Dual- and TRI-agonist compounds for obesity & t2dm

Abstract

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

Description

Attorney Docket No.: PRTH-100 / 12WO 321085-3088DUAL- AND TRI-AGONIST COMPOUNDS FOR OBESITY & T2DMCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 693,980, filed September 12, 2024, U.S. Provisional Application No. 63 / 695,997, filed September 18, 2024, U.S. Provisional Application No. 63 / 712,293, filed October 25, 2024, U.S. Provisional Application No. 63 / 734,601, filed December 16, 2024, U.S. Provisional Application No. 63 / 757,182, filed February 11, 2025, U.S. Provisional Application No. 63 / 770,203, filed March 11, 2025, U.S. Provisional Application No. 63 / 797,763, filed April 30, 2025, U.S. Provisional Application No. 63 / 820,931, filed June 10, 2025, U.S. Provisional Application No. 63 / 830,269, filed June 25, 2025, and U.S. Provisional Application No. 63 / 831,525, filed June 27, 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_100_12WO_ST26.xml. The XML file is 2,108,350 bytes, and created on September 10, 2025, and is being submitted electronically via USPTO Patent Center.FIELD OF THE INVENTION

[0003] The present disclosure relates to peptide compounds which are dual or tri-agonists of the human glucagon-like peptide-1 (GLP-1) receptor (GLP1R), the human glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR), and / or the human glucagon receptor (GCGR). The invention also relates to peptide compounds that are suitable for oral administration. These 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 United1324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088States Food and Drug Administration (FDA) for prolonged use for nonsyndromic 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] Retatrutide (LY3437943) is an agonist of GLP1R, GIPR, and GCGR. In a randomized, double-blind, and placebo-controlled phase 2 study conducted in the United States, 12 involving obese or overweight, patients were administered subcutaneous retatrutide or placebo weekly for nearly 11 months. Phase 2 clinical trial results show retatrutide achieved up to 17.5% mean weight reduction at 24 weeks in adults with obesity and overweight. In a secondary endpoint, retatrutide demonstrated a mean weight reduction up to 24.2% at 48 weeks.

[0009] There remains a need for improved peptide compounds that are dual agonists of GLP1R and GIPR or tri -agonists of GLP1R, GIPR, and GCGR, which are as potent or more potent than tirzepatide or retatrutide and / or are suitable for oral administration.SUMMARY OF THE INVENTION

[0010] The present disclosure provides peptide compounds that are that are dual agonists of GLP1R and GIPR or tri-agonists of GLP1R, GIPR, and GCGR. In some aspects, the peptide compounds of the invention have nanomolar or sub-nanomolar potency for both GLP1R and GIPR or for GLP1R, GIPR, and GCGR (i.e., EC50 in a HEK293 cAMP assay). In additional2324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 aspects, the peptide compounds have nanomolar or sub-nanomolar potencies for both GLP1R and GIPR, or for GLP1R, GIPR, and GCGR, as well as having stability in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) assays (i.e., ti / 2 of the non-degraded peptide in these assays).

[0011] In one aspect, the invention provides peptides that are dual agonists of GLP1R and GIPR or tri-agonists of GLP1R, GIPR, and GCGR, wherein the peptides comprise or consist of a sequence according to Formula (I):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-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37-X38-X39-X40-X41 -X42-X43 -X44-R2, 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 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib, Ala, aMe_Ser, dA, dS, Gin, or Ser;X3 is Aoc, Gin, Glu, Gly, His, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is aMe_Asp, aMe_Glu, Asp, or Tyr;XI 0 is 4Pal, Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_34diOMe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_Diacid, Phe_4_Me, Phe_4_Morph, Phe_4_OMe, Ser, Tyr, or Vai;Xl 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Om Acetyl, Pen, Pro, Ser, Thr, or Tyr;X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, He, Lys, Lys Ac, LysPhAc, O2S, 03 S, O3S_Me, 03 S Me Reduced, O3S_Reduced, O4S, O4S_Reduced, Om Acetyl, or Pen;3324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 3 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Arg, Chg, Cys, Dab_Acetyl, dC, Gin, Glu, Hey, Hhc, He, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, nL, Orn Acetyl, Pen, Ser, Trp, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Ogl, Orn Acetyl, Pen, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc O2S, 03 S, 03S_Me, 03 S Me Reduced, 03S_Reduced, 04S, 04S_Reduced, Om, Orn Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety,Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Albutag,Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_lPEG2_C 19_Phosphonic_Acid; Lys_lPEG2_lPEG2_IsoGlu_C20_diacid,Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid; Lys_lPEG2_IsoGlu_AlbuTag,Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid,Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_Palm,Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_MeOPheTag,Lys_lPEG2_IsoGlu_Palm, Lys Ac, Lys AlbuTag, Lys_dIsoLys_lPEG2_C18_diacid,Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid,Lys_IsoGlu_IsoGlu_C20_Diacid, Lys_Me3, Lys_PEG2_Me3,Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid,Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Orn Acetyl, or Pen;XI 8 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;X19 is Aib, Ala, or Gin;X20 is Aib, aMe_4Pal, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys,Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid,Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac,4324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, orLys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;X21 is Aib, Ala, Asp, Gin, Glu, Ogl, Om, or Phe;X22 is aMe_Phe, He, or Phe;X23 is aMe_Ile, Cys, Glu, He, 03 S, or Vai;X24 is Ala, Asn, Cys, dE, dK, Gin, Glu, Hey, Hhc, Lys_Ac, or Tyr;X25 is Ala, aMe_Lys, aMe_Phe, aMe_Tyr, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Phe_34diOMe, Trp, or Tyr;X26 is aMe_Leu, Cys, lie, Leu, NMe_Leu, Tie, or Vai;X27 is Ache, Aib, aMe_Leu, Cha, dL, Gin, Glu, Gly, His, He, Leu, Lys, NMe_Leu, 03 S, Ogl, Orn, Sar, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, bhE, Cys, dE, Gin, Gly, Glu, Glu OMe, Hey, hE, Hhc, IsoGlu, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is dA, Ala, dK, dR, Gly, Sar, or absent;X30 is Ala, Arg, dR, Gly, Pro, Sar, or absent;X31 is Cys, Pro, Sar, Ser, or absent;X32 is Gly, Pro, Ser, or absent;X33 is Arg, Cys, Gly, Ser or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Glu, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;X37 is Leu, Pro or absent;X38 is Pro, Ser, Vai, or absent;X39 is Glu, Lys, Ser, Thr, or absent;X40 is Arg, Gly, Lys_Palm, or absent;X41 is Gin, Thr, or absent;X42 is Arg, Glu, or absent;X43 is Glu, Tyr or absent; andX44 is Glu or absent; wherein the peptide optionally comprises a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently linked through a cyclization linker, and / or a cyclic structure wherein X23 and X27 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (I).)5324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0012] In one aspect, the invention provides peptides that are dual agonists of GLP1R and GIPR or tri-agonists of GLP1R, GIPR, and GCGR, wherein the peptides comprise 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-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37-X38-X39-X40-X41-X42-X43 -R2, 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 or OH or absent;XI is His or Tyr;X2 is Aib, Ala, dA, dS, Gin, or Ser;X3 is Gin, Glu, Gly, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is Asp or Tyr;XI 0 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_Me, Tyr, or Vai;Xl 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Om Acetyl, Pen, Pro, Ser, Thr, or Tyr;X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, lie, Lys, Lys Ac, LysPhAc, Om Acetyl, or Pen;X13 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Chg, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, Om Acetyl, Pen, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Om Acetyl, Pen, or Tba;XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Om Acetyl, or Pen;6324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Orn Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, He, Lys_lPEG2_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, Lys_Me3, Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Orn Acetyl, or Pen;XI 8 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;X19 is Aib, Ala, or Gin;X20 is Aib, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;X21 is Aib, Ala, Asp, Gin, Glu, or Phe;X22 is aMe_Phe, He, or Phe;X23 is aMe_Ile, Glu, lie, or Vai;X24 is Ala, Asn, Cys, Gin, Glu, Lys_Ac, or Tyr;X25 is aMe Lys, aMe Phe, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Trp, or Tyr;X26 is aMe_Leu, lie, Leu, NMe_Leu, Tie, or Vai;X27 is aMe_Leu, Glu, lie, Leu, Lys, NMe_Leu, Sar, Tie, or Vai;X28 is Aib, Ala, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, Cys, Gin, Gly, Glu, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, Phe, or Thr;X29 is dA, Gly, or absent;X30 is Arg, dR, Gly, Pro, Sar, or absent;X31 is Pro, Sar, or absent;X32 is Pro, Ser, or absent;X33 is Arg, Gly, Ser or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;X37 is Leu, Pro or absent;X38 is Pro, Ser, Vai, or absent; andX39 is Lys, Ser, Thr, or absent;X40 is Arg, Lys_Palm, or absent;X41 is Gin or absent;7324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X42 is Arg or absent;X43 is Tyr or absent; wherein the peptide optionally comprises a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (LA).)

[0013] In one aspect, the invention provides peptides that are dual agonists of GLP1R and GIPR or tri-agonists of GLP1R, GIPR, and GCGR, wherein the peptides comprise or consist of a sequence according to Formula (LB):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-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37-X38-X39-X40-X41-X42-X43 -R2, 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 or OH or absent;XI is His or Tyr;X2 is Aib, Ala, dA, dS, Gin, or Ser;X3 is Gin, Glu, Gly, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is Asp or Tyr;XI 0 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_Me, Tyr, or Vai;Xl 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Om Acetyl, Pen, Pro, Ser, Thr, or Tyr;X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, lie, Lys, Lys Ac, LysPhAc, Om Acetyl, or Pen;8324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 3 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Chg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, Orn_Acetyl, Pen, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Orn Acetyl, Pen, or Tba;XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Orn Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety, Lys_lPEG2_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_lPEG2_MeOPheTag, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, Lys_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid,Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Orn Acetyl, or Pen;XI 8 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;X19 is Aib, Ala, or Gin;X20 is Aib, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;X21 is Aib, Ala, Asp, Gin, Glu, or Phe;X22 is aMe_Phe, He, or Phe;X23 is aMe_Ile, Glu, lie, or Vai;X24 is Ala, Asn, Cys, Gin, Glu, Lys_Ac, or Tyr;X25 is aMe Lys, aMe Phe, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Trp, or Tyr;X26 is aMe_Leu, lie, Leu, NMe_Leu, Tie, or Vai;X27 is aMe_Leu, Glu, lie, Leu, Lys, NMe_Leu, Sar, Tie, or Vai;X28 is Aib, Ala, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, Cys, Gin, Gly, Glu, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, Phe, or Thr;X29 is dA, Gly, or absent;X30 is Arg, dR, Gly, Pro, Sar, or absent;X31 is Pro, Sar, or absent;9324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X32 is Pro, Ser, or absent;X33 is Arg, Gly, Ser, or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;X37 is Leu, Pro, or absent;X38 is Pro, Ser, Vai, or absent; andX39 is Lys, Ser, Thr, or absent;X40 is Arg, Lys_Palm, or absent;X41 is Gin or absent;X42 is Arg or absent;X43 is Tyr or absent; wherein the peptide optionally comprises a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (LB).)

[0014] In one aspect, the invention provides peptides that are dual agonists of GLP1R and GIPR or tri-agonists of GLP1R, GIPR, and GCGR, wherein the peptides comprise or consist of a sequence according to Formula (I.C):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-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37-X38-X39-X40-X41-X42-X43 -R2, 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 or OH or absent;XI is His or Tyr;X2 is Aib, Ala, dA, dS, Gin, or Ser;X3 is Gin, Glu, Gly, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is Asp or Tyr;10324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 0 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_Me, Ser, Tyr, or Vai;XI 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Om Acetyl, Pen, Pro, Ser, Thr, or Tyr;X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, He, Lys, Lys Ac, LysPhAc, Om Acetyl, or Pen;XI 3 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Arg, Chg, Cys, Dab_Acetyl, dC, Gin, Glu, Hey, Hhc, lie, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, nL, Om Acetyl, Pen, Ser, Trp, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Om Acetyl, Pen, or Tba;XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Om Acetyl, or Pen;XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Om Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety,Lys_lPEG2_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_lPEG2_MeOPheTag, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, Lys_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Om Acetyl, or Pen;XI 8 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys_Ac, LysPhAc, Om Acetyl, or Pen;X19 is Aib, Ala, or Gin;X20 is Aib, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys,Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid,Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;X21 is Aib, Ala, Asp, Gin, Glu, or Phe;X22 is aMe_Phe, He, or Phe;11324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X23 is aMe_Ile, Cys, Glu, He, or Vai;X24 is Ala, Asn, Cys, Gin, Glu, Hey, Hhc, Lys_Ac, or Tyr;X25 is Ala, aMe Lys, aMe Phe, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Trp, or Tyr;X26 is aMe_Leu, Cys, He, Leu, NMe_Leu, Tie, or Vai;X27 is Aib, aMe_Leu, Glu, Gly, lie, Leu, Lys, NMe_Leu, Sar, Tie, or Vai;X28 is Aib, Ala, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, Cys, Gin, Gly, Glu, Hey, Hhc, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, Phe, or Thr;X29 is dA, Ala, Gly, or absent;X30 is Ala, Arg, dR, Gly, Pro, Sar, or absent;X31 is Cys, Pro, Sar, Ser, or absent;X32 is Gly, Pro, Ser, or absent;X33 is Arg, Cys, Gly, Ser or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;X37 is Leu, Pro, or absent;X38 is Pro, Ser, Vai, or absent; andX39 is Lys, Ser, Thr, or absent;X40 is Arg, Lys_Palm, or absent;X41 is Gin or absent;X42 is Arg or absent;X43 is Tyr or absent; wherein the peptide optionally comprises a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (I.C).)

[0015] In one aspect, the invention provides peptides that are dual agonists of GLP1R and GIPR or tri-agonists of GLP1R, GIPR, and GCGR, wherein the peptides comprise 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-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37-X38-X39-X40-X41-X42-X43 -R2, 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 or OH or absent;12324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib, Ala, dA, dS, Gin, or Ser;X3 is Gin, Glu, Gly, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is aMe_Asp, Asp, or Tyr;XI 0 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_Me, Phe_4_OMe, Ser, Tyr, or Vai;Xl 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Om Acetyl, Pen, Pro, Ser, Thr, or Tyr;X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, lie, Lys, Lys Ac, LysPhAc, O2S, 03 S, 03S_Me, 03 S Me Reduced, 03S_Reduced, 04S, 04S_Reduced, Om Acetyl, or Pen;X13 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Arg, Chg, Cys, Dab_Acetyl, dC, Gin, Glu, Hey, Hhc, lie, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, nL, Om Acetyl, Pen, Ser, Trp, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Om Acetyl, Pen, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Om Acetyl, or Pen;XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc 02S, 03 S, 03S_Me, 03 S Me Reduced, 03S_Reduced, 04S, 04S_Reduced„ Om Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety, Lys_lPEG2_lPEG2_Ahx_C18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Albutag, Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C 18_diacid,13324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_lPEG2_lPEG2_IsoGlu_C20_diacid, , Lys_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_Palm, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, Lys_dIsoLys_lPEG2 C18_diacid, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Orn Acetyl or Pen;XI 8 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;XI 9 is Aib, Ala, or Gin;X20 is Aib, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys,Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid,Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;X21 is Aib, Ala, Asp, Gin, Glu, Ogl, or Phe;X22 is aMe_Phe, He, or Phe;X23 is aMe_Ile, Cys, Glu, He, or Vai;X24 is Ala, Asn, Cys, dE, Gin, Glu, Hey, Hhc, Lys_Ac, or Tyr;X25 is Ala, aMe Lys, aMe Phe, aMe Tyr, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Trp, or Tyr;X26 is aMe_Leu, Cys, He, Leu, NMe_Leu, Tie, or Vai;X27 is Aib, aMe_Leu, Glu, Gly, His, He, Leu, Lys, NMe_Leu, Sar, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, Cys, Gin, Gly, Glu, Hey, Hhc, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr; X29 is dA, Ala, Gly, or absent;X30 is Ala, Arg, dR, Gly, Pro, Sar, or absent;X31 is Cys, Pro, Sar, Ser, or absent;X32 is Gly, Pro, Ser, or absent;X33 is Arg, Cys, Gly, Ser or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;X37 is Leu, Pro or absent;X38 is Pro, Ser, Vai, or absent; and14324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X39 is Lys, Ser, Thr, or absent;X40 is Arg, Lys_Palm, or absent;X41 is Gin or absent;X42 is Arg or absent;X43 is Tyr or absent; wherein the peptide optionally comprises a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (I D).)

[0016] In one aspect, the invention provides peptides that are dual agonists of GLP1R and GIPR or tri-agonists of GLP1R, GIPR, and GCGR, wherein the peptides comprise or consist of a sequence according to Formula (I D ):Rkxi^-xs-xd-xs-xe-x -xs-X -xio-xn-xn-XB-XM-xis-xie-xn-xis-xi -X20-X21 -X22-X23 -X24-X25 -X26-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37-X38-X39-X40-X41 -X42-X43 -R2, wherein:R1is Ra-C(O)- or hydrogen, wherein Rais Cl-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, or absent;R2is NH2 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib, Ala, dA, dS, Gin, or Ser;X3 is Gin, Glu, Gly, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is aMe_Asp, Asp, or Tyr;XI 0 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_Me, Phe_4_OMe, Ser, Tyr, or Vai;Xl 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Om Acetyl, Pen, Pro, Ser, Thr, or Tyr;15324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, He, Lys, Lys Ac, LysPhAc, 02S, 02S_Me, 03 S, 03S_Me, 04S, 04S_Me, 02S_Reduced, 03S_Reduced, 04S_Reduced, 02S_Me_Reduced, 03 S Me Reduced, 04S_Me_Reduced, Orn Acetyl, or Pen;XI 3 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Chg, Cys, Dab_Acetyl, dC, Gin, Glu, Hey, Hhc, He, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, nL, Orn Acetyl, Pen, Ser, Trp, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Orn Acetyl, Pen, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, 02S, 02S_Me, 03 S, 03S_Me, 04S, 04S_Me, 02S_Reduced, 03S_Reduced, 04S_Reduced, 02S_Me_Reduced, 03 S Me Reduced, 04S_Me_Reduced, Orn Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety, aLys_lPEG2 1PEG2_IsoGlu_C18_diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_lPEG2_MeOPheTag,Lys_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_IsoGlu_C 12_diacid,Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_C 18_diacid,Lys_lPEG2_IsoGlu_Palm, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, Lys_dIsoLys_lPEG2 C18_diacid, Lys_dIsoLys_lPEG2_IsoGlu_C18_diacid, Lys_Me3,Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Orn Acetyl, or Pen;XI 8 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;X19 is Aib, Ala, or Gin;X20 is Aib, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, or Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;X21 is Aib, Ala, Asp, Gin, Glu, Ogl, or Phe;X22 is aMe_Phe, He, or Phe;16324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X23 is aMe_Ile, Cys, Glu, He, or Vai;X24 is Ala, Asn, Cys, dE, Gin, Glu, Hey, Hhc, Lys_Ac, or Tyr;X25 is Ala, aMe Lys, aMe Phe, aMe Tyr, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Trp, or Tyr;X26 is aMe_Leu, Cys, He, Leu, NMe_Leu, Tie, or Vai;X27 is Aib, aMe_Leu, Glu, Gly, His, He, Leu, Lys, NMe_Leu, Sar, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, Cys, Gin, Gly, Glu, Hey, Hhc, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr; X29 is dA, Ala, Gly, or absent;X30 is Ala, Arg, dR, Gly, Pro, Sar, or absent;X31 is Cys, Pro, Sar, Ser, or absent;X32 is Gly, Pro, Ser, or absent;X33 is Arg, Cys, Gly, Ser or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;X37 is Leu, Pro or absent;X38 is Pro, Ser, Vai, or absent; andX39 is Lys, Ser, Thr, or absent;X40 is Arg, Lys_Palm, or absent;X41 is Gin or absent;X42 is Arg or absent; andX43 is Tyr or absent; wherein the peptide optionally comprises a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently linked through a cyclization linker (Formula (I D ).)

[0017] In one aspect, the invention provides peptides that are dual agonists of GLP1R and GIPR or tri-agonists of GLP1R, GIPR, and GCGR, wherein the peptides comprise 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-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37-X38-X39-X40-X41 -X42-X43 -X44-R2, 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 or OH or absent;17324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid or Tyr;X2 is Aib, Ala, dA, dS, Gin, or Ser;X3 is Gin, Glu, Gly, His, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is aMe_Asp, aMe_Glu, Asp, or Tyr;XI 0 is 4Pal, Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_34diOMe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_Me, Phe_4_Morph, Phe_4_OMe, Ser, Tyr, or Vai;Xl 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Om Acetyl, Pen, Pro, Ser, Thr, or Tyr;X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, lie, Lys, Lys Ac, LysPhAc, O2S, 03 S, 03S_Me, 03 S Me Reduced, 03S_Reduced, 04S, 04S_Reduced, Om Acetyl, or Pen;X13 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Arg, Chg, Cys, Dab_Acetyl, dC, Gin, Glu, Hey, Hhc, lie, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, nL, Om Acetyl, Pen, Ser, Trp, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Om Acetyl, Pen, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Om Acetyl, or Pen;XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc 02S, 03 S, 03S_Me, 03 S Me Reduced, 03S_Reduced, 04S, 04S_Reduced, Om, Om Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety, Lys_lPEG2_lPEG2_Ahx_C18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Albutag, Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C 18_diacid,18324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_lPEG2_lPEG2_IsoGlu_C20_diacid, , Lys_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_Palm, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, Lys_dIsoLys_lPEG2 C18_diacid,Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid, Lys_Me3,Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid,Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Orn Acetyl, or Pen;XI 8 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys_Ac, LysPhAc, Orn Acetyl or Pen;XI 9 is Aib, Ala, or Gin;X20 is Aib, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys,Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid,Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;X21 is Aib, Ala, Asp, Gin, Glu, Ogl, Om, or Phe;X22 is aMe_Phe, He, or Phe;X23 is aMe_Ile, Cys, Glu, He, 03 S, or Vai;X24 is Ala, Asn, Cys, dE, Gin, Glu, Hey, Hhc, Lys_Ac, or Tyr;X25 is Ala, aMe Lys, aMe Phe, aMe Tyr, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Trp, or Tyr;X26 is aMe_Leu, Cys, He, Leu, NMe_Leu, Tie, or Vai;X27 is Aib, aMe_Leu, Glu, Gly, His, He, Leu, Lys, NMe_Leu, 03 S, Sar, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, Cys, dE, Gin, Gly, Glu, Hey, Hhc, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is dA, Ala, Gly, Sar, or absent;X30 is Ala, Arg, dR, Gly, Pro, Sar, or absent;X31 is Cys, Pro, Sar, Ser, or absent;X32 is Gly, Pro, Ser, or absent;X33 is Arg, Cys, Gly, Ser or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Glu, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;X37 is Leu, Pro or absent;19324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X38 is Pro, Ser, Vai, or absent;X39 is Glu, Lys, Ser, Thr, or absent;X40 is Arg, Gly, Lys_Palm, or absent;X41 is Gin, Thr, or absent;X42 is Arg, Glu, or absent;X43 is Glu, Tyr or absent; andX44 is Glu or absent; wherein the peptide optionally comprises a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently linked through a cyclization linker, and / or a cyclic structure wherein X23 and X27 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (I E).)

[0018] In one aspect, the invention provides peptides that are dual agonists of GLP1R and GIPR or tri-agonists of GLP1R, GIPR, and GCGR, wherein the peptides comprise or consist of a sequence according to Formula (I E ):Rkxi^-xs-xd-xs-xe^-xs-X -xio-xn-xn-XB-XM-xis-xie-xn-xis-xi -X20-X21 -X22-X23 -X24-X25 -X26-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37- X38-X39-X40-X41 -X42-X43 -X44-R2, wherein:R1is Ra-C(O)- or hydrogen, wherein Rais Cl-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, or absent;R2is NH2 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid or Tyr;X2 is Aib, Ala, dA, dS, Gin, or Ser;X3 is Gin, Glu, Gly, His, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is aMe_Asp, aMe_Glu, Asp, or Tyr;XI 0 is 4Pal, Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_34diOMe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_Me, Phe_4_Morph, Phe_4_OMe, Ser, Tyr, or Vai;20324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Orn Acetyl, Pen, Pro, Ser, Thr, or Tyr;X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, He, Lys, Lys Ac, LysPhAc, O2S, 02S_Me, 03 S, 03S_Me, 04S, 04S_Me, 02S_Reduced, 03S_Reduced, 04S_Reduced, 02S_Me_Reduced, 03 S Me Reduced, 04S_Me_Reduced, Orn Acetyl, or Pen;XI 3 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Chg, Cys, Dab_Acetyl, dC, Gin, Glu, Hey, Hhc, lie, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, nL, Orn Acetyl, Pen, Ser, Trp, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Orn Acetyl, Pen, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, 02S, 02S_Me, 03 S, 03S_Me, 04S, 04S_Me, 02S_Reduced, 03S_Reduced, 04S_Reduced, 02S_Me_Reduced, 03 S Me Reduced, 04S_Me_Reduced, Om, Orn Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety, aLys_lPEG2 1PEG2_IsoGlu_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_lPEG2_MeOPheTag, Lys_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_Palm, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, Lys_dIsoLys_lPEG2 C18_diacid, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid, Lys_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Orn Acetyl, or Pen;XI 8 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;X19 is Aib, Ala, or Gin;X20 is Aib, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid,21324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;X21 is Aib, Ala, Asp, Gin, Glu, Ogl, Om, or Phe;X22 is aMe_Phe, He, or Phe;X23 is aMe_Ile, Cys, Glu, He, 03 S, or Vai;X24 is Ala, Asn, Cys, dE, Gin, Glu, Hey, Hhc, Lys_Ac, or Tyr;X25 is Ala, aMe Lys, aMe Phe, aMe Tyr, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Trp, or Tyr;X26 is aMe_Leu, Cys, lie, Leu, NMe_Leu, Tie, or Vai;X27 is Aib, aMe_Leu, Glu, Gly, His, He, Leu, Lys, NMe_Leu, 03 S, Sar, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, Cys, dE, Gin, Gly, Glu, Hey, Hhc, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is dA, Ala, Gly, Sar, or absent;X30 is Ala, Arg, dR, Gly, Pro, Sar, or absent;X31 is Cys, Pro, Sar, Ser, or absent;X32 is Gly, Pro, Ser, or absent;X33 is Arg, Cys, Gly, Ser or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Glu, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;X37 is Leu, Pro, or absent;X38 is Pro, Ser, Vai, or absent;X39 is Glu, Lys, Ser, Thr, or absent;X40 is Arg, Gly, Lys_Palm, or absent;X41 is Gin, Thr, or absent;X42 is Arg, Glu, or absent;X43 is Glu, Tyr, or absent; andX44 is Glu or absent; wherein the peptide optionally comprises: a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently linked through a cyclization linker, and / or a cyclic structure wherein X23 and X27 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (I E ).)22324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0019] In one aspect, the invention provides peptides that are dual agonists of GLP1R and GIPR or tri-agonists of GLP1R, GIPR, and GCGR, wherein the peptides comprise 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-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37-X38-X39-X40-X41 -X42-X43 -X44-R2, 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 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib, Ala, aMe_Ser, dA, dS, Gin, or Ser;X3 is Aoc, Gin, Glu, Gly, His, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is aMe_Asp, aMe_Glu, Asp, or Tyr;XI 0 is 4Pal, Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_34diOMe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_Diacid, Phe_4_Me, Phe_4_Morph, Phe_4_OMe, Ser, Tyr, or Vai;Xl 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Om Acetyl, Pen, Pro, Ser, Thr, or Tyr;X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, He, Lys, Lys Ac, LysPhAc, O2S, 03 S, O3S_Me, 03 S Me Reduced, O3S_Reduced, O4S, O4S_Reduced, Om Acetyl or Pen;XI 3 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Arg, Chg, Cys, Dab_Acetyl, dC, Gin, Glu, Hey, Hhc, lie, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, nL, Om Acetyl, Pen, Ser, Trp, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Ogl, Om Acetyl, Pen, Phe_4ad, Phe_4_2ae, Tba, or Tyr;23324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Orn Acetyl or Pen;XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, O2S, 03 S, 03S_Me, 03S_Me_Reduced, 03S_Reduced, 04S, 04S_Reduced, Om, Orn Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety, Lys_lPEG2_lPEG2_Ahx_C18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Albutag, Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_Palm, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, Lys_dIsoLys_lPEG2 C18_diacid, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid, Lys_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Orn Acetyl, or Pen;XI 8 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys_Ac, LysPhAc, Orn Acetyl or Pen;X19 is Aib, Ala, or Gin;X20 is Aib, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;X21 is Aib, Ala, Asp, Gin, Glu, Ogl, Om, or Phe;X22 is aMe_Phe, He, or Phe;X23 is aMe_Ile, Cys, Glu, lie, 03 S, or Vai;X24 is Ala, Asn, Cys, dE, dK, Gin, Glu, Hey, Hhc, Lys_Ac, or Tyr;X25 is Ala, aMe Lys, aMe Phe, aMe Tyr, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Trp, or Tyr; X26 is aMe_Leu, Cys, He, Leu, NMe_Leu, Tie, or Vai;X27 is Aib, aMe_Leu, Glu, Gly, His, He, Leu, Lys, NMe_Leu, 03 S, Sar, Tba, Tie, or Vai;24324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, Cys, dE, Gin, Gly, Glu, Hey, Hhc, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is dA, Ala, dR, Gly, Sar, or absent;X30 is Ala, Arg, dR, Gly, Pro, Sar, or absent;X31 is Cys, Pro, Sar, Ser, or absent;X32 is Gly, Pro, Ser, or absent;X33 is Arg, Cys, Gly, Ser or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Glu, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;X37 is Leu, Pro or absent;X38 is Pro, Ser, Vai, or absent; andX39 is Glu, Lys, Ser, Thr, or absent;X40 is Arg, Gly, Lys_Palm, or absent;X41 is Gin, Thr, or absent;X42 is Arg, Glu, or absent;X43 is Glu, Tyr or absent; andX44 is Glu or absent; wherein the peptide optionally comprises a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently linked through a cyclization linker, and / or a cyclic structure wherein X23 and X27 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (I F).)

[0020] In one aspect, the invention provides peptides that are dual agonists of GLP1R and GIPR or tri-agonists of GLP1R, GIPR, and GCGR, wherein the peptides comprise or consist of a sequence according to Formula (I F ):Rkxi^-xs-xd-xs-xe^-xs^-xio-xn-xn-XB-XM-xis-xie-xn-xis-x^-X20-X21 -X22-X23 -X24-X25 -X26-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37- X38-X39-X40-X41 -X42-X43 -X44-R2, wherein:R1is Ra-C(O)- or hydrogen, wherein Rais Cl-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, or absent;R2is NH2 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib, Ala, aMe_Ser, dA, dS, Gin, or Ser;25324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X3 is Aoc, Gin, Glu, Gly, His, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is aMe_Asp, aMe_Glu, Asp, or Tyr;XI 0 is 4Pal, Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_34diOMe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_Diacid, Phe_4_Me, Phe_4_Morph, Phe_4_OMe, Ser, Tyr, or Vai;Xl 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Om Acetyl, Pen, Pro, Ser, Thr, or Tyr;X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, He, Lys, Lys Ac, LysPhAc, O2S, O2S_Me, 03 S, 03S_Me, 04S, 04S_Me, 02S_Reduced, 03S_Reduced, 04S_Reduced, 02S_Me_Reduced, 03 S Me Reduced, 04S_Me_Reduced, Om Acetyl, or Pen;XI 3 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Chg, Cys, Dab_Acetyl, dC, Gin, Glu, Hey, Hhc, lie, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, nL, Om Acetyl, Pen, Ser, Trp, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Ogl, Om Acetyl, Pen, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Om Acetyl, or Pen;XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, 02S, 02S_Me, 03 S, 03S_Me, 04S, 04S_Me, 02S_Reduced, 03S_Reduced, 04S_Reduced, 02S_Me_Reduced, 03 S Me Reduced, 04S_Me_Reduced, Om, Om Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety, aLys_lPEG2 1PEG2_IsoGlu_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_lPEG2_MeOPheTag, Lys_lPEG2_IsoGlu_AlbuTag,26324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid,Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_Palm,Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, Lys_dIsoLys_lPEG2 C18_diacid,Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid, Lys_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Orn Acetyl, or Pen;XI 8 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;XI 9 is Aib, Ala, or Gin;X20 is Aib, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid,Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;X21 is Aib, Ala, Asp, Gin, Glu, Ogl, Om, or Phe;X22 is aMe_Phe, He, or Phe;X23 is aMe_Ile, Cys, Glu, He, 03 S, or Vai;X24 is Ala, Asn, Cys, dE, dK, Gin, Glu, Hey, Hhc, Lys_Ac, or Tyr;X25 is Ala, aMe Lys, aMe Phe, aMe Tyr, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Trp, or Tyr;X26 is aMe_Leu, Cys, He, Leu, NMe_Leu, Tie, or Vai;X27 is Aib, aMe_Leu, Glu, Gly, His, He, Leu, Lys, NMe_Leu, 03 S, Sar, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, Cys, dE, Gin, Gly, Glu, Hey, Hhc, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is Ala, dA, dR, Gly, Sar, or absent;X30 is Ala, Arg, dR, Gly, Pro, Sar, or absent;X31 is Cys, Pro, Sar, Ser, or absent;X32 is Gly, Pro, Ser, or absent;X33 is Arg, Cys, Gly, Ser, or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Glu, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;X37 is Leu, Pro or absent;X38 is Pro, Ser, Vai, or absent;27324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X39 is Glu, Lys, Ser, Thr, or absent;X40 is Arg, Gly, Lys_Palm, or absent;X41 is Gin, Thr, or absent;X42 is Arg, Glu, or absent;X43 is Glu, Tyr, or absent; andX44 is Glu or absent; wherein the peptide optionally comprises: a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently linked through a cyclization linker, and / or a cyclic structure wherein X23 and X27 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (I F ).)

[0021] In one aspect, the invention provides peptides that are dual agonists of GLP1R and GIPR or tri-agonists of GLP1R, GIPR, and GCGR, wherein the peptides comprise or consist of a sequence according to Formula (LG):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-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37-X38-X39-X40-X41 -X42-X43 -X44-R2, 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 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib, Ala, aMe_Ser, dA, dS, Gin, or Ser;X3 is Aoc, Gin, Glu, Gly, His, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is aMe_Asp, aMe_Glu, Asp, or Tyr;XI 0 is 4Pal, Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_34diOMe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_Diacid, Phe_4_Me, Phe_4_Morph, Phe_4_OMe, Ser, Tyr, or Vai;28324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Orn Acetyl, Pen, Pro, Ser, Thr, or Tyr;X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, He, Lys, Lys Ac, LysPhAc, O2S, 03 S, 03S_Me, 03 S Me Reduced, 03S_Reduced, 04S, 04S_Reduced, Orn Acetyl, or Pen;XI 3 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Arg, Chg, Cys, Dab_Acetyl, dC, Gin, Glu, Hey, Hhc, lie, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, nL, Orn Acetyl, Pen, Ser, Trp, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Ogl, Orn Acetyl, Pen, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc 02S, 03 S, 03S_Me, 03 S Me Reduced, 03S_Reduced, 04S, 04S_Reduced, Om, Orn Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety,Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Albutag,Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_lPEG2_C 19_Phosphonic_Acid;Lys_lPEG2_lPEG2_IsoGlu_C20_diacid,Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid; Lys_lPEG2_IsoGlu_AlbuTag,Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid,Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_Palm,Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_MeOPheTag,Lys_lPEG2_IsoGlu_Palm, Lys Ac, Lys AlbuTag, Lys_dIsoLys_lPEG2_C18_diacid, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid, Lys_IsoGlu_IsoGlu_C20_Diacid, Lys_Me3, Lys_PEG2_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Orn Acetyl, or Pen;29324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 8 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;XI 9 is Aib, Ala, or Gin;X20 is Aib, aMe_4Pal, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys,Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, orLys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;X21 is Aib, Ala, Asp, Gin, Glu, Ogl, Om, or Phe;X22 is aMe_Phe, He, or Phe;X23 is aMe_Ile, Cys, Glu, He, 03 S, or Vai;X24 is Ala, Asn, Cys, dE, dK, Gin, Glu, Hey, Hhc, Lys_Ac, or Tyr;X25 is Ala, aMe_Lys, aMe_Phe, aMe_Tyr, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Phe_34diOMe, Trp, or Tyr;X26 is aMe_Leu, Cys, lie, Leu, NMe_Leu, Tie, or Vai;X27 is Ache, Aib, aMe_Leu, Cha, dL, Gin, Glu, Gly, His, He, Leu, Lys, NMe_Leu, 03 S, Ogl, Orn, Sar, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, bhE, Cys, dE, Gin, Gly, Glu, Glu OMe, Hey, hE, Hhc, IsoGlu, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is dA, Ala, dK, dR, Gly, Sar, or absent;X30 is Ala, Arg, dR, Gly, Pro, Sar, or absent;X31 is Cys, Pro, Sar, Ser, or absent;X32 is Gly, Pro, Ser, or absent;X33 is Arg, Cys, Gly, Ser or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Glu, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;X37 is Leu, Pro or absent;X38 is Pro, Ser, Vai, or absent;X39 is Glu, Lys, Ser, Thr, or absent;X40 is Arg, Gly, Lys_Palm, or absent;X41 is Gin, Thr, or absent;X42 is Arg, Glu, or absent;30324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X43 is Glu, Tyr or absent; andX44 is Glu or absent; wherein the peptide optionally comprises a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently linked through a cyclization linker, and / or a cyclic structure wherein X23 and X27 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (LG).)

[0022] In one aspect, the invention provides peptides that are dual agonists of GLP1R and GIPR or tri-agonists of GLP1R, GIPR, and GCGR, wherein the peptides comprise or consist of a sequence according to Formula (LG ):Rkxi^-xs-xd-xs-xe^-xs-X -xio-xn-xn-XB-XM-xis-xie-xn-xis-xi -X20-X21 -X22-X23 -X24-X25 -X26-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37- X38-X39-X40-X41 -X42-X43 -X44-R2, wherein:R1is Ra-C(O)- or hydrogen, wherein Rais Cl-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, or absent;R2is NH2 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid or Tyr;X2 is Aib, Ala, aMe_Ser, dA, dS, Gin, or Ser;X3 is Aoc, Gin, Glu, Gly, His, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is aMe_Asp, aMe_Glu, Asp, or Tyr;XI 0 is 4Pal, Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_34diOMe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_Diacid, Phe_4_Me, Phe_4_Morph, Phe_4_OMe, Ser, Tyr, or Vai;Xl 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Om Acetyl, Pen, Pro, Ser, Thr, or Tyr;X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, He, Lys, Lys Ac, LysPhAc, O2S, O2S_Me, 03 S, O3S_Me, O4S, O4S_Me, O2S_Reduced,31324222975Attorney Docket No.: PRTH-100 / 12WO 321085-308803S_Reduced, 04S_Reduced, 02S_Me_Reduced, 03 S Me Reduced, 04S_Me_Reduced, Orn Acetyl, or Pen;XI 3 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Chg, Cys, Dab_Acetyl, dC, Gin, Glu, Hey, Hhc, He, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, nL, Orn Acetyl, Pen, Ser, Trp, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Ogl, Orn Acetyl, Pen, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Orn Acetyl, or Pen;XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, 02S, 02S_Me, 03 S, 03S_Me, 04S, 04S_Me, 02S_Reduced, 03S_Reduced, 04S_Reduced, 02S_Me_Reduced, 03 S Me Reduced, 04S_Me_Reduced, Om, Orn Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety, Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Albutag,Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm,Lys_lPEG2_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_lPEG2_C 19_Phosphonic_Acid;Lys_lPEG2_lPEG2_IsoGlu_C20_diacid,Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid; Lys_lPEG2_IsoGlu_AlbuTag,Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid,Lys_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_IsoGlu_Palm,Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_MeOPheTag,Lys_lPEG2_IsoGlu_Palm, Lys Ac, Lys AlbuTag, Lys_dIsoLys_lPEG2_ C18_diacid,Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid,Lys_IsoGlu_IsoGlu_C20_Diacid, Lys_Me3, Lys_PEG2_Me3,Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Orn_Acetyl, or Pen;X18 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys Ac, LysPhAc, Orn Acetyl, or Pen;X19 is Aib, Ala, or Gin;X20 is Aib, aMe_4Pal, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid,32324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, or Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac,Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, orLys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;X21 is Aib, Ala, Asp, Gin, Glu, Ogl, Om, or Phe;X22 is aMe_Phe, He, or Phe;X23 is aMe_Ile, Cys, Glu, He, 03 S, or Vai;X24 is Ala, Asn, Cys, dE, dK, Gin, Glu, Hey, Hhc, Lys_Ac, or Tyr;X25 is Ala, aMe_Lys, aMe_Phe, aMe_Tyr, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Phe_34diOMe, Trp, or Tyr;X26 is aMe_Leu, Cys, lie, Leu, NMe_Leu, Tie, or Vai;X27 is Ache, Aib, aMe_Leu, Cha, dL, Gin, Glu, Gly, His, He, Leu, Lys, NMe_Leu, 03 S, Ogl, Orn, Sar, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, bhE,Cys, dE, Gin, Gly, Glu, Glu OMe, Hey, hE, Hhc, IsoGlu, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is Ala, dA, dK, dR, Gly, Sar, or absent;X30 is Ala, Arg, dR, Gly, Pro, Sar, or absent;X31 is Cys, Pro, Sar, Ser, or absent;X32 is Gly, Pro, Ser, or absent;X33 is Arg, Cys, Gly, Ser, or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Glu, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;X37 is Leu, Pro or absent;X38 is Pro, Ser, Vai, or absent;X39 is Glu, Lys, Ser, Thr, or absent;X40 is Arg, Gly, Lys_Palm, or absent;X41 is Gin, Thr, or absent;X42 is Arg, Glu, or absent;X43 is Glu, Tyr, or absent; andX44 is Glu or absent; wherein the peptide optionally comprises: a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently33324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 linked through a cyclization linker, and / or a cyclic structure wherein X23 and X27 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (LG ).)

[0023] In one aspect for Formula (I) peptides, the peptide exhibits an EC50 less than 20 nM in activating (or increasing or agonizing) cAMP intracellular accumulation in HEK-293 cells that stably express human GLP1R and in HEK-293 cells that stably express human GIPR.

[0024] In another aspect of Formula (I) peptides, the peptide exhibits an EC50 less than 10 nM in activating (or increasing or agonizing) cAMP intracellular accumulation in HEK-293 cells that stably express human GLP1R, in HEK-293 cells that stably express human GIPR, and in HEK-293 cells that stably express human GCGR.

[0025] In some aspects of Formula (I), the residue options for X10-X18, X23, and X27 includes, but are not limited to:• If a residue in X10-X18, X23, or X27, is not part of an intramolecular cross-link (i.e., directly or indirectly covalently linked with another residue at X10-X18, X23, or X27), then: o If X10 is not part of an intramolecular cross-link, then XI 0 is 4Pal, Ache, Aib, aMe Leu, aMe Phe, aMe Ser, Bip, Bip_2pEt4pOMe, Chg, Leu, Lys IsoGlu Palm, Phe, Phe_34diOMe, Phe_4COOH, Phe_4ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_Me, Phe_4_Morph, Phe_4_OMe, Tyr, Ser, or Vai; o If Xl 1 is not part of an intramolecular cross-link, then Xl 1 is Ache, Aib, Ala, aMe_Ser, Asp, Chg, Gly, HhPhe_35Me, Hyp, He, NMe_Ser, Pro, Ser, Thr, Tyr; o If X12 is not part of an intramolecular cross-link, then X12 is aMe Leu, Cys, Glu, He, Lys, or Lys Ac; o If X13 is not part of an intramolecular cross-link, then X13 is Ache, Aib, aMe Leu, aMe Phe, Arg, Chg, Gin, Glu, lie, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys Ac, nL, Ser, Trp, or Tyr; o If X14 is not part of an intramolecular cross-link, then X14 is Asp, Ogl, Leu, Phe_4ad, Phe_4_2ae, Tba, or Tyr; o If X15 is not part of an intramolecular cross-link, then X15 is Asp, Glu, or Lys; o If X16 is not part of an intramolecular cross-link, then X16 is Arg, Cys, Glu, Lys, Lys_Ac, Orn, or Ser; o If X17 is not part of an intramolecular cross-link, then X17 is Ala, aMe lle, aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, a Lys with a side-chain34324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 comprising a half-life extension moiety, Lys,Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Albutag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_lPEG2_C 19_Phosphonic_Acid, Lys_lPEG2_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_AlbuTab, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_Palm, Lys Ac, Ly s AlbuT ag, Ly s dlsoLy s_ 1 PEG2 C 18_di aci d, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid, Lys_IsoGlu_IsoGlu_C20_Diacid, Lys_Me3, Lys_PEG2_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid; o If XI 8 is not part of an intramolecular cross-link, then XI 8 is Aib, Ala, Arg, or Gin. o If X23 is not part of an intramolecular cross-link, then X23 is aMe_Ile, Cys, Glu, He, or Vai; and o If X27 is not part of an intramolecular cross-link, then X27 is Ache, Aib, aMe Leu, Cha, dL, Gin, Glu, Gly, His, He, Leu, Lys, NMe Leu, Ogl, Om, Sar, Tba, Tie, or Vai.• If the side-chain of this amino acid residue is part of an intramolecular cross-link to a side-chain of an amino acid residue at a different position in X10-X18, then the residue is aMe_Cys, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Hhc, Hey, Lys_Ac, LysPhAc, O2S, 03 S, 03S_Me, 04S, 03S_Reduced, 03 S Me Reduced, 04S_Reduced, Om Acetyl, or Pen. o If the intramolecular cross-link is directly between the side-chains of the two residues and comprises a disulfide bond, then the two cross-linked residues at X10-X18 are individually or both: aMe Cys, Cys, dC, Hhc, Hey, or Pen (or other residues with a side-chain comprising a free thiol group).35324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088■ In certain aspects, the two residues directly linked through a disulfide bond are both Hey or Hhc. o If the intramolecular cross-link is directly between the side-chains of the two residues and comprises a carbon-carbon double bond, then the two cross-linked residues at X10-X18 are individually or both: O2S, O3S, 03S_Me, or O4S. o If the intramolecular cross-link is directly between the side-chains of the two residues and comprises a carbon-carbon single bond, then the two cross-linked residues at X10-X18 are individually or both: O3S_Reduced, 03 S Me Reduced, or 04S_Reduced. o If the intramolecular cross-link is directly between the side-chains of two residues and comprises a thioether bond, then for one of the two cross-linked residues at X10-X18 is: aMe Cys, Cys, dC, Hhc, Hey, or Pen (or other residues with a side-chain comprising a free thiol group), and for the other cross-linked residue it is: aMe_Lys_Ac, Dab_Acetyl, Lys_Ac, LysPhAc, or Om_Acetyl (or other residues with a side-chain comprising a free acetyl group). o If the intramolecular cross-link is directly between the side-chains of two residues and comprises a lactam, then for one of the two cross-linked residues at X10-X18 is Lys (or another residue with a side-chain comprising a free NH2 group) and the other is Glu (or another residue with a side-chain comprising a free -C00H group). o If the intramolecular cross-link is indirect (mediated by a cyclization linker) between the side-chains of two residues and comprises a thioether bond, then the two cross-linked residues at X10-X18 are individually or both: aMe Cys, Cys, dC, Hhc, Hey, or Pen (or other residues with a side-chain comprising a free thiol group); and the cyclization linker is: a Butane Linker, a Carbonyl Linker, a Dimethylcyclopropane Linker, an Ebutene Linker, a Hexane Linker, an Oxetane Linker, a Pentane Linker, a Propane Linker, a Trimethylbeneze Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker.• If the side-chains of X23 are X27 are cross-linked, then both residues are 03 S (or alternatively, other residues with side chains that can form a carbon-carbon double bond (e.g., individually or both, 03S_Methyl, 02S, 02S_Methyl, 04S, 04S_Methyl, and the like).36324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0026] In one aspect of Formula (I), the side chains of X12 and X16 are directly or indirectly covalently linked.

[0027] In another aspect of Formula (I), the side-chains of X12 and X16 are directly covalently linked through a thioether bond, and the side chains of X23 and X27 are directly covalently linked through a carbon-carbon double bond.

[0028] In another aspect of Formula (I), X30-X44 or X31-X44 are absent.

[0029] In another aspect of Formula (I) and the other Formulas herein, R2 is amine.

[0030] In another aspect of the Formulas herein, R1 is absent.

[0031] Further, to the extent necessary for any of the Formulas or claims herein, the Formulas and claims do not encompass Compounds 9 (tirzepatide) and 11 (retatrutide).

[0032] In another aspect of a peptide according to any of the Formulas herein, the peptide comprises one or more of the following residues: XI is Y: X2 is Aib or aMe_Ser; X3 is Aoc, Gin, Glu, or His; X4 is Gly; X5 is Thr; X6 is Phe, aMe Phe, or aMe_Phe_2F; X7 is Thr; X8 is Ser; X9 is Asp, aMe_Asp, or aMe_Glu, X10 is 4Pal, Ache, Leu, Tyr, Vai, Phe_34diOMe, Phe_4ad, Phe_4_COOH, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_diacid, Phe_4Me, Phe_4Morph, or a tyrosine analog; XI 1 is aMe_Ser, Aib, or Ser; X12 is Cys, Hey, Hhc, Lys Ac, 03 S, or O3S_Reduced; XI 3 is Ache, Aib, aMe_Leu, aMe_Phe, Arg, Chg, Gin, Glu, He, Leu, nL, Ser, Trp, or Tyr; X14 is Leu, Ogl, Phe_4ad, or Tyr; X15 is Asp; X16 is Cys, Dab Acetyl, Hey, Hhc, Lys Ac, 03 S, O3S_Reduced, O4S, or Om Acetyl; XI 7 is aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys, Lys_Ac, a Lys with a side-chain comprising a half-life extension moiety, Lys AlbuTag, Lys_dIsoLys_lPEG2_C18_diacid, Lys_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys IsoGlu IsoGlu C 18_Diacid, Lys_IsoGlu_IsoGlu_C20_Diacid, Lys_PEG2_Me3, Lys_lPEG2_lPEG2_Ahx_C18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C 18_diacid,Lys_lPEG2_lPEG2_IsoGlu_C 19_Phosphonic_Acid, Lys_lPEG2_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid, Lys_lPEG2_IsoGlu_Albutag, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_Palm, Lys_Sar_dIsoLys_lPEG2_l soGlu C 18_Diacid, or Lys_Thz_dIsoLys_lPEG2_lsoGlu_C18_Diacid; XI 8 is Aib or Ala; XI 9 is Gin; X20 is Aib, 37324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 aMe_4Pal, aMe Lys, Lys, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_Sar_dIsoLys_lPEG2_l soGlu C 18_Diacid, or Lys_Thz_dIsoLys_lPEG2_lsoGlu_C18_Diacid; X21 is Ala, Glu, Ogl, or Om; X22 is aMe Phe or Phe; X23 is He, 03 S, or Vai; X24 is dE, dK, Gin, or Glu; X25 is aMe_Phe, aMe_Tyr, Phe_34diOMe, Trp, or Tyr; X26 is aMe_Leu, He, or Leu; X27 is Ache, Aib, aMe Leu, Cha, dL, Gin, His, lie, Leu, Lys, 03 S, Ogl, Om, Tba, Tie, or Vai; X28 is Aib, Ala, aMe Glu, aMe Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, bhE, dE, Gin, Glu, Glu OMe, hE, IsoGlu, Lys_lPEG2_IsoGlu_C20_diacide, Phe, Thp, or Thr; X29 is dK or Gly; X30 is Arg, dR, dK, Gly, Sar, or absent; and no additional residues after X30. In related aspects, the peptide comprises at least five, at least ten, at least fifteen, at least twenty, at least twenty-five, or all of the residue options listed in the preceding sentence. In another aspect of the options listed in this paragraph, the side-chains are directly covalently attached or indirectly covalently attached through a cyclization linker.

[0033] In another aspect of Formula (I), two residues of X10-X18 are directly cross-linked via a disulfide bond, and wherein the two cross-linked residues are individually or both Cys, dC, Hey, Hhc, Pen, HhPen, their D-amino acid forms, or their a-methyl variant forms.

[0034] In another aspect of Formula (I), two residues of X10-X18 are directly cross-linked via a thioether bond, and wherein one cross-linked residue is Cys, dC, Hey, Hhc, Pen, or HhPen, and the other cross-linked residue is aMe Lys Ac, Dab Acetyl, Lys Ac, LysPhAc, or Orn Acetyl. In one aspect, the two residues with side-chains directly cross-linked via a thioether bond are XI 2 and XI 6.

[0035] In another aspect of Formula (I), two residues of X10-X18 are indirectly cross-linked via a cyclization linker, wherein the two cross-linked residues are individually or both Cys, dC, 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, a Trimethylbeneze Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker.

[0036] In another aspect of Formula (I), X12 and X16 are directly cross-linked through a disulfide bond, and wherein X12 and X16 are individually or both Hey or Hhc.

[0037] In another aspect of Formula (I), X12 and X16 are indirectly cross-linked through a thioether bond with a cyclization linker, wherein X12 and X16 are individually or both Cys, Hey, Hhc, Pen, or HhPen, and wherein the cyclization linker is a Butane Linker, Carbonyl Linker, a Dimethylcyclopropane Linker, a Ebutene Linker, a Hexane Linker, an38324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Oxetane Linker a Pentane Linker, a Propane Linker, a Trimethylbenzene Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker.

[0038] In another aspect of Formula (I), X12 and X16 are directly cross-linked through a carbon-carbon double bond, and wherein X12 and X16 are individually or both O2S, O3S, O4S. or their methylated forms, i.e., O2S_Me, O3S_Me, and O4S_Me.

[0039] In another aspect of Formula (I), X12 and X16 are directly cross-linked through a carbon-carbon single bond, and wherein X12 and X16 are individually or both O2S_Reduced, O3S_Reduced, O4S_Reduced, or their methylated forms, i.e., O2S_Me_Reduced, 03 S Me Reduced, or O4S_Me_Reduced.

[0040] In another aspect of Formula (I), the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1 A-1QQQQQ peptides with +, ++, +++, or ++++), less than 1 nM (++, +++, ++++), less than 0.100 nM (+++ or ++++), or less than 0.010 nM (++++) 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).

[0041] 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 dual or tri-agonists of hGLPIR, hGIPR, and hGCGR.

[0042] In another aspect of Formula (I), the peptide has an EC50 potency less than 10 micromolar (e.g., see Figs. 1A-1QQQQQ peptides with +, ++, +++, or ++++), less than 1 micromolar (++, +++, ++++), less than 100 nM (e.g., +++ or ++++), or less than 10 nM (e.g., see Figs. 1 A-1QQQQQ peptides with ++++) in a human GLP1RHEK293 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.

[0043] In Figs. 1 A-1QQQQQ, 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.

[0044] In another aspect of Formula (I), the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1 A-1QQQQQ peptides with +, ++, +++, or ++++), less than 1 nM (++, +++, ++++),39324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 less than 0.100 nM (e.g., see Figs. 1.1 - 1.121 peptides with +++ or ++++), or less than 0.010 nM (e.g., see Figs. 1A-1QQQQQ peptides with ++++) 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 45,000-55,000 receptors / cell.

[0045] In another aspect of Formula (I), the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1A-1QQQQQ peptides with +, ++, +++, or ++++), less than 1 nM (e.g., ++, +++, ++++), less than 0.100 nM (e.g., +++ or ++++), or less than 0.010 nM (e.g., ++++) in a human GCGR HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant human GCGR on their cell surface at a density between about 10,000-13,000 receptors / cell.

[0046] In another aspect of Formula (I), the peptide has an EC50 potency less than 20 nM, less than 1 nM, less than 0.100 nM, or less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay, a human GIPR HEK293 cAMP accumulation assay, and in human GCGR HEK293 cAMP accumulation assay. (See Examples for the cAMP accumulation assay).

[0047] In another aspect of Formula (I), 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.

[0048] In another aspect of Formula (I), the peptide has an EC50 potency less than 20 nM, less than 1 nM, less than 0.100 nM, or less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay, a human GIPR HEK293 cAMP accumulation assay, and / or in human GCGR HEK293 cAMP accumulation assay, and also has a half-life time of stability of greater than 2 hours or 24 hours in an SGF assay and / or an SIF assay.

[0049] In one aspect, the invention provides a peptide that is a dual agonist of GLP1R and GIPR or a tri-agonist of GLP1R, GIPR, and GCGR, wherein the peptide comprises or consists of a sequence according to Formula (II):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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 391), 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 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib or aMe_Ser;X3 is Aoc, Glu, Gin, His, or Tetl;X4 is Gly;40324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X5 is Ser or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Thr;X8 is Ser;X9 is Asp, aMe_Asp, or aMe_Glu;XI 0 is 4Pal, Ache, aMe Leu, Bip, Chg, Leu, Phe, Phe_34diOMe, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_diacid, Phe_4ad, Phe_4CF3, Phe_4COOH, Phe_4Me, Phe_4_Morph, Phe_4_OMe, Phe_4tBu, Tyr, or Vai;XI 1 is Aib, Ala, aMe_Ser or Ser;X12 is Cys, Dab_Acetyl, Glu, Hey, Hhc, Lys, Lys_Ac, 03 S, 03S_Me, or 03 S Reduced;XI 3 is Ache, Aib, aMe Leu, aMe Phe, Arg, Chg, Gin, Glu, He, Leu, nL, Ser, Trp, or Tyr;X14 is Leu, Ogl, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is Asp;XI 6 is Cys, Dab Acetyl, Hey, Hhc, Lys, Lys Ac, 03 S, 03S_Me, 03S_Reduced, 04S, or Orn Acetyl;XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys, Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid,Lys_lPEG2_lPEG2_IsoGlu_C 19_Phosphonic_Acid,Lys_lPEG_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid; Lys_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid,Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_Palm, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys_Me3, Lys IsoGlu IsoGlu C 18_Diacid,Ly s_IsoGlu_IsoGlu_C20_Diacid, Ly s_PEG2_Me3 ,Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid,Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, Lys Ac, or Lys AlbuTag, ;XI 8 is Aib or Ala;XI 9 is Gin;41324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X20 is Aib, aMe_4Pal, aMe_Lys, aMe_Lys_Ac, Lys, Lys_Ac, Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_diacid;X21 is Aib, Ala, Glu, Ogl, or Orn;X22 is aMe_Phe or Phe;X23 is He, 03 S, or Vai;X24 is dE, dK, Gin, or Glu;X25 is aMe_Phe, aMe_Tyr, Phe_34diOMe, Trp, or Tyr;X26 is aMe Leu, He, or Leu;X27 is Ache, Aib, aMe Leu, Cha, dL, Gin, His, lie, Leu, Lys, 03 S, Ogl, Orn, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, bhE, dE, Gin, Glu, Glu OMe, hE, IsoGlu, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is dA, dK, dR, Gly, Sar, or absent;X30 is Arg, dR, Gly, Sar, or absent; andX31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (II).)

[0050] In one aspect, the invention provides a peptide that is a dual agonist of GLP1R and GIPR or a tri-agonist of GLP1R, GIPR, and GCGR, wherein the peptide comprises or consists of a sequence according to Formula (II. 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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 392), 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 or OH or absent;XI is Tyr;X2 is Aib;X3 is Glu or Gin;X4 is Gly;X5 is Thr;42324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X6 is aMe Phe or Phe;X7 is Thr;X8 is Ser;X9 is Asp;X10 is Ache, Bip, Chg, Leu, Phe, Phe_4_2ae, Phe_4ad, Phe_4CF3, Phe_4COOH, Phe_4Me, Phe_4tBu, Tyr, or Vai;XI 1 is Ala, aMe_Ser or Ser;X12 is Cys, Glu, Hey, Hhc, or Lys_Ac;XI 3 is Ache, Aib, aMe_Leu or aMe_Phe;X14 is Leu;XI 5 is Asp;X16 is X12 is Cys, Hey, Hhc, Lys, or Lys_Ac;XI 7 is aMe_Lys, Arg, Glu, Lys, Lys_lPEG2_IsoGlu_C20_diacid, or Lys_Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib, aMe_Lys, Lys, Lys_lPEG2_IsoGlu_C20_diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_diacid, orLys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_diacid;X21 is Ala or Glu;X22 is aMe_Phe or Phe;X23 is He;X24 is Glu;X25 is aMe_Phe, Trp, or Tyr;X26 is aMe Leu, He, or Leu;X27 is lie, Leu, or Lys;X28 is Aib, Ala, aMe_Lys, Gin, Glu, or Thr;X29 is Gly or absent;X30 is Arg, dR, Gly, or absent;X31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (II. A).)

[0051] In one aspect, the invention provides a peptide that is a dual agonist of GLP1R and GIPR or a tri-agonist of GLP1R, GIPR, and GCGR, wherein the peptide comprises or consists of a sequence according to Formula (II.B):43324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088R1-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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 393), 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 or OH or absent;XI is Tyr;X2 is Aib;X3 is Glu or Gin;X4 is Gly;X5 is Ser or Thr;X6 is aMe Phe or Phe;X7 is Thr;X8 is Ser;X9 is Asp;X10 is Ache, Bip, Chg, Leu, Phe, Phe_4_2ae, Phe_4ad, Phe_4CF3, Phe_4COOH, Phe_4Me, Phe_4tBu, Tyr, or Vai;Xl 1 is Aib, Ala, aMe_Ser, or Ser;X12 is Cys, Glu, Hey, Hhc, or Lys_Ac;XI 3 is Ache, Aib, aMe_Leu, or aMe_Phe;X14 is Leu;XI 5 is Asp;XI 6 is is Cys, Hey, Hhc, Lys, or Lys_Ac;XI 7 is aMe_Lys, Arg, Glu, Lys, Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG_lPEG2_IsoGlu_MeOPheTag, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, or Lys Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib, aMe_Lys, Lys, Lys_lPEG2_IsoGlu_C20_diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_diacid, orLys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_diacid;X21 is Ala or Glu;X22 is aMe_Phe or Phe;X23 is He;44324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X24 is Glu;X25 is aMe_Phe, Trp, or Tyr;X26 is aMe Leu, He, or Leu;X27 is He, Leu, Lys, or Tie;X28 is Aib, Ala, aMe_Lys, Gin, Glu, or Thr;X29 is Gly or absent;X30 is Arg, dR, Gly, or absent;X31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (II.B).)

[0052] In one aspect, the invention provides a peptide that is a dual agonist of GLP1R and GIPR or a tri-agonist of GLP1R, GIPR, and GCGR, wherein the peptide comprises or consists of a sequence according to Formula (II. C):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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 394), 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 or OH or absent;XI is Tyr;X2 is Aib;X3 is Glu or Gin;X4 is Gly;X5 is Ser or Thr;X6 is aMe Phe or Phe;X7 is Thr;X8 is Ser;X9 is Asp;X10 is Ache, Bip, Chg, Leu, Phe, Phe_4_2ae, Phe_4ad, Phe_4CF3, Phe_4COOH, Phe_4Me, Phe_4tBu, Tyr, or Vai;Xl 1 is Aib, Ala, aMe_Ser, or Ser;X12 is Cys, Glu, Hey, Hhc, or Lys_Ac;XI 3 is Ache, Aib, aMe Leu, aMe Phe, Arg, Chg, Gin, Glu, He, Leu, nL, Ser, Trp, or Tyr;45324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X14 is Leu;XI 5 is Asp;XI 6 is is Cys, Hey, Hhc, Lys, or Lys_Ac;XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, He, Lys, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_C20_diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid,Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, or Lys Ac;XI 8 is Aib or Ala;XI 9 is Gin;X20 is Aib, aMe_Lys, Lys, Lys_lPEG2_IsoGlu_C20_diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_diacid, orLys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_diacid;X21 is Ala or Glu;X22 is aMe_Phe or Phe;X23 is He;X24 is Glu;X25 is aMe_Phe, Trp, or Tyr;X26 is aMe Leu, lie, or Leu;X27 is Aib, aMe_Leu, lie, Leu, Lys, or Tie;X28 is Aib, Ala, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Gin, Glu, Lys_lPEG2_IsoGlu_C20_diacid, Phe, or Thr;X29 is Gly or absent;X30 is Arg, dR, Gly, or absent;X31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (II.C).)

[0053] In one aspect, the invention provides a peptide that is a dual agonist of GLP1R and GIPR or a tri-agonist of GLP1R, GIPR, and GCGR, wherein the peptide comprises or consists of a sequence according to Formula (ILD):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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 395), 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;46324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088R2 is NH2 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib;X3 is Glu, Gin, or Tetl;X4 is Gly;X5 is Ser or Thr;X6 is aMe Phe or Phe;X7 is Thr;X8 is Ser;X9 is Asp or aMe_Asp;X10 is Ache, aMe Leu, Bip, Chg, Leu, Phe, Phe_4_2ae, Phe_4ad, Phe_4CF3, Phe_4COOH, Phe_4Me, Phe_4_OMe, Phe_4tBu, Tyr, or Vai;XI I is Aib, Ala, aMe_Ser, or Ser;X12 is Cys, Glu, Hey, Hhc, Lys, Lys Ac, or O3S_Me;XI 3 is Ache, Aib, aMe Leu, aMe Phe, Arg, Chg, Gin, Glu, He, Leu, nL, Ser, Trp, or Tyr;X14 is Leu, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is Asp;XI 6 is Cys, Hey, Hhc, Lys, Lys Ac, or O3S_Me;XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, He, Lys, Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_AlbuTab, Lys_lPEG2_IsoGlu_C12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_IsoGlu_Palm, Lys_lPEG2_IsoGlu_C20_diacid, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid Lys_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, or Lys Ac;XI 8 is Aib or Ala;XI 9 is Gin;X20 is Aib, aMe_Lys, aMe_Lys_Ac, Lys, Lys_lPEG2_IsoGlu_C20_diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_diacid, orLys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_diacid;47324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X21 is Aib, Ala, Glu, or Ogl;X22 is aMe_Phe or Phe;X23 is He or Vai;X24 is dE, Gin, or Glu;X25 is aMe_Phe, aMe_Tyr, Trp, or Tyr;X26 is aMe Leu, He, or Leu;X27 is Aib, aMe Leu, His, He, Leu, Lys, Tba, or Tie;X28 is Aib, Ala, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Gin, Glu, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is dA, Gly, or absent;X30 is Arg, dR, Gly, Sar, or absent;X31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (II.D).)

[0054] In one aspect, the invention provides a peptide that is a dual agonist of GLP1R and GIPR or a tri-agonist of GLP1R, GIPR, and GCGR, wherein the peptide comprises or consists of a sequence according to Formula (ILE):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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 396), 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 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib;X3 is Glu, Gin, His, or Tetl;X4 is Gly;X5 is Ser or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Thr;X8 is Ser;X9 is Asp, aMe_Asp, or aMe_Glu;XI 0 is 4Pal, Ache, aMe Leu, Bip, Chg, Leu, Phe, Phe_34diOMe, Phe_4_2ae, Phe_4ad, Phe_4CF3, Phe_4COOH, Phe_4Me, Phe_4_Morph, Phe_4_OMe, Phe_4tBu, Tyr, or Vai;48324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 1 is Aib, Ala, aMe_Ser, or Ser;X12 is Cys, Dab_Acetyl, Glu, Hey, Hhc, Lys, Lys_Ac, 03 S, or 03S_Me;XI 3 is Ache, Aib, aMe Leu, aMe Phe, Arg, Chg, Gin, Glu, He, Leu, nL, Ser, Trp, or Tyr;X14 is Leu, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is Asp;XI 6 is Cys, Dab_Acetyl, Hey, Hhc, Lys, Lys_Ac, 03 S, or 03S_Me;XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, He, Lys, Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_AlbuTab, Lys_lPEG2_IsoGlu_C12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_IsoGlu_Palm, Lys_lPEG2_IsoGlu_C20_diacid,Ly s dlsoLy s_lPEG2_IsoGlu_C 18_diacid Ly s_Me3 , Ly s_IsoGlu_IsoGlu_C 18_Diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, or Lys Ac;XI 8 is Aib or Ala;XI 9 is Gin;X20 is Aib, aMe_Lys, aMe_Lys_Ac, Lys, Lys_lPEG2_IsoGlu_C20_diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_diacid, orLys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_diacid;X21 is Aib, Ala, Glu, or Ogl;X22 is aMe_Phe or Phe;X23 is lie, 03 S, or Vai;X24 is dE, Gin, or Glu;X25 is aMe_Phe, aMe_Tyr, Trp, or Tyr;X26 is aMe Leu, He, or Leu;X27 is Ache, Aib, aMe Leu, Cha, dL, Gin, His, He, Leu, Lys, 03 S, Ogl, Orn, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, dE, Gin, Glu, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is dA, Gly, Sar, or absent;X30 is Arg, dR, Gly, Sar, or absent; and49324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (II.E).)

[0055] In one aspect, the invention provides a peptide that is a dual agonist of GLP1R and GIPR or a tri-agonist of GLP1R, GIPR, and GCGR, wherein the peptide comprises or consists of a sequence according to Formula (ILF):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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 397), 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 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib or aMe_Ser;X3 is Aoc, Glu, Gin, His, or Tetl;X4 is Gly;X5 is Ser or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Thr;X8 is Ser;X9 is Asp, aMe_Asp, or aMe_Glu;XI 0 is 4Pal, Ache, aMe Leu, Bip, Chg, Leu, Phe, Phe_34diOMe, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_diacid, Phe_4ad, Phe_4CF3, Phe_4COOH, Phe_4Me, Phe_4_Morph, Phe_4_OMe, Phe_4tBu, Tyr, or Vai;Xl 1 is Aib, Ala, aMe_Ser, or Ser;X12 is Cys, Dab_Acetyl, Glu, Hey, Hhc, Lys, Lys_Ac, 03 S, O3S_Me, or 03 S Reduced;XI 3 is Ache, Aib, aMe Leu, aMe Phe, Arg, Chg, Gin, Glu, He, Leu, nL, Ser, Trp, or Tyr;X14 is Leu, Ogl, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is Asp;XI 6 is Cys, Dab Acetyl, Hey, Hhc, Lys, Lys Ac, 03 S, O3S_Me, 03S_Reduced, O4S, or Orn Acetyl;50324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, He, Lys, Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_AlbuTab, Lys_lPEG2_IsoGlu_C12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_IsoGlu_Palm, Lys_lPEG2_IsoGlu_C20_diacid,Ly s dlsoLy s_lPEG2_IsoGlu_C 18_diacid Ly s_Me3 , Ly s_IsoGlu_IsoGlu_C 18_Diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, or Lys Ac;XI 8 is Aib or Ala;XI 9 is Gin;X20 is Aib, aMe_Lys, aMe_Lys_Ac, Lys, Lys_lPEG2_IsoGlu_C20_diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_diacid, orLys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_diacid;X21 is Aib, Ala, Glu, or Ogl;X22 is aMe_Phe or Phe;X23 is He, 03 S, or Vai;X24 is dE, dK, Gin, or Glu;X25 is aMe_Phe, aMe_Tyr, Trp, or Tyr;X26 is aMe Leu, lie, or Leu;X27 is Ache, Aib, aMe Leu, Cha, dL, Gin, His, lie, Leu, Lys, 03 S, Ogl, Orn, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, dE, Gin, Glu, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is dA, dK, Gly, Sar, or absent;X30 is Arg, dR, Gly, Sar, or absent; andX31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (II.F).)

[0056] In one aspect, the invention provides a peptide that is a dual agonist of GLP1R and GIPR or a tri-agonist of GLP1R, GIPR, and GCGR, wherein the peptide comprises or consists of a sequence according to Formula (II.G):51324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088R1-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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 398), 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 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib or aMe_Ser;X3 is Aoc, Glu, Gin, His, or Tetl;X4 is Gly;X5 is Ser or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Thr;X8 is Ser;X9 is Asp, aMe_Asp, or aMe_Glu;XI 0 is 4Pal, Ache, aMe Leu, Bip, Chg, Leu, Phe, Phe_34diOMe, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_diacid, Phe_4ad, Phe_4CF3, Phe_4COOH, Phe_4Me, Phe_4_Morph, Phe_4_OMe, Phe_4tBu, Tyr, or Vai;Xl 1 is Aib, Ala, aMe_Ser, or Ser;X12 is Cys, Dab_Acetyl, Glu, Hey, Hhc, Lys, Lys_Ac, 03 S, 03S_Me, or 03 S Reduced;XI 3 is Ache, Aib, aMe Leu, aMe Phe, Arg, Chg, Gin, Glu, He, Leu, nL, Ser, Trp, or Tyr;X14 is Leu, Ogl, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is Asp;XI 6 is Cys, Dab Acetyl, Hey, Hhc, Lys, Lys Ac, 03 S, 03S_Me, 03S_Reduced, 04S, or Orn Acetyl;XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys, Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid,Lys_lPEG2_lPEG2_IsoGlu_C 19_Phosphonic_Acid,Lys_lPEG_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid; Lys_lPEG2_IsoGlu_AlbuTag,52324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_Palm, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys_Me3, Lys IsoGlu IsoGlu Cl 8_Diacid, Ly s_IsoGlu_IsoGlu_C20_Diacid, Ly s_PEG2_Me3 , Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, Lys Ac, or Lys AlbuTag, ;XI 8 is Aib or Ala;XI 9 is Gin;X20 is Aib, aMe_4Pal, aMe_Lys, aMe_Lys_Ac, Lys, Lys Ac, Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_diacid;X21 is Aib, Ala, Glu, Ogl, or Orn;X22 is aMe_Phe or Phe;X23 is He, 03 S, or Vai;X24 is dE, dK, Gin, or Glu;X25 is aMe_Phe, aMe_Tyr, Phe_34diOMe, Trp, or Tyr;X26 is aMe Leu, He, or Leu;X27 is Ache, Aib, aMe Leu, Cha, dL, Gin, His, lie, Leu, Lys, 03 S, Ogl, Orn, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, bhE, dE, Gin, Glu, Glu OMe, hE, IsoGlu, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is dA, dK, dR, Gly, Sar, or absent;X30 is Arg, dR, Gly, Sar, or absent; andX31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (II. G).)

[0057] In another aspect of Formula (II), X12 and X16 are directly cross-linked through a disulfide bond, and wherein X12 and X16 are individually, or both, Hey or Hhc.

[0058] In another aspect of Formula (II), X12 and X16 are directly cross-linked through a lactam, wherein X12 is Glu and X16 is Lys.53324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0059] In another aspect of Formula (II), X12 is Cys, Hey, or Hhc and X16 is Dab Ac, Lys Ac, or Orn Acetyl, and X12 and X16 are directly cross-linked through a thioether bond.

[0060] In another aspect of Formula (II), X12 is Dab Ac or Lys Ac and X16 is Cys, Hey, or Hhc, and X12 and X16 are directly cross-linked through a thioether bond.

[0061] In another aspect of Formula (II), X12 and X16 are indirectly cross-linked through a thioether bond with a cyclization linker, wherein X12 and X16 are individually, or both Cys, Hey, or Hhc, and wherein the cyclization linker is a Butane Linker, a Carbonyl Linker, a Dimethylcyclopropane Linker, an Ebutene Linker, a Hexane Linker, an Oxetane Linker a Pentane Linker, a Propane Linker, a Trimethylbenzene Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker.

[0062] In another aspect of Formula (II), X12 and X16 are indirectly cross-linked through a thioether bond with a cyclization linker, wherein X12 and X16 are both Cys, and wherein the cyclization linker is a Butane Linker or a Propane Linker.

[0063] In another aspect of Formula (II), X12 and X16 are directly cross-linked through a carbon-carbon double bond, wherein X12 and X16 are individually or both O3S, O4S, or O3S_Me.

[0064] In another aspect of Formula (II), X12 and X16 are directly cross-linked through a carbon-carbon single bond, wherein X12 and X16 are both O3S_Reduced.

[0065] In another aspect of Formula (II), in addition to the intramolecular cross-link between the side-chains of X12 and X16, the peptide further comprises an intramolecular cross-link between X23 and X27, wherein the cross-link comprises a carbon-carbon double bond when X23 and X27 are individually, or both, 03 S or O3S_Me.

[0066] In another aspect of Formula (II), the peptide has an EC50 potency less than 0.100 nM in a human HD GLP1R HEK293 cAMP accumulation assay or an EC50 potency less than 1 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and less than 0.100 nM in in a human GIPR HEK293 cAMP accumulation assay.

[0067] In another aspect of Formula (II), the peptide has an EC50 potency less than 0.100 nM in a human HD GLP1R HEK293 cAMP accumulation assay and in a human GIPR HEK293 cAMP accumulation assay, and an EC50 potency less than 20 nM in a human GCGR HEK293 cAMP accumulation assay.

[0068] In another aspect of Formula (II), the peptide has a half-life time of stability of greater than 2 hours or 24 hours in an SGF assay or an SIF assay, or in both assays.

[0069] In one aspect, the invention provides a peptide that is at least a dual agonist of GLP1R and GIPR, wherein the peptide has an EC50 potency less than 0.100 nM in a human HD GLP1R54324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088HEK293 cAMP accumulation assay or less than 100 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, wherein the peptide has a half-life time of stability greater than 2 hours in both an SGF assay and an SIF assay, and wherein the peptide comprises or consists of a sequence according to Formula (III):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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 399), wherein:R1 is absent;R2 is NH2 or absent;XI is Tyr;X2 is Aib or aMe_Ser;X3 is Aoc, Gin, Glu, or His;X4 is Gly;X5 is Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Thr;X8 is Ser;X9 is aMe_Asp, aMe_Glu, or Asp;XI 0 is 4Pal, Ache, aMe_Leu, Chg, Leu, Phe_34diOMe, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_diacid, Phe_4_ad, Phe_4_Morph, Phe_4OMe, Tyr, or Vai;Xl 1 is Aib, aMe_Ser, or Ser;X12 is Cys, Hey, Hhc, Lys Ac, 03 S, or O3S_Reduced;X13 is Ache, Aib, aMe_Leu, or aMe_Phe;X14 is Leu, Ogl, Phe_4_2ae, Phe_4ad, or Tyr;X15 is Asp;XI 6 is Cys, Dab Acetyl, Hey, Hhc, Lys Ac, 03 S, O3S_Reduced, O4S, or Orn Acetyl;XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys,Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid, Lys_lPEG2_IsoGlu_Albutag, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_C 18_diacid,55324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_Palm, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys_IsoGlu_IsoGlu_C20_Diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, or Lys Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib, aMe_4Pal, aMe_Lys, aMe_Lys_Ac, or Lys_Ac;X21 is Aib, Ala, Glu, Ogl, or Orn;X22 is aMe_Phe or Phe;X23 is He, 03 S, or Vai;X24 is dE, dK, Gin or Glu;X25 is aMe_Phe, aMe_Tyr, Trp, or Tyr;X26 is aMe Leu, He, or Leu;X27 is Ache, aMe Leu, Cha, dL, His, lie, Leu, Lys, 03 S, Om, Tba, Tie, or Vai;X28 is Aib, Ala, aMe Glu, aMe Lys, bhE, dE, Gin, Glu, Glu OMe, hE, Lys Ac, Thp, or Thr;X29 is dA, dR, Gly, Sar, or absent;X30 is Arg, dR, Gly, Sar, or absent; andX31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (III).)

[0070] In one aspect, the invention provides a peptide that is at least a dual agonist of GLP1R and GIPR, wherein the peptide has an EC50 potency less than 0.100 nM in a human HD GLP1R HEK293 cAMP accumulation assay or less than 10 nM in a human LD GLP 1R HEK293 cAMP accumulation assay, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, wherein the peptide has a half-life time of stability greater than 2 hours in both an SGF assay and an SIF assay, and wherein the peptide comprises or consists of a sequence according to Formula (III. 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-X27-X28-X29-X30 -R2 (SEQ ID NO: 400), wherein:R1 is absent;R2 is NH2 or absent;XI is Tyr;56324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X2 is Aib;X3 is Gin or Glu;X4 is Gly;X5 is Thr;X6 is aMe_Phe;X7 is Thr;X8 is Ser;X9 is Asp;X10 is Ache, Leu, Tyr, or Vai;XI 1 is aMe_Ser;X12 is Cys, Hey, Hhc, or Lys_Ac;XI 3 is aMe_Leu;X14 is Leu;XI 5 is Asp;XI 6 is Cys, Hey, Hhc, or Lys_Ac;XI 7 is aMe_Lys, Arg, Glu, or Lys_Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib;X21 is Ala or Glu;X22 is aMe_Phe;X23 is He;X24 is Glu;X25 is aMe_Phe;X26 is aMe Leu or Leu;X27 is Leu or Lys;X28 is Aib, aMe_Lys, Gin, or Thr;X29 is Gly;X30 is dR or Gly; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (III. A).)

[0071] In one aspect, the invention provides a peptide that is at least a dual agonist of GLP1R and GIPR, wherein the peptide has an EC50 potency less than 0.100 nM in a human HD GLP1R57324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088HEK293 cAMP accumulation assay or less than 100 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, wherein the peptide has a half-life time of stability greater than 2 hours in both an SGF assay and an SIF assay, and wherein the peptide comprises or consists of a sequence according to Formula (III.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-X27-X28-X29-X30 -R2 (SEQ ID NO: 401), wherein:R1 is absent;R2 is NH2 or absent;XI is Tyr;X2 is Aib;X3 is Gin or Glu;X4 is Gly;X5 is Thr;X6 is aMe_Phe;X7 is Thr;X8 is Ser;X9 is Asp;X10 is Ache, Leu, Tyr, or Vai;Xl 1 is Aib or aMe_Ser;X12 is Cys, Hey, Hhc, or Lys_Ac;X13 is Aib or aMe_Leu;X14 is Leu;X15 is Asp;X16 is Cys, Hey, Hhc, or Lys_Ac;X17 is aMe Lys, Arg, Glu, Lys, Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_C20_Diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid,Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, or Lys Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib;X21 is Ala or Glu;X22 is aMe_Phe;58324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X23 is He;X24 is Glu;X25 is aMe_Phe;X26 is aMe Leu, He, or Leu;X27 is Leu, Lys, or Tie;X28 is Aib, aMe_Lys, Gin, or Thr;X29 is Gly;X30 is dR or Gly; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (III.B).)

[0072] In one aspect, the invention provides a peptide that is at least a dual agonist of GLP1R and GIPR, wherein the peptide 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, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, wherein the peptide has a half-life time of stability greater than 2 hours in both an SGF assay and an SIF assay, and wherein the peptide comprises or consists of a sequence according to Formula (III.C):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-X27-X28-X29-X30 -R2 (SEQ ID NO: 402), wherein:R1 is absent;R2 is NH2 or absent;XI is Tyr;X2 is Aib;X3 is Gin or Glu;X4 is Gly;X5 is Thr;X6 is aMe_Phe;X7 is Thr;X8 is Ser;X9 is Asp;X10 is Ache, Leu, Tyr, or Vai;Xl 1 is Aib or aMe_Ser;X12 is Cys, Hey, Hhc, or Lys_Ac;59324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 3 is Aib, aMe_Leu, or aMe_Phe;X14 is Leu;XI 5 is Asp;XI 6 is Cys, Hey, Hhc, or Lys_Ac;X17 is aMe Lys, Arg, Gin, Glu, Lys, Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_C20_Diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid,Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid,or Lys Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib;X21 is Ala or Glu;X22 is aMe_Phe;X23 is He;X24 is Glu;X25 is aMe_Phe;X26 is aMe Leu, He, or Leu;X27 is aMe_Leu, Leu, lie, Lys, or Tie;X28 is Aib, aMe_Lys, Gin, Glu, or Thr;X29 is Gly; andX30 is Arg, dR, or Gly; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (III.C).)

[0073] In one aspect, the invention provides a peptide that is at least a dual agonist of GLP1R and GIPR, wherein the peptide 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, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, wherein the peptide has a half-life time of stability greater than 2 hours in both an SGF assay and an SIF assay, and wherein the peptide comprises or consists of a sequence according to Formula (HI 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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 403), wherein:R1 is absent;R2 is NH2 or absent;60324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI is Tyr;X2 is Aib;X3 is Gin or Glu;X4 is Gly;X5 is Thr;X6 is aMe_Phe;X7 is Thr;X8 is Ser;X9 is aMe_Asp or Asp;XI 0 is Ache, aMe_Leu, Chg, Leu, Phe_4_2ae, Phe_4_ad, Phe_4OMe, Tyr, or Vai;XI I is Aib, aMe_Ser, or Ser;X12 is Cys, Hey, Hhc, or Lys_Ac;XI 3 is Aib, aMe_Leu, or aMe_Phe;X14 is Leu, Phe_4_2ae, Phe_4ad, or Tyr;XI 5 is Asp;XI 6 is Cys, Hey, Hhc, or Lys_Ac;XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, Lys,Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm,Lys_lPEG2_IsoGlu_Albutag, Lys_lPEG2_IsoGlu_C12_diacid,Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_Palm,Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_C20_Diacid,Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid,Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, or Lys Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib, aMe_Lys, or aMe_Lys_Ac;X21 is Aib, Ala, Glu, or Ogl;X22 is aMe_Phe or Phe;X23 is He or Vai;X24 is dE, Gin or Glu;X25 is aMe_Phe, aMe_Tyr, or Trp;X26 is aMe Leu, He, or Leu;X27 is aMe_Leu, Leu, lie, Lys, or Tie;61324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X28 is Aib, Ala, aMe_Lys, Gin, Glu, Lys_Ac, Thp, or Thr;X29 is dA, Gly, or absent;X30 is Arg, dR, Gly, Sar, or absent; andX31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (III.D).)

[0074] In one aspect, the invention provides a peptide that is at least a dual agonist of GLP1R and GIPR, wherein the peptide 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, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, wherein the peptide has a half-life time of stability greater than 2 hours in both an SGF assay and an SIF assay, and wherein the peptide comprises or consists of a sequence according to Formula (III.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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 404), wherein:R1 is absent;R2 is NH2 or absent;XI is Tyr;X2 is Aib;X3 is Gin, Glu, or His;X4 is Gly;X5 is Thr;X6 is aMe Phe or aMe_Phe_2F;X7 is Thr;X8 is Ser;X9 is aMe_Asp, aMe_Glu, or Asp;XI 0 is 4Pal, Ache, aMe Leu, Chg, Leu, Phe_34diOMe, Phe_4_2ae, Phe_4_ad, Phe_4OMe, Tyr, or Vai;Xl 1 is Aib, aMe_Ser, or Ser;X12 is Cys, Hey, Hhc, Lys_Ac, or 03 S;X13 is Aib, aMe_Leu, or aMe_Phe;X14 is Leu, Phe_4_2ae, Phe_4ad, or Tyr;X15 is Asp;62324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 6 is Cys, Dab Acetyl, Hey, Hhc, Lys Ac, or 03 S;XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, Lys,Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_IsoGlu_Albutag, Lys_lPEG2_IsoGlu_C12_diacid,Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_Palm,Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_C20_Diacid, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, or Lys Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib, aMe_Lys, or aMe_Lys_Ac;X21 is Aib, Ala, Glu, or Ogl;X22 is aMe_Phe or Phe;X23 is He, 03 S, or Vai;X24 is dE, Gin or Glu;X25 is aMe_Phe, aMe_Tyr, or Trp;X26 is aMe Leu, He, or Leu;X27 is Ache, aMe Leu, dL, He, Leu, Lys, 03 S, or Tie;X28 is Aib, Ala, aMe_Lys, Gin, Glu, Lys_Ac, Thp, or Thr;X29 is dA, Gly, or absent;X30 is Arg, dR, Gly, Sar, or absent; andX31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (III.E).)

[0075] In one aspect, the invention provides a peptide that is at least a dual agonist of GLP1R and GIPR, wherein the peptide 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, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, wherein the peptide has a half-life time of stability greater than 2 hours in both an SGF assay and an SIF assay, and wherein the peptide comprises or consists of a sequence according to Formula (III.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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 405),63324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 wherein:R1 is absent;R2 is NH2 or absent;XI is Tyr;X2 is Aib or aMe_Ser;X3 is Aoc, Gin, Glu, or His;X4 is Gly;X5 is Thr;X6 is aMe Phe or aMe_Phe_2F;X7 is Thr;X8 is Ser;X9 is aMe_Asp, aMe_Glu, or Asp;XI 0 is 4Pal, Ache, aMe_Leu, Chg, Leu, Phe_34diOMe, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_diacid, Phe_4_ad, Phe_4OMe, Tyr, or Vai;XI I is Aib, aMe_Ser, or Ser;X12 is Cys, Hey, Hhc, Lys Ac, 03 S, or 03S_Reduced;XI 3 is Ache, Aib, aMe_Leu, or aMe_Phe;X14 is Leu, Ogl, Phe_4_2ae, Phe_4ad, or Tyr;XI 5 is Asp;XI 6 is Cys, Dab Acetyl, Hey, Hhc, Lys Ac, 03 S, 03S_Reduced, 04S, or Om Acetyl;XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, Gin, Glu, Lys,Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Palm,Lys_lPEG2_IsoGlu_Albutag, Lys_lPEG2_IsoGlu_C12_diacid,Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_Palm,Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_C20_Diacid,Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, or Lys Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib, aMe_Lys, or aMe_Lys_Ac;X21 is Aib, Ala, Glu, Ogl, or Orn;X22 is aMe_Phe or Phe;X23 is He, 03 S, or Vai;64324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X24 is dE, dK, Gin or Glu;X25 is aMe_Phe aMe_Tyr, or Trp;X26 is aMe Leu, He, or Leu;X27 is Ache, aMe_Leu, dL, He, Leu, Lys, 03 S, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, Gin, Glu, Lys_Ac, Thp, or Thr;X29 is dA, dR, Gly, or absent;X30 is Arg, dR, Gly, Sar, or absent; andX31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (III.F).)

[0076] In one aspect, the invention provides a peptide that is at least a dual agonist of GLP1R and GIPR, wherein the peptide 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, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, wherein the peptide has a half-life time of stability greater than 2 hours in both an SGF assay and an SIF assay, and wherein the peptide comprises or consists of a sequence according to Formula (III.G):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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 406), wherein:R1 is absent;R2 is NH2 or absent;XI is Tyr;X2 is Aib or aMe_Ser;X3 is Aoc, Gin, Glu, or His;X4 is Gly;X5 is Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Thr;X8 is Ser;X9 is aMe_Asp, aMe_Glu, or Asp;XI 0 is 4Pal, Ache, aMe_Leu, Chg, Leu, Phe_34diOMe, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_diacid, Phe_4_ad, Phe_4_Morph, Phe_4OMe, Tyr, or Vai;Xl 1 is Aib, aMe_Ser, or Ser;65324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X12 is Cys, Hey, Hhc, Lys Ac, 03 S, or 03S_Reduced;XI 3 is Ache, Aib, aMe_Leu, or aMe_Phe;X14 is Leu, Ogl, Phe_4_2ae, Phe_4ad, or Tyr;XI 5 is Asp;XI 6 is Cys, Dab Acetyl, Hey, Hhc, Lys Ac, 03 S, 03S_Reduced, 04S, or Om Acetyl;XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys,Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag,Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm,Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid, Lys_lPEG2_IsoGlu_Albutag,Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_C12_diacid,Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_C 18_diacid,Lys_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_Palm,Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys_IsoGlu_IsoGlu_C20_Diacid,Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid,Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, or Lys Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib, aMe_4Pal, aMe_Lys, aMe_Lys_Ac, or Lys_Ac;X21 is Aib, Ala, Glu, Ogl, or Orn;X22 is aMe_Phe or Phe;X23 is He, 03 S, or Vai;X24 is dE, dK, Gin or Glu;X25 is aMe_Phe, aMe_Tyr, Trp, or Tyr;X26 is aMe Leu, lie, or Leu;X27 is Ache, aMe Leu, Cha, dL, His, lie, Leu, Lys, 03 S, Orn, Tba, Tie, or Vai;X28 is Aib, Ala, aMe Glu, aMe Lys, bhE, dE, Gin, Glu, Glu OMe, hE, Lys Ac, Thp, or Thr;X29 is dA, dR, Gly, Sar, or absent;X30 is Arg, dR, Gly, Sar, or absent; andX31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (III.G).)66324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0077] In one aspect, the invention provides a peptide that is tri -agonist of GLP1R, GIPR, and GCGR, wherein the peptide 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, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, and less than 20 nM in a human GCGR HEK293 cAMP accumulation assay, wherein the peptide has a half-life time of stability greater than 2 hours in both an SGF assay and an SIF assay, and wherein the peptide comprises or consists of a sequence according to Formula (IV):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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 407), wherein:R1 is absent;R2 is NH2 or absent;XI is Tyr;X2 is Aib;X3 is Gin or His;X4 is Gly;X5 is Thr;X6 is aMe Phe or aMe_Phe_2F;X7 is Thr;X8 is Ser;X9 is aMe_Asp or Asp;XI 0 is Phe_34diOMe, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_diacid, Phe_4_ad, Tyr, or Vai;Xl 1 is Aib, aMe_Ser, or Ser;X12 is Cys, Hey, Hhc, or Lys_Ac;X13 is Ache, Aib, or aMe_Leu;X14 is Leu or Phe_4ad;X15 is Asp;X16 is Cys, Dab_Acetyl, Hey, Hhc, Lys_Ac, or Orn_Acetyl;X17 is Glu, Lys, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid, Lys_lPEG2_IsoGlu_Albutag, Lys_lPEG2_IsoGlu_C 16_diacid,67324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_Palm,Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diaicd, Lys_PEG2_Me3, or Lys Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib;X21 is Ala;X22 is aMe_Phe;X23 is He;X24 is dE or Glu;X25 is aMe_Phe or aMe_Tyr;X26 is He, or Leu;X27 is Leu or Vai;X28 is aMe_Glu, aMe_Lys, or Thp;X29 is dR or Gly;X30 is Gly or absent; andX31 is absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (IV).)

[0078] In one aspect of Formula (IV), X10 is Phe_34diOMe, X12 is Cys, X16 is LysAc, X17 is Lys Ac or Lys_lPEG2_lPEG2_IsoGlu_C18_Diacid, X24 is Glu, X28 is aMe Lys, X29 is Gly, and X30 is Gly.

[0079] Representative compounds of Formula (IV) include, but are not limited to, Compounds 103, 105, 107, 109, 110, 140, 157, 159, 207, 213, 214, 217, 222, 224, 227, 235, 239, 241, 242,243, 244, 245, 246, 253, 254, 255, 256, 268, 272, 273, 276, 279, 291, 292, 293, 294, 307, 315,338, 339, 340, 341, 348, 349, 358, 360, 361, 362, 363, 364, 365, 366, 368, 375, 380, 381, 382,383, and 384. (See Figs. 1A-1QQQQQ for the SEQ ID NOs and other structure / function information.)

[0080] In one aspect of Formula (III) or Formula (IV), X12 and X16 are directly covalently linked through a thioether bond. In another aspect of Formula (III), X12 and X16 are directly covalently linked through a carbon-carbon double bond. In another aspect of Formula (III), X12 and X16 are directly covalently linked through a carbon-carbon single bond.68324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0081] In another aspect of Formula (III) or Formula (IV), X12 and X16 are indirectly covalently linked through a thioether bond, wherein X12 and X16 are individually, or both, Cys, Hey, or Hhc, which side-chains are cross-linked via a cyclization linker such as a Propane Linker.

[0082] In another aspect of Formula (III), X12 and X16 are directly covalently linked through a thioether bond, and X23 and X27 are directly covalently linked through a carbon-carbon double bond.

[0083] In one aspect of Formula (III) or Formula (IV), the peptide exhibits a half-life time of stability greater than 24 hours in an SGF assay.

[0084] In another aspect of Formula (III) or Formula (IV), the peptide exhibits a half-life time of stability greater than 24 hours in an SIF assay.

[0085] In another aspect of Formula (IV), R1 is absent, XI is Tyr, X2 is Aib, X3 is Gin, X4 is Gly, X5 is Thr, X6 is aMe_Phe_2F, X7 is Thr, X8 is Ser, X9 is Asp, X10 is Phe_34diOMe, XI 1 is aMe_Ser, X12 is Cys, X13 is aMe_Leu, X14 is Leu, X15 is Asp, X16 is Lys_Ac, X17 is Lys, Lys Ac, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag,Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid, Lys_lPEG2_IsoGlu_AlbuTag,Lys_lPEG2_IsoGlu_C18_Diacid, Lys_lPEG2_IsoGlu_C20_Diacid, orLys_IsoGlu_IsoGlu_C18_Diacid, XI 8 is Ala, XI 9 is Gin, X20 is Aib, X21 is Ala, X22 is aMe Phe, X23 is He, X24 is Glu, X24 is aMe_Phe, X25 is aMe_Tyr, X26 is Leu, X27 is Vai, X28 is aMe_Lys, X29 is Gly, X30 is Gly, and R2 is NH2, and wherein the side-chains of X12 and XI 6 are directly covalently linked through a thioether bond.

[0086] In another aspect of Formula (IV), R1 is absent, XI is Tyr, X2 is Aib, X3 is Gin, X4 is Gly, X5 is Thr, X6 is aMe_Phe, X7 is Thr, X8 is Ser, X9 is Asp, X10 is Phe_34diOMe, Xl 1 is aMe_Ser, X12 is Cys, X13 is aMe_Leu, X14 is Leu, X15 is Asp, X16 is Lys_Ac, X17 is Lys, Lys Ac, Lys_lPEG2_IsoGlu_MeOPheTag, or Lys_IsoGlu_IsoGlu_C18_Diacid, X18 is Ala, XI 9 is Gin, X20 is Aib, X21 is Ala, X22 is aMe_Phe, X23 is He, X24 is Glu, X24 is aMe_Phe, X25 is aMe Phe, X26 is Leu, X27 is Vai, X28 is aMe_Lys, X29 is Gly, X30 is Gly, and R2 is NH2, and wherein the side-chains of X12 and X16 are directly covalently linked through a thioether bond.

[0087] In another aspect, the invention provides a peptide comprising or consisting of a sequence according to any one of SEQ ID NOs: l-8, 10, 12-387.

[0088] In another aspect, the present disclosure provides a peptide compound as described by its SMILES formula as listed in Figs. 1A-1QQQQQ.69324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0089] In another aspect, the invention provides a peptide comprising or consisting of the chemical structure depicted in Figs. 3A, 3B, 3C, 3D, 3E, 3F, 3G, 3H, 31, 3J, 3K, 3L, 3M, 3N, 30, 3P, 3Q, 3R, 3S, 3T, or 3U. In embodiments, the peptide comprises or consists of the chemical structure with extended view depicted in Figs. 3A', 3B', 3C', 3D', 3E', 3F', 3G', 3H', 31', 3J', 3K', 3L', 3M', 3N', 30', 3P', 3Q', 3R', 3S', 3T', or 3U'.

[0090] 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 2 hours is suitable for oral formulation and administration.

[0091] 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 12 hours, 20 hours, or 24 hours is suitable for oral formulation and administration.

[0092] 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.

[0093] 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.

[0094] In other aspects, the invention provides a method for treating obesity or inducing weight loss, the method comprising orally administering 40-60 mg per day of a Formula (IV) peptide, or a pharmaceutically acceptable salt or solvate thereof, to an individual in need of such a treatment.

[0095] In other aspects, the invention provides a method for treating obesity or inducing weight loss, the method comprising subcutaneously administering 15-25 mg per week of a Formula (IV) peptide, or a pharmaceutically acceptable salt or solvate thereof, to an individual in need of such a treatment.

[0096] In other aspects, the invention provides a method for treating T2D, the method comprising orally administering 40-60 mg per day of a Formula (IV) peptide, or a pharmaceutically acceptable salt or solvate thereof, to an individual in need of such a treatment.

[0097] In other aspects, the invention provides a method for treating T2D, the method comprising subcutaneously administering 15-25 mg per week of a Formula (IV) peptide, or a pharmaceutically acceptable salt or solvate thereof, to an individual in need of such a treatment.70324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0098] Additional therapeutic methods include methods for treating a metabolic syndrome including cardiometabolic prevention, NASH (nonalcoholic steatohepatitis), metabolic dysfunction-associated steatohepatitis (MASH), NAFLD (non-alcoholic fatty liver disease), lipodystrophy, short bowel syndrome, intestinal disorders, inflammatory bowel disease, or more generally, any condition or disease where reductions in blood glucose, increase in insulin, reduction in HbAlc, and / or reduction in weight. Further potential methods of treatment include methods for treating: cardiovascular disease such as heart attack and stroke, chronic kidney diseases, polycystic ovary syndrome (PCOS), neurodegenerative disease including Alzheimer’s and Parkinson’s, sleep apnea, addiction (reducing cravings and improving impulse control), appetite (appetite suppression), anxiety, depression, polycystic ovary syndrome, gastrointestinal disorders (e.g., gastroparesis and dyspepsia), and arthritis.BRIEF DESCRIPTION OF THE FIGURES

[0099] Figs. 1 A-1QQQQQ 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, GIPR, and / or GCGR 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.

[0100] Figs. 1A-1QQQQQ 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 Figs. 2A-2G chemical structures were generated by inputting the SMILES code for the peptides (from Figs. 1A-1QQQQQ) into Chemdraw. Conversely, SMILES codes can be generated from a two-dimensional structure in Chemdraw.71324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0101] The first column provides information as to molecular weight (MW) in Daltons.Currently, the specific peptides of Figs. 1A-1QQQQQ 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.

[0102] 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 cross-linked, whether directly or indirectly. Further, the Cyclization Positions can inform whether the first amino acid residue in a string sequence starts at XI, X0, X00, etc., with respect to the Formulas herein. For example, Compound 1 has a sequence of Y-Aib-Q-G-T-F-T-S-D- Y-S-Hcy-aMe_Leu-L-D-Hcy-Lys_Ac-A-Q-Aib-A-F-I-E-Y-L-L-E-G-am (SEQ ID NO: l).The first residue, “Y” or tyrosine is at position XI as Figure 1 states that the Cyclization Positions for SEQ ID NO: 1 are X12Hcy and X16Hcy. 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 besides those formed at pairs selected from X10-X18.

[0103] The column “Additional Information” relates to structural or functional features not otherwise described in Figs. 1A-1QQQQQ.

[0104] 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 +.

[0105] The final column presents potency data, i.e., whether the compound exhibits activating or agonist characteristics for human GLP1R, GIPR, or GCGR biological activity or72324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 function. The column provides EC50 data for the peptide compounds with respect to increasing cAMP accumulation in human HEK293 cells expressing GLP1R, GIPR, or GCGR at the cellsurface. 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. For GCGR EC50, human HEK293 cells expressing about 10,000-13,000 human GCGR at the cell-surface were used. See Examples. The legend for the EC50 data is: GLP1R HD assay, GCGR 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, GCGR 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, GCGR 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, GCGR 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. 1A-1QQQQQ have a potency less than 20 nM in the human GLP1R HD assay or less than 10 micromolar in the human GLP1R LD assay.

[0106] Figs. 2A-2G show results of a mouse Glucose Tolerance Test (GTT), which was used to assess the in vivo glycemic control of the peptides of the invention. See Example 4 regarding Figs. 2A-2D and Example 5 regarding Figs. 2E, 2F, and 2G.

[0107] Fig. 2A shows that Compound 3 administered sc was able to significantly reduce blood glucose levels at all doses. Fig. 2B also shows that Compound 5 administered subcutaneously (sc) was able to significantly reduce blood glucose levels with all doses. Fig. 2C shows that when Compound 5 was administered orally, glycemic control was still significantly improved as compared to control at all doses. Fig. 2D shows results from a dosedown study with orally administered (PO) Compound 5. Glycemic control is still significantly improved at 5 mg / kg and 1 mg / kg PO.

[0108] Figs. 2E and 2F show that Compounds 102 and 103 administered orally (PO) were able to significantly reduce blood glucose levels in a dose-dependent fashion. Fig. 2G also shows that Compound 207 administered orally was also able to significantly reduce blood glucose levels in a dose-dependent fashion. Fig. 2H shows that a Formula (IV) peptide administered orally (PO) or subcutaneously (SC) was able to significantly reduce blood glucose levels when compared to vehicle control and was comparable to subcutaneous injection with retatrutide (Reta). Fig. 21 shows that this same Formula (IV) peptide administered orally or73324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 subcutaneously was able to significantly reduce blood glucose levels when compared to vehicle control and was comparable to subcutaneous injection with retatrutide when the GTT test was conducted using diet-induced obese (DIO) mice.

[0109] Figs. 3A-3U show the two-dimensional chemical structures of the peptide sequences listed in Figs. 1A-1QQQQQ. Figs. 3A'-3U' show extended views of the chemical structures of the peptide sequences listed in Figs. 1A-1QQQQQ. Figs. 3A-3H and 3A -3H' show the structures and their extended views for peptide compounds 1-8, respectively. Figs. 31 and 3F provide the structure and its extended view for peptide compound 102; Figs. 3 J and 3 J' provide the structure and its extended view for peptide compound 103; Figs. 3K and 3K' provide the structure and its extended view for peptide compound 108; Figs. 3L and 3L' provide the structure and its extended view for peptide compound 109; Figs. 3M and 3M' provide the structure and its extended view for peptide compound 110; Figs. 3N and 3N' provide the structure and its extended view for peptide compound 153; Figs. 30 and 30' provide the structure and its extended view for peptide compound 179; Figs. 3P and 3P' provide the structure and its extended view for peptide compound 207; Figs. 3Q and 3Q' provide the structure and its extended view for peptide compound 239; Figs. 3R and 3R' provide the structure and its extended view for peptide compound 317; Figs. 3S and 3S' provide the structure and its extended view for peptide compound 381; Figs. 3T and 3T' provide the structure and its extended view for peptide compound 362, and Figs. 3U and 3U' provide the structure and its extended view for peptide compound 384.

[0110] Figs. 4A-4F provide pcDNA3.1 expression plasmid maps and coding sequences for human GLP1R (Figs. 4A and 4B, respectively), GIPR (Figs. 4C and 4D, respectively), and GCGR (Figs. 4E and 4F, respectively) used in the HEK293 cAMP accumulation assays described herein.DETAILED DESCRIPTION OF THE INVENTION

[0111] In general, the present disclosure relates to synthetic or recombinant peptides exhibiting GLP1R, GIPR, and / or GCGR agonist activities and methods of using the same. In some embodiments, the peptides disclosed herein have a cyclic structure, such as a direct or indirect (via a cyclization linker) intramolecular cross-link between the side chains of two residues of the peptide. Peptide cyclic ring structures are formed (usually between free74324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 chemical moieties in amino acid side-chains) either by direct covalent linkage between two peptide residues or by indirect covalent linkage between two peptide residues, wherein each residue makes a direct covalent linkage with a linker, often at the terminal ends of the linker. Cyclization structures are described for peptide compounds, most of which are between 30-40 residues, wherein the side chains of two residues selected from XI 0 through XI 8 are directly or indirectly covalently linked. In other embodiments, the peptides disclosed herein have a non- cyclic or linear structure. When a linker is used to mediate cyclization, it is referred to as a cyclization linker. The invention provides a set of compounds that are at least potent agonists of both GLP1R and GIPR, which is exhibited by their nanomolar or sub-nanomolar potency in cAMP functional assays. Some compound are tri-agonists of GLP1R, GIPR, and GCGR. 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

[0112] The present disclosure provides peptide compounds that are dual agonists of human GIPR and GLP1R or tri-agonists of human GLP1R, GIPR, and GCGR. 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.

[0113] 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.

[0114] 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.

[0115] As used herein, the following terms have the meanings ascribed to them in the art unless specified otherwise.

[0116] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer (or75324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 components) or group of integers (or components), but not the exclusion of any other integer (or components) or group of integers (or components).

[0117] The singular forms “a,” “an,” and “the” include the plurals unless the context clearly dictates otherwise.

[0118] The term “including” is used to mean “including but not limited to.” “Including” and “including but not limited to” are used interchangeably.

[0119] 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 any mammalian species such as a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit, livestock, and the like.

[0120] 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.

[0121] “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.

[0122] 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., the76324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 window size), and multiplying the result by 100 to yield the percentage of sequence identity.

[0123] 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 first and 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.

[0124] 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.

[0125] 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 4.77324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0126] 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 related sequences. 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.

[0127] 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.78324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0128] 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: aromatic.

[0129] The term “amino acid” or “any amino acid” as used here refers to any and all amino acids, including naturally occurring amino acids (e.g., a-amino acids), unnatural amino acids, 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 and other eukaryotes), selenocysteine (present in many non¬79324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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.

[0130] 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 side-chain). 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.

[0131] 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.80324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] 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, acetic81324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 acid or lactic acid. When the solvent in question is water, such a solvate is normally referred to as a hydrate.

[0138] 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, / / -propyl, n- butyl, / / -pentyl, / / -hexyl, and the like, while saturated branched alkyls include, without limitation, isopropyl, ec-butyl, isobutyl, te / 7-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.

[0139] 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.

[0140] 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, n- propyl, / / -butyl, / / -pentyl, / / -hexyl, and the like, while saturated branched alkyls include, without limitation, isopropyl, ec-butyl, isobutyl, tert-butyl, isopentyl, and the like.

[0141] 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.

[0142] 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.

[0143] The term “alkenyl” alone or in combination with other terms, means a straightchain 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. Example82324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 alkenyl groups include, but are not limited to, ethenyl, / / -propenyl, isopropenyl, / / -butenyl, sec- butenyl, 5-pentenyl, 8-octenyl, and the like.

[0144] The term “alkenylene” means a straight or branched bivalent hydrocarbon chain containing at least one carbon-carbon double bond. Representative alkenylene include - CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, -CH2CH=CHCH2-, and the like

[0145] 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.

[0146] The term “halo” or “halogen” refers to atoms occupying group VIIA of the periodic table, such as fluoro, chloro, bromo or iodo.

[0147] 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 moieties 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.

[0148] 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.

[0149] “Benzyl” means a phenyl-CH2- group. Representative benzyl include 4- bromobenzyl, 4-methoxybenzyl, 4-aminobenzyl, and the like.

[0150] “Carbamoyl” means a group of formula R’TVNCO- wherein Rxand Ryare independently hydrogen or alkyl. Representative carbamoyl groups include carbamoyl (H2NCO-), methylcarbamoyl (MeNHCO-), and the like.

[0151] Thiol”, “mercapto” or “sulfanyl” means an -SH group.83324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0152] 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.

[0153] 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.

[0154] 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.

[0155] The term “carboxy,” as used herein, refers to -CO2H.

[0156] 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- or four-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), 8Ado (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.

[0157] 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 moieties 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.84324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Peptide Formulas of the invention refer to N-terminal moieties as an “Rl” (or Ri) group and C-terminal moieties as an “R2” (or R2) group.

[0158] 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 that has been cyclized or “cross-linked” (an intramolecular cross-link) by covalently bonding two amino acids together, whether directly or indirectly through a cyclization linker.

[0159] 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.

[0160] “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.

[0161] “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.

[0162] 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 in85324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0163] 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 quaternized 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 NX (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.), Informa Healthcare USA (Inc.), NY, USA, 2007, and in J. Pharm. Sci. 66: 2 (1977). Also, for a review on suitable salts, see Handbook of Pharmaceutical86324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Salts: Properties, Selection, and Use 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.

[0164] 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,17O,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.

[0165] 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 ( / ?)- 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 (S)-, 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 is87324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 understood that the aspect encompasses, but is not limited to, the specific diastereotnericaliy 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.

[0166] 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).

[0167] 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.

[0168] “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, an effective 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 co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0169] 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 of88324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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.

[0170] 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 one or 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.

[0171] 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 chemically89324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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 moieties include polyethylene glycols (PEG), homo- or co-polymers of PEG, a monomethylsubstituted 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 halflife 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.

[0172] 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.

[0173] 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 400.90324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0174] 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.

[0175] 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.

[0176] 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.

[0177] Table 1. Abbreviations of Non-Natural Amino Acids and ChemicalMoieties91324222975Attorney Docket No.: PRTH-100 / 12WO 321085-308892324222975Attorney Docket No.: PRTH-100 / 12WO 321085-308893324222975Attorney Docket No.: PRTH-100 / 12WO 321085-308894324222975Attorney Docket No.: PRTH-100 / 12WO 321085-308895324222975Attorney Docket No.: PRTH-100 / 12WO 321085-308896324222975Attorney Docket No.: PRTH-100 / 12WO 321085-308897324222975Attorney Docket No.: PRTH-100 / 12WO 321085-308898324222975Attorney Docket No.: PRTH-100 / 12WO 321085-308899324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088100324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088101324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088102324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088103324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088104324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088105324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088106324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088107324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088108324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088109324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088110324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088111324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088112324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088113324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088114324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088115324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088116324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088117324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088118324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088119324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088120324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088121324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088122324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088123324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088124324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088125324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088126324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088127324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088128324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088129324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088130324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088131324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088132324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088133324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088134324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088135324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088136324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088137324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088138324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088139324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088140324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088141324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088142324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088143324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088144324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088145324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088146324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088147324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088148324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088149324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088150324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0178] Peptide Structures

[0179] The peptide compounds of the invention are synthetic or recombinant peptide- based compounds that bind to and agonize / activate human GLP1R, human GIPR, and / or human GCGR. 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, GIPR, or GCGR. 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. In some embodiments, the peptide compounds have a cyclic (an intramolecular cross-link between at least two positions of the peptide) or linear structure. As explained hereinbelow, the peptide compounds of the invention can be categorized into various groupings based on one or more structural or functional features.

[0180] 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 29-43 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 of the 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.

[0181] 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 are151324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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-1QQQQQ 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).

[0182] 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.

[0183] 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.

[0184] In some embodiments, the invention provides peptides comprising an amino acid sequence according to Formula (I):RkXl-X -XS-Xd-XS-Xe-X -XS-X -XlO-Xl l-Xl -XlS-XM-XlS-Xie-Xn-XlS-Xl -X20-X21 -X22-X23 -X24-X25 -X26-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37-X38-X39 X40-X41-X42-X43-X44-R2, wherein:R1is Ra-C(O)- or hydrogen, wherein Ra is Cl -20 alkyl or C3-8 cycloalkyl; or Rl is acetyl, isovaleric acid, cyclohexanecarboxylic acid, glutaric acid, or absent;R2is NH2 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib, Ala, aMe_Ser, dA, dS, Gin, or Ser;X3 is Aoc, Gin, Glu, Gly, His, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is aMe_Asp, aMe_Glu, Asp or Tyr;152324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 0 is 4Pal, Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_34diOMe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_Diacid, Phe_4_Me, Phe_4_Morph, Phe_4_OMe, Ser, Tyr, or Vai;XI 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Om Acetyl, Pen, Pro, Ser, Thr, Tyr;X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Gin, Glu, Hey, Hhc, He, Lys, Lys Ac, LysPhAc, O2S, O2S_Me, 03 S, 03S_Me, 04S, 04S_Me, 02S_Reduced, 03S_Reduced, 04S_Reduced, 02S_Me_Reduced, 03 S Me Reduced, 04S_Me_Reduced, Om Acetyl or Pen;XI 3 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Arg, Chg, Cys, Dab_Acetyl, dC, Gin, Glu, Hey, Hhc, lie, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, nL, Om Acetyl, Pen, Ser, Trp, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Ogl, Om Acetyl, Pen, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, Om Acetyl or Pen;XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys_Ac, LysPhAc, 02S, 02S_Me, 03 S, 03S_Me, 04S, 04S_Me, 02S_Reduced, 03S_Reduced, 04S_Reduced, 02S_Me_Reduced, 03 S Me Reduced, 04S_Me_Reduced, Om, Om Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety,Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Albutag, Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_lPEG2_C 19_Phosphonic_Acid, Lys_lPEG2_lPEG2_IsoGlu_C20_diacid,Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid, Lys_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_C 18_diacidLys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_C20_diacid,153324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_Palm, Lys Ac, Lys AlbuTag,Lys_dIsoLys_lPEG2_ C 18_diacid, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid,Ly s_IsoGlu_IsoGlu_C 18_Diacid, Ly s_IsoGlu_IsoGlu_C20_Diacid, Ly s_Me3 ,Lys_PEG2_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid,Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Orn Acetyl or Pen;XI 8 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys_Ac, LysPhAc, Orn Acetyl or Pen;XI 9 is Aib, Ala, or Gin;X20 is Aib, aMe_4Pal, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys,Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid,Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac,Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;Ly s Thz dlsoLy s_lPEG2_IsoGlu_C 18_Diacid; ;X21 is Aib, Ala, Asp, Gin, Glu, Ogl, Om, or Phe;X22 is aMe_Phe, He, or Phe;X23 is aMe_Ile, Cys, Glu, He, 03 S, or Vai;X24 is Ala, Asn, Cys, dE, dK, Gin, Glu, Hey, Hhc, Lys_Ac, or Tyr;X25 is Ala, aMe_Lys, aMe_Phe, aMe_Tyr, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Phe_34diOMe, Trp, or Tyr;X26 is aMe_Leu, Cys, He, Leu, NMe_Leu, Tie, or Vai;X27 is Ache, Aib, aMe_Leu, Cha, dL, Gin, Glu, Gly, His, He, Leu, Lys, NMe_Leu, 03 S, Ogl, Orn, Sar, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, bhE,Cys, dE, Gin, Gly, Glu, Glu OMe, Hey, hE, Hhc, IsoGlu, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is Ala, dA, dK, dR, Gly, Sar, or absent;X30 is Ala, Arg, dR, Gly, Pro, Sar, or absent;X31 is Cys, Pro, Sar, Ser, or absent;X32 is Gly, Pro, Ser, or absent;X33 is Arg, Cys, Gly, Ser or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Glu, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;154324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X37 is Leu, Pro or absent;X38 is Pro, Ser, Vai, or absent;X39 is Glu, Lys, Ser, Thr, or absent;X40 is Arg, Gly, Lys_Palm, or absent;X41 is Gin, Thr, or absent;X42 is Arg, Glu, or absent;X43 is Glu, Tyr, or absent; andX44 is Glu or absent; wherein the peptide optionally comprises a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently linked through a cyclization linker, and / or a cyclic structure wherein X23 and X27 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (I).)

[0185] In one embodiment of Formula (I), X17 is Ala, aMe lle, aMe Lys, aMe Lys Ac, Arg, dK, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety, Lys_lPEG2_lPEG2_Ahx_C18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Albutag, Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_lPEG2_C 19_Phosphonic_Acid;Lys_lPEG2_lPEG2_IsoGlu_C20_diacid,Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid; Lys_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_Palm, Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_Palm, Lys Ac, Lys AlbuTag, Lys_dIsoLys_lPEG2_ C18_diacid, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid, Lys_IsoGlu_IsoGlu_C20_Diacid, Lys_Me3, Lys_PEG2_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid.

[0186] In another embodiment of Formula (I), XI 7 is a Lys with a side-chain comprising a half-life extension moiety. In a related embodiment, X17 is a Lys with a sidechain comprising a half-life extension linker moiety and a half-life extension moiety.

[0187] In another embodiment of Formula (I), XI 7 is a lysine with a side-chain comprising: (1) a linker element, and (2) fatty acid element, which are covalently attached to each other. The linker element and the fatty acid can be in either order with respect to the155324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 attachment of the side-chain to the alpha-carbon of the lysine. The linker element can comprise, for example, one or more of a PEG moiety, Ahx, IsoGlu, Sar, Thz, and dlsoLys, including multiple copies of the same moiety. In some embodiments, the PEG moiety is 1PEG2 or 1PEG2 1PEG2. The fatty acid element can comprise, for example, a Cl 0-20 diacid, Palm, AlbuTag, or MeOPheTag. In another embodiment, X17 is a lysine with a side-chain comprising a fatty acid element without a linker element.

[0188] In another embodiment of Formula (I), X30-X44 or X31-X44 are absent.

[0189] In another embodiment of Formula (I), R2 is amine.

[0190] In another embodiment of Formula (I), R1 is absent.

[0191] In other embodiments of Formula (I), the residue options for X10-X18 includes, but are not limited to:• If a residue in X10-X18, X23, or X27, is not part of an intramolecular cross-link (i.e., directly or indirectly covalently linked with another residue at X10-X18, X23, or X27), then: o If X10 is not part of an intramolecular cross-link, then XI 0 is 4Pal, Ache, Aib, aMe Leu, aMe Phe, aMe Ser, Bip, Bip_2pEt4pOMe, Chg, Leu, Lys IsoGlu Palm, Phe, Phe_34diOMe, Phe_4COOH, Phe_4ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_Me, Phe_4_Morph, Phe_4_OMe, Tyr, Ser, or Vai; o If Xl 1 is not part of an intramolecular cross-link, then Xl 1 is Ache, Aib, Ala, aMe_Ser, Asp, Chg, Gly, HhPhe_35Me, Hyp, He, NMe_Ser, Pro, Ser, Thr, Tyr; o If X12 is not part of an intramolecular cross-link, then X12 is aMe Leu, Cys, Glu, He, Lys, or Lys Ac; o If X13 is not part of an intramolecular cross-link, then X13 is Ache, Aib, aMe Leu, aMe Phe, Arg, Chg, Gin, Glu, lie, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys Ac, nL, Ser, Trp, or Tyr; o If X14 is not part of an intramolecular cross-link, then X14 is Asp, Ogl, Leu, Phe_4ad, Phe_4_2ae, Tba, or Tyr; o If X15 is not part of an intramolecular cross-link, then X15 is Asp, Glu, or Lys; o If X16 is not part of an intramolecular cross-link, then X16 is Arg, Cys, Glu, Lys, Lys_Ac, Orn, or Ser; o If X17 is not part of an intramolecular cross-link, then X17 is Ala, aMe lle, aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, a Lys with a side-chain156324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 comprising a half-life extension moiety, Lys, Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Albutag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_lPEG2_C 19_Phosphonic_Acid, Lys_lPEG2_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_AlbuTab, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_Palm, Lys Ac, Ly s AlbuT ag, Ly s dlsoLy s_ 1 PEG2 C 18_di aci d, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid, Lys_IsoGlu_IsoGlu_C20_Diacid, Lys_Me3, Lys_PEG2_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid; o If XI 8 is not part of an intramolecular cross-link, then XI 8 is Aib, Ala, or Arg o If X23 is not part of an intramolecular cross-link, then X23 is aMe_Ile, Cys, Glu, He, or Vai; and o If X27 is not part of an intramolecular cross-link, then X27 is Ache, Aib, aMe Leu, Cha, dL, Gin, Glu, Gly, His, He, Leu, Lys, NMe Leu, Ogl, Om, Sar, Tba, Tie, or Vai.

[0192] In another embodiment of Formula (I), a peptide comprises two cross-linked amino acid residues selected from X10-X18, wherein if the two residues are cross-linked / cyclized, the two residues are: aMe_Cys, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Hhc, Hey, Lys Ac, LysPhAc, O2S, 03 S, O3S_Me, O4S, O3S_Reduced, 03 S Me Reduced, O3S_Reduced, Om Acetyl, or Pen.

[0193] In one embodiment of Formula (I), two residues of X10-X18 are directly crosslinked via a disulfide bond. In this case, the two cross-linked residues both have 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, Hhc, Pen, HhPen, and their alpha-methyl forms.

[0194] In another embodiment of Formula (I), two residues of X10-X18 are directly cross-linked via a thioether bond. In this case, the two cross-linked residues are one residue157324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 with a side chain comprising a free / reactive thiol group and the other residue with a side chain comprising a free / reactive alkyl group, such that the thiol and alkyl groups can form a thioether bond. As stated, residues that have a side chain with a free thiol group include, but are not limited to, Cys, dC, Hey, Hhc, Pen, and HhPen. Residues that have a side chain a free alkyl group include, but are not limited to, aMe Lys Ac, Dab Acetyl, Lys Ac, LysPhAc, and Orn Acetyl (e.g., these residues have a side chain comprising an acetyl group (Ac), which itself comprises a free alkyl group).

[0195] In another embodiment of Formula (I), two residues of X10-X18 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, a Trimethylbenzene 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, Hhc, Pen, and HhPen, and their alpha-methyl forms.

[0196] In another embodiment of Formula (I), X12 and X16 are directly cross-linked through a carbon-carbon double bond, and wherein X12 and X16 are individually or both O2S, O2S_Me, 03 S, O3S_Me, O4S, or O4S_Me.In another aspect of Formula (I), X12 and X16 are directly cross-linked through a carboncarbon single bond, and wherein X12 and X16 are individually or both O2S_Reduced, O2S_Me_Reduced, O3S_Reduced, 03 S Me Reduced, O4S_Reduced, or O4S_Me_Reduced.

[0197] In one embodiment of Formula (I), the cyclized residues are X12 and X16, wherein X12 and X16 are individually or both Hey or Hhc, wherein the two residues are directly cross-linked via a disulfide bond.

[0198] In another embodiment of Formula (I), the cyclized residues are X12 and X16, wherein X12 and X16 are individually or both Cys, Hey, Hhc, Pen, or HhPen, and wherein the two residues are indirectly cross-linked via a cyclization linker such that the side chain of X12 forms a thioether bond with one end (or part) of the cyclization linker and the side chain of XI 6 forms a thioether bond with the other end (or different part) of the cyclization linker.

[0199] In various embodiments of Formula (I), the side chains of X12 and X16 are directly or indirectly covalently linked.158324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0200] In another embodiment of Formula (I), the side-chains of X12 and X16 are directly covalently linked through a thioether bond, and the side chains of X23 and X27 are directly covalently linked through a carbon-carbon double bond.

[0201] In another embodiment, besides cyclization between two residues of X10-X18, a peptide can be cyclized by covalently linking, i.e., “cross-linking,” any two positions of a peptide monomer (i.e., Ri, XI through X44, 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.

[0202] 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.

[0203] 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 (a lactam when the amide bond forms a cyclic structure, i.e., a cyclic amide; as opposed to amide bond based dimerization of peptide monomers, where the amide bond is not part of a linkage forming a cyclic structure); 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.

[0204] In addition to Figs. 1A-1QQQQQ, 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 (vice-versa). Figs. 3A-3U and 3A'-3U' provide two-dimensional depictions and their extended views of several compounds of the invention, and these chemical structures show some of the main types159324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 of cyclization chemistry used herein. In addition, representative cross-links of cyclized peptides are shown below:

[0205] Representative cross-linked structures are shown below:160324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0206] In other embodiments, the peptide is cyclized by covalently linking two pairs of any two residues in the monomer, or any of three of the residues, directly or indirectly through a cyclization linker to form a bicyclic peptide (e.g., X12 and X16, and X23 and X27).

[0207] In one embodiment, for any one of the peptides comprising a sequence of SEQ ID NO: 1-8, 10, 12-387, any of the amino acids, natural or unnatural, can be substituted with its corresponding D-amino acid, or vice versa. Up to all, 30, 25, 20, 15, 14, 13, 12, 11, 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.

[0208] In another embodiment, for any one of the peptides comprising a sequence of SEQ ID NO: 1-8, 10, 12-387, 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 alpha-methyl or N- methyl variant of the amino acid.

[0209] In another embodiment, for any one of the peptides comprising a sequence of SEQ ID NO: 1-8, 10, 12-387, 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).

[0210] In one aspect, any one of the peptides of the invention may be in the form of a pharmaceutically acceptable salt or solvate.

[0211] 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 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.

[0212] In one aspect, a PEG linker comprises -(OCH2CH2)n-, wherein n is between 5 and 25.

[0213] 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,161324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088PEG13DA, 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.

[0214] Potency and Stability

[0215] The peptide compounds of the invention can exhibit nanomolar or sub- nanomolar potency in agonizing or activating at least both human GLP1R and human GIPR, and in most instances, all three of human GLP1R, human GIPR, and human GCGR. As stated, potency is reflected by the nanomolar and subnanomolar EC50 values for the peptides in activating, inducing, stimulating, and / or increasing cAMP accumulation in the HEK 293 cells that stably express one of these receptors. The peptide compounds may also exhibit stability in simulated gastrointestinal environments, i.e., the SGF and SIF assays. In some embodiments, peptides are considered sufficiently stable for oral administration / formulation if the peptides have a half-life time greater than 2 hours in an SGF assay or in an SIF assay. In other embodiments, peptides are considered sufficiently stable for oral administration / formulation if the peptides have a half-life time greater than 2 hours in both an SGF and an SIF assay. In some embodiments, peptides are considered sufficiently stable for oral administration / formulation if the peptides have a half-life time greater than 12 hours, 18 hours, 20 hours, or 24 hours in an SGF assay or an SIF assay. In other embodiments, peptides are considered sufficiently stable for oral administration / formulation if the peptides have a half-life time greater than 12 hours, 18 hours, 20 hours, or 24 hours in both an SGF and an SIF assay. Representative peptide compounds with these potency and stability characteristics are provided in Figs. 1 A-1QQQQQ.

[0216] In some embodiments, the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1 A-1QQQQQ peptides with +, ++, +++, or ++++), less than 1 nM (++, +++, ++++), less than 0.100 nM (+++ or ++++), or less than 0.010 nM (++++) 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).

[0217] In embodiments 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). EC50 can also be referred to as IC50, although EC50162324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 is the more appropriate term as the peptides of the invention are dual or tri-agonists of hGLPIR, hGIPR, and hGCGR.

[0218] In some embodiments, the peptide has an EC50 potency less than 10 micromolar (e.g., see Figs. 1 A-1QQQQQ peptides with +, ++, +++, or ++++), less than 1 micromolar (++, +++, ++++), less than 100 nM (e.g., +++ or ++++), or less than 10 nM (e.g., see Figs. 1A- 1QQQQQ 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 (LD) cell surface receptor expression of human GLP1R is about less than 2,000 receptors / cell.

[0219] In Figs. 1A-1QQQQQ, 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.

[0220] In some embodiments, the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1 A-lQQQQQpeptides with +, ++, +++, or ++++), less than 1 nM (++, +++, ++++), less than 0.100 nM (e.g., see Figs. 1A-1QQQQQ peptides with +++ or ++++), or less than 0.010 nM (e.g., see Figs. 1 A- 1QQQQQ peptides with ++++) in a human GIPRHEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant human GIPR on their cell surface at a density between about 45,000-55,000 receptors / cell.

[0221] In some embodiments, the peptide has an EC50 potency less than 20 nM (e.g., see Figs. 1A-1QQQQQ peptides with +, ++, +++, or ++++), less than 1 nM (e.g., ++, +++, ++++), less than 0.100 nM (e.g., +++ or ++++), or less than 0.010 nM (e.g., ++++) in a human GCGR HEK293 cAMP accumulation assay, wherein the human HEK293 cells express recombinant human GCGR on their cell surface at a density between about 10,000-13,000 receptors / cell.

[0222] In some embodiments, the peptide has an EC50 potency less than 20 nM, less than 1 nM, less than 0.100 nM, or less than 0.010 nM in a human HD GLP1R HEK293 cAMP accumulation assay, a human GIPR HEK293 cAMP accumulation assay, and in human GCGR HEK293 cAMP accumulation assay.

[0223] In some embodiments, the peptide has an EC50 potency less than 20 nM, less than 1 nM, less than 0.100 nM, or less than 0.010 nM in a human GIPR HEK293 cAMP accumulation assay and in human GCGR HEK293 cAMP accumulation assay, and an EC50 potency less than 10 micromolar, 1 micromolar, 100 nanomolar, or 10 nanomolar in a human LD GLP1R HEK293 cAMP accumulation assay.163324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0224] In one embodiment, the invention provides a peptide that is a dual agonist of GLP1R and GIPR or a tri-agonist of GLP1R, GIPR, and GCGR, wherein the peptide comprises or consists of a sequence according to Formula (II):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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 391), 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 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib or aMe_Ser;X3 is Aoc, Glu, Gin, His, or Tetl;X4 is Gly;X5 is Ser or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Thr;X8 is Ser;X9 is Asp, aMe_Asp, or aMe_Glu;XI 0 is 4Pal, Ache, aMe Leu, Bip, Chg, Leu, Phe, Phe_34diOMe, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_diacid, Phe_4ad, Phe_4CF3, Phe_4COOH, Phe_4Me, Phe_4_Morph, Phe_4_OMe, Phe_4tBu, Tyr, or Vai;Xl 1 is Aib, Ala, aMe_Ser, or Ser;X12 is Cys, Dab Acetyl, Glu, Hey, Hhc, Lys, Lys Ac, 03 S, O3S_Me, or O3S_Reduced;XI 3 is Ache, Aib, aMe Leu, aMe Phe, Arg, Chg, Gin, Glu, He, Leu, nL, Ser, Trp, or Tyr;X14 is Leu, Ogl, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is Asp;X16 is X12 is Cys, Dab_Acetyl, Hey, Hhc, Lys, Lys_Ac, O3S, O3S_Me, O3S_Reduced, O4S, or Orn Acetyl;XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys,Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_Dap_C 18_diacid, , Lys_lPEG2_lPEG2_IsoGlu_AlbuTag,Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid,Lys_lPEG2_lPEG2_IsoGlu_C 19_Phosphonic_Acid,Lys_lPEG_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm,164324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid; Lys_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_C18_diacid, , Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_Palm, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid, Lys_IsoGlu_IsoGlu_C20_Diacid, Lys_Me3, Lys_PEG2_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, Lys Ac, or Lys AlbuTag;XI 8 is Aib or Ala;XI 9 is Gin;X20 is Aib, aMe_4Pal, aMe_Lys, aMe_Lys_Ac, Lys, Lys_Ac,Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag,Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_diacid; ;X21 is Aib, Ala, Glu, Ogl, or Orn;X22 is aMe_Phe or Phe;X23 is He, 03 S, or Vai;X24 is dE, dK, Gin, or Glu;X25 is aMe_Phe, aMe_Tyr, Phe_34diOMe, Trp, or Tyr;X26 is aMe Leu, He, or Leu;X27 is Ache, Aib, aMe Leu, Cha, dL, Gin, His, lie, Leu, Lys, 03 S, Ogl, Orn, Tba, Tie, or Vai; X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, bhE, dE, Gin, Glu, Glu OMe, hE, IsoGlu, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is dA, dK, dR, Gly, Sar, or absent;X30 is Arg, dR, Gly, Sar, or absent; andX31 is Pro or absent. wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (II).)

[0225] In one embodiment of Formula (II), X12 and X16 are directly cross-linked through a disulfide bond, and wherein X12 and X16 are individually, or both, Hey or Hhc.

[0226] In another embodiment of Formula (II), X12 and X16 are directly cross-linked through a lactam, wherein X12 is Glu and X16 is Lys.165324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0227] In another embodiment of Formula (II), X12 is Cys, Hey, or Hhc and X16 is Dab Ac, Lys Ac, or Orn Acetyl, and X12 and X16 are directly cross-linked through a thioether bond.

[0228] In another embodiment of Formula (II), X12 is Dab Ac or Lys Ac, and X16 is Cys, Hey, or Hhc, and X12 and X16 are directly cross-linked through a thioether bond.

[0229] In another embodiment of Formula (II), X12 and X16 are indirectly cross-linked through a thioether bond with a cyclization linker, wherein X12 and X16 are individually, or both Cys, Hey, or Hhc, and wherein the cyclization linker is a Butane Linker, a Carbonyl Linker, a Dimethylcyclopropane Linker, an Ebutene Linker, a Hexane Linker, an Oxetane Linker a Pentane Linker, a Propane Linker, a Trimethylbenzene Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker.

[0230] In another embodiment of Formula (II), X12 and X16 are indirectly cross-linked through a thioether bond with a cyclization linker, wherein X12 and X16 are both Cys, and wherein the cyclization linker is a Butane Linker or a Propane Linker.

[0231] In another aspect of Formula (II), X12 and X16 are directly cross-linked through a carbon-carbon double bond, wherein X12 and X16 are individually, or both, O3S, O3S_Me, or O4S. In another aspect of Formula (II), X12 and X16 are directly cross-linked through a carbon-carbon single bond, wherein both X12 and X16 are O3S_Reduced.

[0232] In another aspect of Formula (II), in addition to the intramolecular cross-link between the side-chains of X12 and X16, the peptide further comprises an intramolecular crosslink between X23 and X27, wherein the cross-link comprises a carbon-carbon double bond when X23 and X27 are individually, or both, 03 S or O3S_Me.

[0233] In another embodiment of Formula (II), the peptide 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, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay.

[0234] In another embodiment of Formula (II), 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, and less than 0.10 nM in a human GIPR HEK293 cAMP accumulation assay.

[0235] In another embodiment of Formula (II), the peptide 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 GLP1RHEK293 cAMP accumulation assay, less than 0.100 nM in a human166324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088GIPR HEK293 cAMP accumulation assay, and an EC50 potency less than 20 nM in a human GCGR HEK293 cAMP accumulation assay.

[0236] In another embodiment of Formula (II), 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.

[0237] In one embodiment, the invention provides a peptide that is at least a dual agonist of GLP1R and GIPR, wherein the peptide has an EC50 potency less than 0.100 nM, in a human GLP1R HD HEK293 cAMP accumulation assay or less than 10 nM in a human GLP1R LD HEK293 cAMP accumulation assay, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, wherein the peptide has a half-life time of stability greater than 2 hours in both an SGF assay and an SIF assay, and wherein the peptide comprises or consist of a sequence according to Formula (III):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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 399), wherein:R1 is absent;R2 is NH2 or absent;XI is Tyr;X2 is Aib;X3 is Gin, Glu, or His;X4 is Gly;X5 is Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Thr;X8 is Ser;X9 is aMe_Asp, aMe_Glu, or Asp;XI 0 is 4Pal, Ache, aMe Leu, Chg, Leu, Phe_34diOMe, Phe_4_2ae, Phe_4_ad, Phe_4_Morph, Phe_4OMe, Tyr, or Vai;Xl 1 is Aib, aMe_Ser, or Ser;X12 is Cys, Hey, Hhc, Lys Ac, 03 S, or O3S_Reduced;X13 is Ache, Aib, aMe_Leu, or aMe_Phe;X14 is Leu, Ogl, Phe_4_2ae, Phe_4_ad, or Tyr;X15 is Asp;XI 6 is Cys, Dab Acetyl, Hey, Hhc, Lys Ac, 03 S, O3S_Reduced, O4S, or Orn Acetyl;167324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys, Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid, Lys_lPEG2_IsoGlu_Albutag, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_Palm, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys_IsoGlu_IsoGlu_C20_Diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid,or Lys Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib, aMe_4Pal, aMe_Lys, aMe_Lys_Ac, or Lys_Ac;X21 is Aib, Ala, or Glu, Ogl, or Orn;X22 is aMe_Phe or Phe;X23 is He, 03 S, or Vai;X24 is dE, dK, Gin, or Glu;X25 is aMe_Phe, aMe_Tyr, Trp, or Tyr;X26 is aMe Leu, lie, or Leu;X27 is Ache, aMe Leu, Cha, dL, His, lie, Leu, Lys, 03 S, Om, Tba, Tie, or Vai;X28 is Aib, Ala, aMe Glu, aMe Lys, bhE, dE, Gin, Glu, Glu OMe, hE, Lys Ac, Thp, or Thr;X29 is dA, dR, Gly, Sar, or absent;X30 is Arg, dR, Gly, Sar, or absent; and;X31 is Pro or absent. wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (III).)

[0238] In one embodiment of Formula (III), X12 and X16 are directly covalently linked through a thioether bond, i.e., the side-chain of Cys, Hey, or Hhc at X12 or X16 is cross-linked with the side-chain of Lys Ac or Dab Ac at X12 or X16. In another embodiment, X12 and X16 are directly covalently linked through a carbon-carbon double bond, wherein X12 is O3S and X16 is O3S or O4S. In another embodiment, X12 and X16 are directly covalently linked through a carbon-carbon single bond, wherein X12 is O3S_Reduced and XI 6 is O3S_Reduced.168324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0239] In another embodiment of Formula (III), X12 and X16 are indirectly covalently linked through a thioether bond, wherein X12 and X16 are individually, or both, Cys, Hey, or Hhc, which side-chains are cross-linked via a cyclization linker such as a Propane Linker.

[0240] In another embodiment of Formula (III), X12 and X16 are directly covalently linked through a thioether bond, and X23 and X27 are directly covalently linked through a carbon-carbon double bond.

[0241] In one embodiment of Formula (III), the peptide exhibits a half-life time of stability greater than 24 hours in an SGF assay.

[0242] In another embodiment of Formula (III), the peptide exhibits a half-life time of stability greater than 24 hours in an SIF assay.

[0243] In one aspect, the invention provides a peptide that is tri-agonist of GLP1R, GIPR, and GCGR, wherein the peptide 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, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, and less than 20 nM in a human GCGR HEK293 cAMP accumulation assay, wherein the peptide has a half-life time of stability greater than 2 hours in both an SGF assay and an SIF assay, and wherein the peptide comprises or consist of a sequence according to Formula (IV):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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 407), wherein:R1 is absent;R2 is NH2 or absent;XI is Tyr;X2 is Aib;X3 is Gin or His;X4 is Gly;X5 is Thr;X6 is aMe Phe or aMe_Phe_2F;X7 is Thr;X8 is Ser;X9 is aMe_Asp or Asp;XI 0 is Phe_34diOMe, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_diacid, Phe_4_ad, Tyr, or Vai;169324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 1 is Aib, aMe_Ser, or Ser;X12 is Cys, Hey, Hhc, or Lys_Ac;XI 3 is Ache, Aib, or aMe_Leu;XI 4 is Leu or Phe_4ad;XI 5 is Asp;XI 6 is Cys, Dab_Acetyl, Hey, Hhc, Lys_Ac, or Orn_Acetyl;XI 7 is Glu, Lys, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_LPEG2_IsoGlu_Palm, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid, Lys_lPEG2_IsoGlu_Albutag, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_C 18_diacid, Lys_LPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_Palm, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid, Lys_PEG2_Me3, or Lys Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib;X21 is Ala;X22 is aMe_Phe;X23 is He;X24 is dE or Glu;X25 is aMe_Phe or aMe_Tyr;X26 is He, or Leu;X27 is Leu or Vai;X28 is aMe_Glu, aMe_Lys, or Thp;X29 is dR or Gly;X30 is Gly or absent; andX31 is absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (IV).)

[0244] In one embodiment of Formula (IV), X12 and X16 are directly covalently linked through a thioether bond, i.e., the side-chain of Cys, Hey, or Hhc at X12 or X16 is cross-linked with the side-chain of Lys Ac, Dab Ac, or Orn Acetyl at X12 or X16.170324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0245] In one embodiment of Formula (IV), X10 is Phe_34diOMe, X12 is Cys, X16 is LysAc, XI 7 is Lys Ac or Lys_lPEG2_lPEG2_IsoGlu_C18_Diacid, X24 is Glu, X28 is aMe_Lys, X29 is Gly, and X30 is Gly.

[0246] Representative compounds of Formula (IV) include, but are not limited to, Compounds Compound 103, 105, 107, 109, 110, 140, 157, 159, 207, 213, 214, 217, 222, 224, 227, 235, 239, 241, 242, 243, 244, 245, 246, 253, 254, 255, 256, 268, 272, 273, 276, 279, 291, 292, 293, 294, 307, 315, 338, 339, 340, 341, 348, 349, 358, 360, 361, 362, 363, 364, 365, 366, 368, 375, 380, 381, 382, 383, or 384. (See Figure 1 for the SEQ ID NOs and other structure / function information.) Of this list, two of these representative compounds of Formula (IV) are Peptide A and Peptide B referred to in the Examples.

[0247] In other embodiments of Formula (IV), the peptide comprises or consists of the following sequence: R1 is absent, XI is Tyr, X2 is Aib, X3 is Gin, X4 is Gly, X5 is Thr, X6 is aMe_Phe_2F, X7 is Thr, X8 is Ser, X9 is Asp, XI 0 is Phe_34diOMe, XI 1 is aMe_Ser, X12 is Cys, X13 is aMe_Leu, X14 is Leu, X15 is Asp, X16 is Lys_Ac, X17 is Lys, Lys_Ac, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid,Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid, Lys_lPEG2_IsoGlu_AlbuTag,Lys_lPEG2_IsoGlu_C18_Diacid, Lys_lPEG2_IsoGlu_C20_Diacid, orLys_IsoGlu_IsoGlu_C18_Diacid, X18 is Ala, X19 is Gin, X20 is Aib, X21 is Ala, X22 is aMe Phe, X23 is He, X24 is Glu, X24 is aMe_Phe, X25 is aMe_Tyr, X26 is Leu, X27 is Vai, X28 is aMe_Lys, X29 is Gly, X30 is Gly, and R2 is NH2, and wherein the side-chains of X12 and XI 6 are directly covalently linked through a thioether bond. Representative peptides of these embodiments include, but are not limited to, Compounds 361, 362, 363, 364, 380, 381, 382, 383, and 384.

[0248] In other embodiments of Formula (IV), the peptide comprises or consists of the following sequence: R1 is absent, XI is Tyr, X2 is Aib, X3 is Gin, X4 is Gly, X5 is Thr, X6 is aMe Phe, X7 is Thr, X8 is Ser, X9 is Asp, X10 is Phe_34diOMe, XI 1 is aMe_Ser, X12 is Cys, X13 is aMe_Leu, X14 is Leu, X15 is Asp, X16 is Lys_Ac, X17 is Lys, Lys Ac, Lys_lPEG2_IsoGlu_MeOPheTag, or Lys_IsoGlu_IsoGlu_C18_Diacid, XI 8 is Ala, XI 9 is Gin, X20 is Aib, X21 is Ala, X22 is aMe_Phe, X23 is He, X24 is Glu, X24 is aMe_Phe, X25 is aMe Phe, X26 is Leu, X27 is Vai, X28 is aMe_Lys, X29 is Gly, X30 is Gly, and R2 is NH2,171324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 and wherein the side-chains of X12 and X16 are directly covalently linked through a thioether bond. Representative peptides of these embodiments include, but are not limited to, Compounds 239, 335, 338, 348, 360, and 375.

[0249] In another embodiment of Formula (IV), the peptide exhibits a half-life time of stability greater than 12, 18, 20, or 24 hours in an SGF assay.

[0250] In another embodiment of Formula (IV), the peptide exhibits a half-life time of stability greater than 12, 18, 20, or 24 hours in an SIF assay.

[0251] Prodrug

[0252] 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.

[0253] 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 intramolecular cyclization 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 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.

[0254] 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.172324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0255] 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).

[0256] 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.

[0257] 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 linking moiety 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.

[0258] 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, polyglycolic 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 more173324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 polyethylene glycol chains linked to the dipeptide element wherein the combined molecular weight of polymer(s) is 40,000 to 80,000 Daltons.

[0259] 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, (Cl -Cl 8 alkyl)OH, (Cl -Cl 8 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, Cl- 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).)

[0260] 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):174324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088wherein(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 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 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 form175324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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 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 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 an176324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 amide bond between A-B and an aromatic amino group on an amino acid side chain of a 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 C1-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 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-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 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, (C1-C18 alkyl)OH, (C1-C18 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 the177324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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.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-methyl), Met(N-m ethyl), 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.

[0261] In some embodiments, the half-life of the prodrug, e.g., the chemical cleavage half-life (tl / 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)).

[0262] 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-alkylated178324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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.

[0263] 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.

[0264] In other embodiments, a dipeptide that is attached to a peptide of Figs. 1 A- 1QQQQQ comprises Thz-dIsoLys_lPEG2_IsoGlu_C20_Diacid, Thz- dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Sar-dIsoLys_lPEG2_IsoGlu_C20_Diacid, dIsoLys_lPEG2_IsoGlu_C20_Diacid-Thz, 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. 1A- 1QQQQQ. In one embodiment, the dipeptide is attached to the side chain of a Lys or dK residue. In other embodiments, the dipeptide is present in the side chain of a Lys or dK residue at X17 or X20.

[0265] 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.

[0266] 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 halflife extension conjugate (see below) is attached to a side chain of the first or second amino acid of the dipeptide.

[0267] Peptide-Half-Life Extension Conjugates179324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0268] 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).

[0269] 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.

[0270] 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 an acyl group, and accordingly the hydrocarbon chain may form part of an alkanoyl group, for example palmitoyl, caproyl, lauroyl, myristoyl or stearoyl.

[0271] 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 of180324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Cys 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] Other suitable polymeric moieties include poly-amino acids such as poly-lysine, poly-aspartic 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.

[0276] 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 often181324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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.

[0277] A skilled worker will be well aware of suitable techniques which can be used to perform the oxidation step.

[0278] 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.

[0279] 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

[0280] In certain embodiments, a peptide of the present invention comprises a conjugated half-life extension moiety shown in Table 2 - Illustrative Half-Life Extension Moieties:182324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088183324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088184324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0281] 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 — Illustrative Half-Life Extension Linker Moieties185324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088*(Peg) is -(OCH2CH2)-186324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0282] In some embodiments, a peptide of the present invention comprises any of the linker moieties shown in Table 3 and any of the half-life extension moieties shown in Table 2, including any of the following combinations shown in Table 4.

[0283] Table 4 - Illustrative Combinations of Linkers and Half-Life Extension Moieties

[0284] 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, 30,187324222975Attorney Docket No.: PRTH-100 / 12WO 321085-308840, 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] Methods Based on Activation of GLP1R, GIPR, and / or GCGR

[0289] The peptide compounds of the invention are potent agonists of GLP1R, GIPR, and / or GCGR. As discussed, representative peptide compounds include single digit picomolar EC50 values in human cAMP accumulation assays with HEK293 cells expressing GLP1R, GIPR, or GCGR.

[0290] 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 as described herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof.188324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0291] 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.

[0292] Additional therapeutic methods include methods for treating a metabolic syndrome, metabolic dysfunction-associated steatohepatitis (MASH), 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 body weight is desired.

[0293] Yet another therapeutic method is a method for treating addiction or substance abuse. Additional indications for treatment with the peptides of the invention include: cardiometabolic prevention, cardiovascular conditions such as heart failure, heart attack, stroke, atherosclerosis, and hypertension; metabolic dysfunction-associated steatotic liver disease (MASLD), lipodystrophy, polycystic ovary syndrome (PCOS), neurodegenerative diseases such as Alzheimer’s and Parkinson’s, gastrointestinal disorders such as irritable bowel syndrome (IBS), short bowel syndrome, and inflammatory bowel disease (IBD), mental health or psychiatric disorders including depression and conditions related to the gut-brain axis, addiction (reducing cravings and improving impulse control), appetite (appetite suppression), anxiety, arthritis including osteoarthritis, sleep apnea including obstructive sleep apnea (OSA), and chronic kidney disease (CKD).

[0294] 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.

[0295] 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 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 pharmaceutical189324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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 10 nM or less in a human cAMP accumulation assay utilizing a HEK 293 cell line expressing less than about 5000, 4000, 3000, 2000, or 1000 human GLP1 receptors per cell. In some embodiments, when administration is by oral ingestion, the pharmaceutical composition comprises a peptide compound of the invention that exhibits: (a) 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 cAMP accumulation assay; or an EC50 of 100 nM or less or 10 nM or less in a human LD GLP1R cAMP accumulation assay; and (b) exhibits a half-life of at least 2 hours, 12 hours, 20 hours, or 24 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 both a human cAMP GLP1R assay and a human cAMP GIPR assay, and a half-life of greater than 24 hours in both an SGF and an SIF 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 GIPR assay, a single digit nanomolar potency in a human LD GLP1R cAMP accumulation assay, and a half-life of greater than 12 hours, 20 hours, or 24 hours in both an SGF and an SIF assay.

[0296] Pharmaceutical Compositions

[0297] 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.

[0298] 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.

[0299] 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's190324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Pharmaceutical 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-buff ering 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.

[0300] In certain embodiments, the compositions comprise two or more peptides disclosed herein.

[0301] 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 singledose 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.

[0302] 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 biodegradable matrix is a matrix of one of either polylactide, polyglycolide, or polylactide co-glycolide (co-polymers of lactic acid and glycolic acid).191324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0303] In certain embodiments, the compositions are administered parenterally, subcutaneously or orally. In particular embodiments, the compositions are administered orally, intracisternally, 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, intrastemal, 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.

[0304] 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, betacyclodextrin, 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.

[0305] Inj ectable 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 of release of the peptide can be controlled. Depot injectable formulations are also prepared by entrapping the peptide in liposomes or microemulsions compatible with body tissues.

[0306] The inj ectable 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.

[0307] 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 phospholipids192324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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.

[0308] 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.

[0309] 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.

[0310] 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 a solid-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.

[0311] 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 provided193324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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.

[0312] 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.

[0313] 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.

[0314] 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.

[0315] 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 bioresponsive194324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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.

[0316] 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- [hydroxybenzoyljamino] 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.

[0317] Dosages and administrations

[0318] 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 the195324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 treatment; f) drugs used in combination or coincidental with the specific peptide employed, and like factors well known in the medical arts.

[0319] 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 weight daily. 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, including for subcutaneous dosing, a total dosage is about 0.25 mg, 0.50 mg., 0.75 mg, 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 10 mg, or about 1 mg to about 3 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. In certain embodiments, including for oral dosing, a total dosage is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg per human patient, e.g., about once or twice daily.

[0320] In certain embodiments, a Formula (IV) peptide is administered subcutaneously weekly at a total dosage amount of between 10-50 mg, or 10-20 mg, of the peptide. In one embodiment, a Formula (IV) peptide is administered subcutaneously weekly at a total dosage amount of 15-25 mg of the peptide. The total dosage amount for subcutaneously weekly can be administered in a single injection once per week or through multiple injections during the week to achieve the total dosage amount. In another embodiment, a Formula (IV) peptide is administered orally daily at a total dosage amount of between 25-100 mg, or 40-80 mg, of the peptide. In one embodiment, a Formula (IV) peptide is administered orally daily at a total dosage amount of 40-60 mg of the peptide. The total dosage amount for daily oral administration can be in a single administration once per day or multiple administrations per day to achieve the total dosage amount.

[0321] In other embodiments, the invention provides a method for treating obesity or inducing weight loss, the method comprising orally administering 40-60 mg per day of a Formula (IV) peptide, or a pharmaceutically acceptable salt or solvate thereof, to an individual in need of such a treatment.196324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0322] In other embodiments, the invention provides a method for treating obesity or inducing weight loss, the method comprising subcutaneously administering 15-25 mg per week of a Formula (IV) peptide, or a pharmaceutically acceptable salt or solvate thereof, to an individual in need of such a treatment.

[0323] In other embodiments, the invention provides a method for treating T2D, the method comprising orally administering 40-60 mg per day of a Formula (IV) peptide, or a pharmaceutically acceptable salt or solvate thereof, to an individual in need of such a treatment.

[0324] In other embodiments, the invention provides a method for treating T2D, the method comprising subcutaneously administering 15-25 mg per week of a Formula (IV) peptide, or a pharmaceutically acceptable salt or solvate thereof, to an individual in need of such a treatment.

[0325] 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.

[0326] 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 of administration). 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 regimen197324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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.

[0327] 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.

[0328] 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.

[0329] 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.

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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.198324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088

[0334] 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.

[0335] 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.

[0336] 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.

[0337] 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.

[0338] In some embodiments, the present invention provides kits comprising at least one peptide of the invention, or a composition (e.g., pharmaceutical composition) as disclosed herein packaged together with a reagent, a device, instructional material, or a combination thereof.

[0339] 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.

[0340] 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 or199324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 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

[0341] 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-dimethylformamideNMP: N-methylpyrolidoneHBTU : O-(Benzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphateHATU : 2-(7-aza- IH-benzotri azole- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphateDCC: DicyclohexylcarbodiimideNHS: N-hy doxy succinimideDIPEA: diisopropylethylamineEtOH: ethanolEt2O: diethyl etherHy: hydrogenTFA: trifluoroacetic acidTIS: triisopropylsilaneACN: acetonitrileHPLC: high performance liquid chromatographyESI-MS:...

Claims

Attorney Docket No.: PRTH-100 / 12WO 321085-3088What is Claimed:

1. A peptide comprising or consisting of the sequence according to Formula (I):RCxi-xz-xs-xd-xs-xe-xv-xs-XQ-xio-xi i-xn-xis-xid-xis-xie-xn-xis-xiQ-X20-X21 -X22-X23 -X24-X25 -X26-X27-X28-X29-X30-X31 -X32-X33 -X34-X35 -X36-X37- X38-X39-X40-X41-X42-X43-X44-R2, or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is Ra-C(O)- or hydrogen, wherein Rais Cl-20 alkyl or C3-8 cycloalkyl; or R1is acetyl, isovaleric acid, cyclohexanecarboxylic acid, or absent;R2is NH2 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;X2 is Aib, Ala, aMe_Ser, dA, dS, Gin, or Ser;X3 is Aoc, Gin, Glu, Gly, His, or Tetl;X4 is dA, Gly, or Thr;X5 is Phe, Ser, or Thr;X6 is aMe Phe, aMe_Phe_2F, Phe, or Thr;X7 is aMe_Val, He, Ser, or Thr;X8 is Asp or Ser;X9 is aMe_Asp, aMe_Glu, Asp, or Tyr;XI 0 is 4Pal, Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, aMe_Ser, Bip, Bip_2pEt4pOMe, Chg, Cys, Dab Acetyl, dC, Hhc, Hey, Leu, Lys Ac, Lys IsoGlu Palm, LysPhAc, Om Acetyl, Pen, Phe, Phe_34diOMe, Phe_4COOH, Phe_4Ad, Phe_4tBu, Phe_4CF3, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_Diacid, Phe_4_Me, Phe_4_Morph, Phe_4_OMe, Ser, Tyr, or Vai;Xl 1 is Ache, Aib, Ala, aMe_Cys, aMe_Lys_Ac, aMe_Ser, Asp, Chg, Cys, Dab_Acetyl, dC, Gly, Hey, Hhc, HHPhe_35Me, Hyp, He, Lys Ac, LysPhAc, NMe Ser, Om Acetyl, Pen, Pro, Ser, Thr, or Tyr;X12 is aMe_Cys, aMe_Leu, aMe_Lys_Ac, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, He, Lys, Lys Ac, LysPhAc, O2S, O2S_Me, 03 S, 03S_Me, 04S, 04S_Me, 02S_Reduced, 03S_Reduced, 04S_Reduced, 02S_Me_Reduced, 03 S Me Reduced, 04S_Me_Reduced, Om Acetyl, or Pen;224324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 3 is Ache, Aib, aMe_Cys, aMe_Leu, aMe_Lys_Ac, aMe_Phe, Chg, Cys, Dab Acetyl, dC, Gin, Glu, Hey, Hhc, He, Leu, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_C12, Lys Ac, LysPhAc, nL, Orn Acetyl, Pen, Ser, Trp, or Tyr;X14 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Hey, Hhc, Leu, Lys_Ac, LysPhAc, Ogl, Orn Acetyl, Pen, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is aMe_Cys, aMe_Lys_Ac, Asp, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys Ac, LysPhAc, Orn Acetyl, or Pen;XI 6 is aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Glu, Hey, Hhc, Lys, Lys Ac, LysPhAc, O2S, 02S_Me, 03 S, 03S_Me, 04S, 04S_Me, 02S_Reduced, 03S_Reduced, 04S_Reduced, 02S_Me_Reduced, 03 S Me Reduced, 04S_Me_Reduced, Orn, Orn Acetyl, Pen, or Ser;XI 7 is Ala, aMe_Cys, aMe_Ile, aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys, a Lys with a side-chain comprising a half-life extension moiety,Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_Albutag,Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm,Lys_lPEG2_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_lPEG2_C 19_Phosphonic_Acid;Lys_lPEG2_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid; Lys_lPEG2_IsoGlu_AlbuTag,Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid,Lys_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_IsoGlu_Palm,Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_MeOPheTag,Lys_lPEG2_IsoGlu_Palm, Lys Ac, Lys AlbuTag, Lys_dIsoLys_lPEG2_ C18_diacid,Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid,Lys_IsoGlu_IsoGlu_C20_Diacid, Lys_Me3, Lys_PEG2_Me3,Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, Cys, Dab Acetyl, dC, Hhc, Hey, LysPhAc, Orn Acetyl, or Pen;XI 8 is Aib, Ala, aMe_Cys, aMe_Lys_Ac, Arg, Cys, Dab_Acetyl, dC, Gin, Hey, Hhc, Lys Ac, LysPhAc, Orn Acetyl or Pen;X19 is Aib, Ala, or Gin;X20 is Aib, aMe_4Pal, aMe_Lys, aMe_Lys_Ac, aMe_Phe, Arg, Gin, Lys, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_C20_Diacid, or Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac,225324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, orLys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_Diacid;X21 is Aib, Ala, Asp, Gin, Glu, Ogl, Om, or Phe;X22 is aMe_Phe, He, or Phe;X23 is aMe_Ile, Cys, Glu, He, 03 S, or Vai;X24 is Ala, Asn, Cys, dE, dK, Gin, Glu, Hey, Hhc, Lys_Ac, or Tyr;X25 is Ala, aMe_Lys, aMe_Phe, aMe_Tyr, Leu, Lys_lPEG2_IsoGlu_C12, Phe, Phe_34diOMe, Trp, or Tyr;X26 is aMe_Leu, Cys, lie, Leu, NMe_Leu, Tie, or Vai;X27 is Ache, Aib, aMe_Leu, Cha, dL, Gin, Glu, Gly, His, He, Leu, Lys, NMe_Leu, 03 S, Ogl, Orn, Sar, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, Asp, bhE, Cys, dE, Gin, Gly, Glu, Glu OMe, Hey, hE, Hhc, IsoGlu, Lys, Lys_lPEG2_IsoGlu_C20_Diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is Ala, dA, dK, dR, Gly, Sar, or absent;X30 is Ala, Arg, dR, Gly, Pro, Sar, or absent;X31 is Cys, Pro, Sar, Ser, or absent;X32 is Gly, Pro, Ser, or absent;X33 is Arg, Cys, Gly, Ser or absent;X34 is Aib, Ala, Gly, His, or absent;X35 is Ala, Glu, Leu, Lys, Pro, or absent;X36 is Asn, Pro, or absent;X37 is Leu, Pro or absent;X38 is Pro, Ser, Vai, or absent;X39 is Glu, Lys, Ser, Thr, or absent;X40 is Arg, Gly, Lys_Palm, or absent;X41 is Gin, Thr, or absent;X42 is Arg, Glu, or absent;X43 is Glu, Tyr, or absent; andX44 is Glu or absent; wherein the peptide optionally comprises: a cyclic structure wherein two of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18, are directly covalently linked or indirectly covalently linked through a cyclization linker, and / or a cyclic structure wherein X23 and X27 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (I)).226324222975Attorney Docket No.: PRTH-100 / 12WO 321085-30882. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein two residues of X10-X18 (i.e., of X10, XI 1, X12, X13, X14, X15, X16, X17, and X18) are directly cross-linked via a disulfide bond, and wherein the two cross-linked residues are individually or both aMe Cys, Cys, dC, Hhc, Hey, or Pen.

3. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein two residues of X10-X18 are directly cross-linked via a thioether bond, and wherein one crosslinked residue is aMe Cys, Cys, dC, Hhc, Hey, or Pen, and the other cross-linked residue is aMe_Lys_Ac, Dab_Acetyl, Lys_Ac, LysPhAc, or Orn_Acetyl.

4. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein two residues of X10-X18 are indirectly cross-linked via a cyclization linker, wherein the two cross-linked residues are individually or both Cys, dC, Hey, Hhc, Pen, or HhPen, and wherein the cyclization linker is a Butane Linker, a Carbonyl Linker, a Dimethylcyclopropane Linker, an Ebutene Linker, a Hexane Linker, an Oxetane Linker, a Pentane Linker, a Propane Linker, a Trimethylbenzene Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker.

5. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein either: (a) X12 and X16 are directly cross-linked through a disulfide bond, and wherein X12 and X16 are individually or both Hey or Hhc, (b) X12 and X16 are directly cross-linked through a carbon-carbon double bond, and wherein X12 is O3S or 03S_Me and X16 is O3S, 03S_Me, or O4S, or (c) X12 and X16 are directly cross-linked through a carbon-carbon single bond, and wherein both X12 and X16 are O3S_Reduced.

6. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein X12 and XI 6 are indirectly cross-linked through a thioether bond with a cyclization linker, wherein X12 and X16 are individually or both Cys, 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, a Trimethylbenzene Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker.227324222975Attorney Docket No.: PRTH-100 / 12WO 321085-30887. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 1, wherein the peptide 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, or has an EC50 potency less than 1 micromolar, 100 nM, or less than 10 nM in a human LD GLP1R HEK293 cAMP accumulation assay, and wherein 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.

8. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 7, 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.

9. A peptide comprising or consisting of a sequence according to any one of SEQ ID NO: 1-8,10. and 12-387, or a pharmaceutically acceptable salt or a solvate thereof.

10. A peptide comprising or consisting of a two-dimensional structure as encoded by its SMILES formula listed in Figs. 1A-1QQQQQ or a pharmaceutically acceptable salt or a solvate thereof.

11. A peptide comprising or consisting of a two-dimensional chemical structure depicted in Figs. 3 A-3U or a pharmaceutically acceptable salt or a solvate thereof.

12. A peptide that is a dual agonist of human GLP1R and human GIPR or a tri-agonist of human GLP1R, human GIPR, and human GCGR, wherein the peptide comprises or consists of a sequence according to Formula (II):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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 391), 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 or OH or absent;XI is 4_Hydroxyphenylpropionic_Acid, His, Imidazole PropanoicAcid, or Tyr;228324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088X2 is Aib or aMe_Ser;X3 is Aoc, Glu, Gin, His, or Tetl;X4 is Gly;X5 is Ser or Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Thr;X8 is Ser;X9 is Asp, aMe_Asp, or aMe_Gln;XI 0 is 4Pal, Ache, aMe Leu, Bip, Chg, Leu, Phe, Phe_34diOMe, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_diacid, Phe_4ad, Phe_4CF3, Phe_4COOH, Phe_4Me, Phe_4_Morph, Phe_4_OMe, Phe_4tBu, Tyr, or Vai;XI 1 is Aib, Ala, aMe_Ser, or Ser;X12 is Cys, Dab_Acetyl, Glu, Hey, Hhc, Lys, Lys_Ac, 03 S, 03S_Me, or 03 S Reduced;XI 3 is Ache, Aib, aMe Leu, aMe Phe, Arg, Chg, Gin, Glu, He, Leu, nL, Ser, Trp, or Tyr;X14 is Leu, Ogl, Phe_4ad, Phe_4_2ae, Tba, or Tyr;XI 5 is Asp;XI 6 is Cys, Dab Acetyl, Hey, Hhc, Lys, Lys Ac, 03 S, 03S_Me, 03S_Reduced, 04S, or Orn Acetyl;XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys, Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag, Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid,Lys_lPEG2_lPEG2_IsoGlu_C 19_Phosphonic_Acid,Lys_lPEG_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid; Lys_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid,Lys_lPEG2_IsoGlu_Cl 8_diacid, Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_Palm, Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diacid, Lys_IsoGlu_IsoGlu_C20_Diacid, Lys_PEG2_Me3, Lys_Me3, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid, Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, Lys Ac, or Lys AlbuTag;229324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 8 is Aib or Ala;XI 9 is Gin;X20 is Aib, aMe_4Pal, aMe_Lys, aMe_Lys_Ac, Lys, Lys_Ac, Lys_lPEG2_IsoGlu_C20_diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_diacid, or Lys_Thz_dIsoLys_lPEG2_IsoGlu_C 18_diacid;X21 is Aib, Ala, Glu, Ogl, or Orn;X22 is aMe_Phe or Phe;X23 is He, 03 S, or Vai;X24 is dE, dK, Gin, or Glu;X25 is aMe_Phe, aMe_Tyr, Phe_34diOMe, Trp, or Tyr;X26 is aMe Leu, He, or Leu;X27 is Ache, Aib, aMe Leu, Cha, dL, Gin, His, lie, Leu, Lys, 03 S, Ogl, Orn, Tba, Tie, or Vai;X28 is Aib, Ala, aMe_Glu, aMe_Lys, aMe_Lys_lPEG2_IsoGlu_C20_Diacid, Arg, bhE, dE, Gin, Glu, Glu OMe, hE, IsoGlu, Lys_lPEG2_IsoGlu_C20_diacid, Lys Ac, NMe Glu, Phe, Thp, or Thr;X29 is dA, dK, dR, Gly, Sar, or absent;X30 is Arg, dR, Gly, Sar, or absent; andX31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker(Formula (II)).

13. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 12, wherein X12 and X16 are directly cross-linked through a disulfide bond, and wherein X12 and X16 are individually, or both, Hey or Hhc; or wherein X12 and X16 are directly cross-linked through a thioether bond, and wherein one of X12 and X16 is Dab Ac, Lys Ac, or Om Acetyl, and the other is Cys, Hey, or Hhc; or wherein X12 and XI 6 are directly cross-linked through a carboncarbon double bond, wherein X12 and X16 are individually or both 03S, 03S_Me, or 04S; or wherein X12 and X16 are directly cross-linked through a carbon-carbon single bond, wherein both X12 and X16 are 03S_Reduced.230324222975Attorney Docket No.: PRTH-100 / 12WO 321085-308814. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 12, wherein X12 and X16 are indirectly cross-linked through a thioether bond with a cyclization linker, wherein X12 and X16 are individually, or both, Cys, Hey, or Pen, and wherein the cyclization linker is a Butane Linker, a Carbonyl Linker, a Dimethylcyclopropane Linker, an Ebutene Linker, a Hexane Linker, an Oxetane Linker a Pentane Linker, a Propane Linker, a Trimethylbenzene Linker, an mXylene Linker, a pXylene Linker, or an oXylene Linker.

15. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 12, wherein X12 and X16 are indirectly cross-linked through a thioether bond with a cyclization linker, wherein X12 and X16 are both Cys, and wherein the cyclization linker is a Butane Linker or a Propane Linker.

16. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 12, wherein the peptide 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, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay.

17. The peptide or pharmaceutically acceptable salt or solvate thereof claim 12, wherein the peptide 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, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, and an EC50 potency less than 20 nM in a human GCGR HEK293 cAMP accumulation assay.

18. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 12, 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. A peptide that is at least a dual agonist of GLP1R and GIPR, wherein the peptide 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, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, wherein the peptide231324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 has a half-life time of stability greater than 2 hours in both an SGF assay and an SIF assay, and wherein the peptide comprises or consists of a sequence according to Formula (III): R^xi-xz-xs-xd-xs-xe-xv-xs-XQ-xio-xi i-xn-xis-xid-xis-xie-xn-xis-xiQ- X20-X21-X22-X23-X24-X25-X26-X27-X28-X29-X30-X31-R2(SEQ ID NO: 399), or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1is absent;R2is absent or NEE;XI is Tyr;X2 is Aib or aMe_Ser;X3 is Aoc, Gin, Glu, or His;X4 is Gly;X5 is Thr;X6 is aMe Phe, aMe_Phe_2F, or Phe;X7 is Thr;X8 is Ser;X9 is aMe_Asp, aMe_Glu, or Asp;XI 0 is 4Pal, Ache, aMe_Leu, Chg, Leu, Phe_34diOMe, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_diacid, Phe_4_ad, Phe_4_Morph, Phe_4OMe, Tyr, or Vai;Xl 1 is Aib, aMe_Ser, or Ser;X12 is Cys, Hey, Hhc, Lys Ac, 03 S, or 03S_Reduced;X13 is Ache, Aib, aMe_Leu, or aMe_Phe;X14 is Leu, Ogl, Phe_4_2ae, Phe_4ad, or Tyr;X15 is Asp;XI 6 is Cys, Dab Acetyl, Hey, Hhc, Lys Ac, 03 S, 03S_Reduced, 04S, or Orn Acetyl;XI 7 is aMe_Lys, aMe_Lys_Ac, Arg, dK, Gin, Glu, He, Lys,Lys_lPEG2_lPEG2_Ahx_C 18_diacid, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_Dap_C 18_diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid, Lys_lPEG2_IsoGlu_Albutag, Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_C 12_diacid, Lys_lPEG2_IsoGlu_C 16_diacid, Lys_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_IsoGlu_C20_Diacid, Lys_lPEG2_IsoGlu_Palm,Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys_IsoGlu_IsoGlu_C20_Diacid,232324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_Sar_dIsoLys_lPEG2_IsoGlu_C 18_Diacid,Lys_Thz_dIsoLys_lPEG2_IsoGlu_C18_Diacid, or Lys Ac;XI 8 is Ala;XI 9 is Gin;X20 is Aib, aMe_4Pal, aMe_Lys, aMe_Lys_Ac, or Lys_Ac;X21 is Aib, Ala, Glu, Ogl, or Orn;X22 is aMe_Phe or Phe;X23 is He, 03 S, or Vai;X24 is dE, dK, Gin, or Glu;X25 is aMe_Phe aMe_Tyr, Trp, or Tyr;X26 is aMe Leu, He, or Leu;X27 is Ache, aMe Leu, Cha, dL, His, lie, Leu, Lys, 03 S, Om, Tba, Tie, or Vai;X28 is Aib, Ala, aMe Glu, aMe Lys, bhE, dE, Gin, Glu, Glu OMe, hE, Lys Ac, Thp, or Thr;X29 is dA, dR, Gly, Sar, or absent;X30 is Arg, dR, Gly, Sar, or absent; andX31 is Pro or absent; wherein the peptide comprises a cyclic structure wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (III).)20. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 19, wherein the peptide exhibits a half-life time of stability greater than 24 hours in an SGF assay.

21. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 19, wherein the peptide exhibits a half-life time of stability greater than 24 hours in an SIF assay.

22. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 21, wherein the peptide is the active ingredient in a pharmaceutical formulation for oral administration.

23. A peptide that is tri-agonist of GLP1R, GIPR, and GCGR, wherein the peptide 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 GLP1RHEK293 cAMP accumulation assay, and less than 0.100 nM in a human GIPR HEK293 cAMP accumulation assay, and less than 20 nM in a human GCGR HEK293 cAMP accumulation assay, wherein the peptide has a half-life time of233324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088 stability greater than 2 hours in both an SGF assay and an SIF assay, and wherein the peptide comprises or consists of a sequence according to Formula (IV):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-X27-X28-X29-X30-X31-R2 (SEQ ID NO: 407), or a pharmaceutically acceptable salt or a solvate thereof, wherein:R1 is absent;R2 is NH2 or absent;XI is Tyr;X2 is Aib;X3 is Gin or His;X4 is Gly;X5 is Thr;X6 is aMe Phe or aMe_Phe_2F;X7 is Thr;X8 is Ser;X9 is aMe_Asp or Asp;XI 0 is Phe_34diOMe, Phe_4_2ae, Phe_4_2ae_lPEG2_IsoGlu_C18_diacid, Phe_4_ad, Tyr, or Vai;Xl 1 is Aib, aMe_Ser, or Ser;X12 is Cys, Hey, Hhc, or Lys_Ac;X13 is Ache, Aib, or aMe_Leu;X14 is Leu or Phe_4ad;X15 is Asp;X16 is Cys, Dab_Acetyl, Hey, Hhc, Lys_Ac, or Orn_Acetyl;X17 is Glu, Lys, Lys_lPEG2_lPEG2_Albutag,Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag,Lys_lPEG2_lPEG2_IsoGlu_Palm, Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid,Lys_lPEG2_IsoGlu_Albutag, Lys_lPEG2_IsoGlu_C 16_diacid,Lys_lPEG2_IsoGlu_C 18_diacid, Lys_lPEG2_IsoGlu_C20_Diacid,Lys_lPEG2_IsoGlu_MeOPheTag, Lys_lPEG2_IsoGlu_Palm,Lys_dIsoLys_lPEG2_IsoGlu_C 18_diacid, Lys IsoGlu IsoGlu C 18_Diaicd, Lys_PEG2_Me3, or Lys Ac; XI 8 is Ala;234324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088XI 9 is Gin;X20 is Aib;X21 is Ala;X22 is aMe_Phe;X23 is He;X24 is dE or Glu;X25 is aMe_Phe or aMe_Tyr;X26 is He, or Leu;X27 is Leu or Vai;X28 is aMe_Glu, aMe_Lys, or Thp;X29 is dR or Gly;X30 is Gly or absent; andX31 is absent; wherein the peptide comprises a cyclic structure, wherein X12 and X16 are directly covalently linked or indirectly covalently linked through a cyclization linker. (Formula (IV).)24. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 23, wherein X10 is Phe_34diOMe, X12 is Cys, X16 is LysAc, X17 is Lys_Ac or Lys_lPEG2_lPEG2_IsoGlu_C18_Diacid, X24 is Glu, X28 is aMe_Lys, X29 is Gly, and X30 is Gly.

25. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 23, wherein the peptide is Compound 103, 105, 107, 109, 110, 140, 157, 159, 207, 213, 214, 217, 222, 224, 227, 235, 239, 241, 242, 243, 244, 245, 246, 253, 254, 255, 256, 268, 272, 273, 276, 279, 291, 292, 293, 294, 307, 315, 338, 339, 340, 341, 348, 349, 358, 360, 361, 362, 363, 364, 365, 366, 368, 375, 380, 381, 382, 383, or 384.

26. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 23, wherein:R1 is absent, XI is Tyr, X2 is Aib, X3 is Gin, X4 is Gly, X5 is Thr, X6 is aMe_Phe_2F, X7 is Thr, X8 is Ser, X9 is Asp, X10 is Phe_34diOMe, XI 1 is aMe_Ser, X12 is Cys, X13 is aMe_Leu, X14 is Leu, X15 is Asp, X16 is Lys_Ac, X17 is Lys, Lys_Ac, Lys_lPEG2_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_lPEG2_IsoGlu_C 18_Diacid,235324222975Attorney Docket No.: PRTH-100 / 12WO 321085-3088Lys_lPEG2_dIsoLys_dIsoLys_dIsoLys_C 18_Diacid, Lys_lPEG2_IsoGlu_AlbuTag, Lys_lPEG2_IsoGlu_C18_Diacid, Lys_lPEG2_IsoGlu_C20_Diacid, orLys_IsoGlu_IsoGlu_C18_Diacid, X18 is Ala, X19 is Gin, X20 is Aib, X21 is Ala, X22 is aMe Phe, X23 is He, X24 is Glu, X24 is aMe_Phe, X25 is aMe_Tyr, X26 is Leu, X27 is Vai, X28 is aMe_Lys, X29 is Gly, X30 is Gly, and R2 is NH2, and wherein the side-chains of X12 and XI 6 are directly covalently linked through a thioether bond.

27. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 26, wherein the peptide is Compound 361, 362, 363, 364, 380, 381, 382, 383, or 384.

28. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 23, wherein: R1 is absent, XI is Tyr, X2 is Aib, X3 is Gin, X4 is Gly, X5 is Thr, X6 is aMe_Phe, X7 is Thr, X8 is Ser, X9 is Asp, X10 is Phe_34diOMe, XI 1 is aMe_Ser, X12 is Cys, X13 is aMe_Leu, X14 is Leu, X15 is Asp, X16 is Lys_Ac, X17 is Lys, Lys Ac, Lys_lPEG2_IsoGlu_MeOPheTag, or Lys_IsoGlu_IsoGlu_C18_Diacid, XI 8 is Ala, XI 9 is Gin, X20 is Aib, X21 is Ala, X22 is aMe_Phe, X23 is He, X24 is Glu, X24 is aMe_Phe, X25 is aMe Phe, X26 is Leu, X27 is Vai, X28 is aMe_Lys, X29 is Gly, X30 is Gly, and R2 is NH2, and wherein the side-chains of X12 and X16 are directly covalently linked through a thioether bond.

29. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 28, wherein the peptide is Compound 239, 335, 338, 348, 360, or 375.

30. The peptide or pharmaceutically acceptable salt or solvate thereof of any one of claim 23-29, wherein the peptide is the active ingredient in a pharmaceutical formulation for oral administration.

31. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 30, wherein the formulation comprises a permeation enhancer.

32. The peptide or pharmaceutically acceptable salt or solvate thereof of claim 31, wherein the formulation is in tablet form, and the permeation enhancer is sodium N-(8-[2- hydroxybenzoyl]amino)caprylate.236324222975Attorney Docket No.: PRTH-100 / 12WO 321085-308833. 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 1-32, or a pharmaceutically acceptable salt or solvate thereof.

34. A method for treating obesity or inducing weight loss, the method comprising orally administering to an individual in need of such a treatment an effective amount of a peptide according to any one of claims 19-32.

35. A method for treating obesity or inducing weight loss, the method comprising orally administering to an individual in need of such a treatment an effective amount of a peptide according to any one of claims 23-32.

36. A method for treating T2D, 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 1-32, or a pharmaceutically acceptable salt or solvate thereof.

37. A method for treating T2D, the method comprising orally administering to an individual in need of such a treatment an effective amount of a peptide according to any one of claims 19-32.

38. A method for treating T2D, the method comprising orally administering to an individual in need of such a treatment an effective amount of a peptide according to any one of claims 23-32.237324222975

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