, or SThioamide;X9 is aMe_Asp, aMe_Glu, Asp, bMeAsp, Cysteate, diMe_Asp, Gia, Glu, Hhc, Lys, NMe_E, 03 S, 03S_Reduced;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2NC2N, Bip_2pEt4pOC2NDMGN2aeC4,Bip_2pEt4pOC2NDMGN2aeC8, Bip_2pEt4pOC2NDMGN2aeC12,Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm,Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_Dap_MeOPheTag, Bip_2pEt4pOC2N_DMG_N_2ae_Palm,Bip_2pEt4pOC2N_IsoGlu_Palm, Bip_2pEt4pOC2N_MeOPheT ag,Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N,Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_C4,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2,Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag,Bip_2pEt4pOC4N_Arg, Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N,Bip_2pEt4pOC4N_ COC8N,Bip_2pEt4pOC4N_Dap_lPEG2_lPEG2_C18_diacid,_Bip_2pEt4pOC4N_Dap_Albutag,Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_Dap_Palm,Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC4N_DMG_N_2ae_C 18_diacid,Bip_2pEt4pOC4N_DMG_N_2ae_LysAc, Bip_2pEt4pOC4N_MeOPheTag,Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOC4N_PEG4_NHAc,Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc,Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4N_PEGl 6_NHAc,Bip_2pEt4pOC4N2DMGN2ae, Bip_2pEt4pOC4NDMGN2ae,Bip_2pEt4pOC4NE)MGN2aeLysAc, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NLys,Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOC4NMe3,_Bip_2pEt4pOMe, Bip_2pMe4pOMe, Bip24_Me, or NMeBip2pMe4pOMe; andXI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphneyl, 35_DimethylPhenyl, 3 chlorophenyl, 3 Methoxy phenyl, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Phe, Phe_2Ad, Pyridin3yl, Quinolin_5_yl, Thr, Tyr, or Vai. (Formula (II).)7. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 6, wherein R1is absent and R2is amine.

8. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 6, wherein the peptide is linear or does not comprise a cyclic structure.

9. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 6, wherein no further amino acid residues are present after XI 1 at the C-terminus.

10. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 6, wherein the peptide has an EC50 potency less than 0.100 nM or less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay, or less than 100 nM or 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay.

11. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 6, wherein the peptide has a half-life time of stability of greater than 2 hours, 12 hours, 20 hours, or 24 hours in an SGF assay or an SIF assay, or in both assays.

12. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 6, wherein the peptide has an EC50 potency less than 1 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 1 micromolar in a human LD GLP1R HEK293 cAMP accumulation assay, and a half-life time of stability of greater than 2 hours, 12 hours, 20 hours, or 24 hours in an SGF assay and / or an SIF assay.

13. A peptide having an EC50 less than 0.100 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 100 nM in a human LD GLP1R HEK293 cAMPaccumulation assay, wherein the peptide comprises or consists of the sequence according to Formula (III):Rj-Xl-X -XS-X -XS-XO-X -XS-XO-XlO-Xl 1-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is acetyl or absent;R2is NH2 or OH or absent;XI is 2Me3ImidazolePA, 2Pal, aMe His, aOH Imidazole PropanoicAcid, Asn, Cit, dH, His, hHis, Imidazole Propanoic Acid, NMe His, Phe, Pyrrole PA, or Tyr;X2 is Aib, Ala, aMe_Pro, aMe_Ser, Gly, Iva, or Vai;X3 is Asp, Cysteate, Gia, Gin, Glu, He, Leu, Tetl, or Tet2;X4 is Gly;X5 is Glu, Hhc, He, Lys, Leu, 03 S, or Thr;X6 is aMe_Phe_2F;X7 is 40H-Val, Diaminobutanoic acid, Ser, Thr, or TThioamide;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, Asp, bMe_Asp, Cysteate, diMe_Asp, Glu, Hhc, Lys, or 03 S;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2NC2N, Bip_2pEt4pOC2NDMGN2aeC4,Bip_2pEt4pOC2NDMGN2aeC8, Bip_2pEt4pOC2NDMGN2aeC12,Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm,Bip_2pEt4pOC2N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm,Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_Dap_MeOPheT ag,Bip_2pEt4pOC2N_DMG_N_2ae_Palm,_Bip_2pEt4pOC2N_IsoGlu_Palm,Bip_2pEt4pOC2N_MeOPheTag, Bip_2pEt4pOC2N_PEG4_am,Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N,Bip_2pEt4pOC4N_lPEG2_lPEG2_C 18_Diacid,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_C4,Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2,Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm,Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Arg, Bip_2pEt4pOC4N_COC 12N,Bip_2pEt4pOC4N_COC4N, Bip_2pEt4pOC4N_ COC8N,Bip_2pEt4pOC4N_Dap_lPEG2_lPEG2_C18_diacid,_Bip_2pEt4pOC4N_Dap_Albutag,Bip_2pEt4pOC4N_Dap_MeOPheT ag, Bip_2pEt4pOC4N_Dap_Palm,Bip_2pEt4pOC4N_DMG_N_2ae_C 18_diacid, Bip_2pEt4pOC4N_DMG_N_2ae_LysAc, Bip_2pEt4pOC4N_IsoGlu_Palm, Bip_2pEt4pOC4N_MeOPheT ag, Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOC4N_PEG4_NHAc,Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc,Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4N_PEGl 6_NHAc,Bip_2pEt4pOC4N2DMGN2ae, Bip_2pEt4pOC4NDMGN2ae, Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOC4NMe3, Bip_2pEt4pOMe, Bip_2pMe4pOMe, or Bip24_Me; andXI 1 is 2Chlorophenyl, 2Pal, 3-pyridylalanine-4, 3_pyridylalanine_4_2_methylphenyl, 34Dimethyoxyphenyl, 3choloro4fluorophenyl, 3 chlorophenyl, 3 Methoxy phenyl, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Phe, Quinolin-5-yl, Thr, Tyr, or Vai. (Formula (III).)14. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 13, wherein R1is absent and R2is amine.

15. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 13, wherein the peptide is linear or does not comprise a cyclic structure.

16. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 6, wherein no further amino acid residues are present after XI 1 at the C-terminus.

17. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 13, wherein the peptide has an EC50 potency less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay.

18. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 13, wherein the peptide has a half-life time of stability of greater than 2 hours, 12 hours, 20 hours, or 24 hours in an SGF assay or an SIF assay, or in both assays.

19. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 13, wherein the peptide has an EC50 potency less than 0.100 nM in a human HD GLP1R HEK293 cAMPaccumulation assay or less than 100 nM in a human LD GLP1R HEK293 cAMP accumulation assay and a half-life time of stability of greater than 2 hours, 12 hours, 20 hours, or 24 hours in an SGF assay and / or an SIF assay.

20. A peptide having an EC50 less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and having a half-life greater than 20 hours in both an SGF assay and an SIF assay, and the peptide comprises or consists of the sequence according to Formula (IV): R1-Xl-X2-X3-X4-X5-X6-X7-X8-X9-X10-Xl 1-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is absent;R2is NH2;XI is 2Me3ImidazolePA, aMe_H, aOH Imidazole PropanoicAcid, Asn, dH, His, Imidazole Propanoic Acid, NMe His, Phe, or Tyr;X2 is Aib, aMe_Pro, or Iva;X3 is Glu or Tetl;X4 is Gly;X5 is Thr;X6 is aMe_Phe_2F;X7 is 4OH_Val, Ser, or Thr;X8 is aMe_Ser or Ser;X9 is aMe_Asp, aMe_Glu, or Asp;X10: Bip_2pEt4pOC2N, Bip_2pEt4pOC2N_lPEG2_lPEG2_Ahx_Palm, Bip_2pEt4pOC2N_lPEG2_lPEG2_isoGlu_Palm, Bip_2pEt4pOC2N_Ahx_Palm, Bip_2pEt4pOC2N_Albutag, Bip_2pEt4pOC2N_Dap_Albutag,Bip_2pEt4pOC2N_DMG_N_2ae_Palm, Bip_2pEt4pOC2NDMGN2aeC4, Bip_2pEt4pOC2NDMGN2aeC8, Bip_2pEt4pOC2NDMGN2aeC12, Bip_2pEt4pOC2NIsoGlu Palm, Bip_2pEt4pOC2N_MeOPheTag, Bip_2pEt4pOC2N_PEG4_am, Bip_2pEt4pOC2NDMGN2aeC 12, Bip_2pEt4pOC4N, Bip_2pEt4pOC4N_lPEG2_lPEG2_Dap_Palm, Bip_2pEt4pOC4N_Ahx_NH2, Bip_2pEt4pOC4N_Ahx_NHAc, Bip_2pEt4pOC4N_Ahx_Palm, Bip_2pEt4pOC4N_Albutag, Bip_2pEt4pOC4N_Arg, Bip_2pEt4pOC4N_COC 12N, Bip_2pEt4pOC4N_COC4N, Bip_2pEt4pOC4N_ COC8N,Bip_2pEt4pOC4N_Dap_lPEG2_lPEG2_C18_diacid,_Bip_2pEt4pOC4N_Dap_Albutag,Bip_2pEt4pOC4N_ Dap Palm, Bip_2pEt4pOC4N_DMG_N_2ae_C 18_diacid, Bip_2pEt4pOC4N_MeOPheTag, Bip_2pEt4pOC4N_PEG4_am, Bip_2pEt4pOC4N_PEG4_NHAc, Bip_2pEt4pOC4N_PEG8_am, Bip_2pEt4pOC4N_PEG8_NHAc, Bip_2pEt4pOC4N_PEGl 6_am, Bip_2pEt4pOC4NAc, Bip_2pEt4pOC4NDMGN2aeLysAc, Bip_2pEt4pOC4NLys, Bip_2pEt4pOC4NLysAc, Bip_2pEt4pOC4NMe3, Bip_2pEt4pOMe, or Bip_2pMe4pOMe; andXI 1 is 3_pyridylalanine_4_2_methylphenyl, Bip_2pMe, Bip24_Me, hhBenzo-dioxol-5-yl, HHPhe_35Me, Hph, Ser, Thr, or Vai. (Formula (IV).)21. A peptide comprising a sequence according to any one of SEQ ID NO: 1-209 or a pharmaceutically acceptable salt or a solvate thereof.

22. A peptide having the two-dimensional structure as encoded by any one of the SMILES sequences in Figs. 1 A-1NN or a pharmaceutically acceptable salt or a solvate thereof.

23. A peptide comprising a chemical structure depicted in Figs. 2A-2R or a pharmaceutically acceptable salt or a solvate thereof.

24. A method for treating T2DM, comprising administering to an individual with T2DM an effective amount of a peptide or pharmaceutically acceptable salt or solvate thereof according to any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof.

25. A method for treating obesity or inducing weight loss, the method comprising administering to an individual in need of such a treatment an effective amount of a peptide according to any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof.

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