Chimeric tetra-receptor agonists of GCGR, GIPR, GLP-1r, and NPY2r

Abstract

Disclosed are chimeric agonists of GCGR, GIPR, GLP-1R, and Y2R, and their use in the treatment of diseases and conditions such as diabetes, obesity, Alzheimer's disease, liver disease, substance addiction, traumatic brain injury, chronic kidney disease, inflammation and cardiovascular diseases.

Description

CHIMERIC TETRA-RECEPTOR AGONISTS OF GCGR,GIPR, GLP-1R, AND NPY2RRELATED APPLICATIONS

[0001] This application claims the benefit of priority to U. S. Provisional Application No.: 63 / 729,657, filed December 9, 2024; U. S. Provisional Application No.: 63 / 729,658, filed December 9, 2024; and U. S. Provisional Patent No.: 63 / 729,660, filed December 9, 2024; the contents of each of which are incorporated by reference in their entirety.GOVERNMENT SUPPORT

[0002] This invention was made with government support under R41DK131842, R42DK131842, and AG061909 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.BACKGROUND

[0003] With an increasing prevalence of obesity and type 2 diabetes, there is a need for novel therapeutics that stimulate weight loss and glycemic control. The metabolic regulation of these processes is partially facilitated by peptide-receptor interactions. The successful use of GLP-1 receptor agonists in type 2 diabetes and obesity treatment has prompted a new class of dual and tri-agonists that expand the pharmacological activity to GIP and glucagon receptor agonism. These additional receptors play a harmonic role with GLP-1 receptor stimulation, and in these dual and tri-agonists there is even greater maintained weight loss observed. A stream of evidence suggests that the incorporation of Y2 receptor agonism can further weight loss, among other favorable outcomes. Therefore, unimolecular multi-receptor agonists that are capable of affecting this receptor are of high therapeutic interest for treating metabolic diseases. The issues that surround this approach include elaborate optimization of peptide sequences to impart high potency at each targeted receptor and introduced lipid acylation to provide improved circulation time via serum albumin binding.SUMMARYIn some aspects, the present invention provides a peptide having at least 85% sequence identity to Formula A:XaaiXaa2Xaa3GTXaaeXaa7 SDXaai oSXaai 2Xaai? X aa 14Xaai X aa i eXaai? Xaai sXaai 9 Xaa2oXaa2iFXaa23Xaa24Xaa25Xaa26Xaa27Xaa2sGGXaa3iSXaa33RXaa35Xaa36Xaa37N Xaa39Xaa4oTRXaa43Xaa44Y -NH-R2Formula A;wherein:Xaai is selected from:wherein R1is selected from hydrogen, alkyl, fluoroalkyl, and alkylheteroaryl;Xaa2 is selected from A, Aib, AzaA, G and V;Xaa3 is selected from Q, E, H, aMeE and aMeQ;Xaae is selected from F, aMeF and a-Me-2-fluorophenylalanine;Xaa? is selected from T and I;Xaaio is selected from Y, L, K and K;Xaai2 is selected from I, K and K;Xaai3 is selected from L, Y, aMeL, Aib, K and K;Xaai4 is selected from L and K;Xaais is selected from D and E;Xaaie is selected from E, R, K and K:;Xaan is selected from R, K and K;Xaais is selected from A, Y and R;Xaai9 is selected from Q and A;Xaa2o is selected from Q, Aib, A, K and K;Xaa2i is selected from E, D, Aib, K, K:and A;Xaa23 is selected from I and V;Xaa24 is selected from E and Q;Xaa25 is selected from W, Y and aMeY;Xaa26 is selected from L, K, and K,Xaa27 is selected from K, K, L and I;Xaa28 is selected from K, K, E, A and D;Xaasi is selected from P, K and K:;Xaa33 is selected from L, D-proline and aMeL;Xaa35 is selected from H and 3-(4-pyridyl)alanine;Xaa36 is selected from Y and 3 -cyclohexylalanine;Xaa37 is selected from L, V, Y, aMeL, Aib and aMeY;Xaa39 is selected from W, L, K, aMeL, Aib and aMeY;Xaa4o is selected from V, L and aMeL;Xaa43 is selected from Q and aMeQ;Xaa44 is selected from R and NMeR;each K:is independentlyHN-RLinker1RLinker2RLinker3RTwhereinRLinker1, RLinker2and RLinker3are each independently selected from alinker group and a covalent bond;RTcomprises a lipid moiety or an oligosaccharide moiety; andR2is selected from hydrogen, alkyl and fluoroalkyl;provided that the peptide is not:Retatrutide: YXQGTFTSDYSIαLDK4AQXAFIEYLLEGGPSSGAPPPS–NH2;Tirzepatide: YXEGTFTSDYSIXLDKIAQ2AFVQWLIAGGPSSGAPPPS–NH2;Triagonist: HXQGTFTSD3SKYLDERAAQDFVQWLLDGGPSSGAPPPS-NH2;Analogue 19: HXEGTFTSDVSSYLEGQALRHYINWLTRQRY-NH2;Compound 16: HXHGTFTSDYSIYLEQKYAXEFVQWLLEGGPSSGAPPPS-NH2;GEP44: HSQGTFTSDLSKYLEEEAVREFIAWLKNGGPSRHYLNLVTRQRY-NH2; or SAR441255: HXHGTFTSDLSKL¶EEQRQXEFIEWLKAaGPPSXKPPPK-NH2;wherein:Ω is Lysine acylated with εLys-εLys-γGlu-C20 diacid;¶ is Lysine acylated with γGlu-γGlu-C16 acyl;s is D-serine;a is D-alanine;4 is Lysine acylated with OEG-y-Glu-C20 diacid;3 is Lysine acylated with y-Glu-C16 acyl;2 is Lysine acylated with OEG-OEG-y-Glu-C2() diacid; anda is a-methyl-L- Leucine, also referred to as (aMeL, L“).In some aspects the present invention provides a method of: a) treating or preventing type 2 diabetes, hyperglycemia, impaired glucose tolerance, or non-insulin dependent diabetes, and / or obesity; b) reducing body weight and / or food intake, and / or inducing satiety; c), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), metabolic dysfunction-associated liver disease (MASLD), and / or nonalcoholic fatty liver disease (NAFLD); d) treating chronic kidney disease; e) treating or preventing emesis; f) treating or preventing effects of aging; g) support of islet transplant survival in Type 1 diabetes; and / or h) treating or preventing arthritis and related diseases, for example, Osteoarthritis, Rheumatoid arthritis, Gout, Ankylosing spondylitis, Psoriatic arthritis, Juvenile arthritis, Fibromyalgia, Infectious arthritis, Spondyloarthritis, Sjogren's syndrome, Scleroderma, and / or Polymyalgia rheumatica; comprising administering to a subject in need thereof an effective amount of a peptide of the invention.BRIEF DESCRIPTION OF THE DRAWINGSFigure 1 (a) Peptide sequence of native agonists of GLP-1R (GLP-1), GIPR (GIP), GcgR (glucagon, Gcg), and Y2R (PYY). Precedented synthetic analogues of one or multiplereceptor agonists are shown with sequence homology (yellow highlight), unnatural amino acids (blue, green, and yellow boxes), and lipid side chains (red box), (b) A cryoEM of PYY3-36 bound to the Y2R (grey ribbon) with only the PYY24-36 C-terminal (c.t.) 13 amino acids shown (green ribbon, blue sequence) showing residue 24 exiting the binding pocket (PDB: 7Y0N). (c) A series of multi-agonists containing the PYY24-36 (c.t.) at position 33. (d) The installation of various linker-lipid motifs on the lysine side chain was conducted using P-alanine (PAla, PA), y-L-glutamic acid (yGlu, yE), and 8-amino-3,6-dioxaoctanoic acid (OEG, O), and lipid diacids or C16 acyl lipids, (e) Lipid side chains used in a and c. (f) Unnatural amino acid that are present in some of the precedented compounds or compounds described in this work.Figure 2 (a) Chemical structures of the tetra-receptor agonist chimeras TC2 and TC3, with TC4 depicting the two Lysl6Arg and Aib20Ala natural amino acid substitutions made from the TC3 scaffold, (b) A representative experiment illustrating concentration-response curves from the cAMP luciferase reporter assays for GLP-1R, GIPR, and GcgR, and the serum response element (SRE) luciferase reporter assay for Y2R. (c) A cartoon depiction of the tetra-receptor agonist chimera with arrows illustrating preferential agonism and fold increase in activity ($) or loss in activity (J,) compared to the native ligand to that receptor, (d) A bar graph representation of the native receptor ligands, the FDA-approved semaglutide, tirzepatide, and retatrutide, and the TC2, TC3, and TC4 analogues. Relative % activity at each receptor = (native ligand EC50 / analogue EC50) x 100 from the data presented in table 1. Errors represent ± SEM in (b). Error represents relative standard error (RSE) to the relative potency value in (d).Figure 3 (a) P-arrestin-2 recruitment to GLP-1R, measured using the BRET assay. Assays were performed using HEK-293T cells that were transiently transfected with GLP-1R-Rluc8 and the GFP2-P-arrestin-2 (R393E, R395E) fusion proteins, (b) An AlphaFold 3 generated interaction of TC3 with the necessary Aib20Ala, K17 no lipid modifications bound to the GLP-1R sequence obtained from cryoEM data (PDB: 6X18). (c) A depiction of the Arginine 44 residue in TC3c demonstrating its predicted distance from the ligand:receptor interaction, and how N-methylation achieved the reduction in potency, (d) Leucine 13 may form important interactions at the interface of the peptides N-terminal binding into the GLP-1R pocket where aMeL placement increased P-arrestin-2 of the TC3f construct with respect to TC3c. (e) The TC4 scaffold that deviates from TC3 via a Lysl6Arg and Aib20Ala substitution has a strong influence on P-arrestin-2 at the GLP-1R with respect to GLP-1. (f)A cartoon representation of the demonstrated bias tuning of the of the tetra-receptor agonist chimera peptides at GLP-1R signaling. Errors represent ± SEM in (a).Figure 4 Concentration-response agonism at the GLP-1R from the cAMP luciferase reporter assay: (a) GLP-1, (b) TC2, and (c) TC3 preincubated with DPP4 or vehicle for 18 hours at 37 °C. Assays were performed using HEK-293 C34L cells stably transfected with GLP-1 R and CRE6x-lucif erase. Errors represent ± SEM.Figures 5 Cell viability assessed using an MTS assay of primary neuronal cells (SH-SY5Y) expressing GLP-1 R, GIPR and GCGR. (a) No challenge, where control represents no addition; (b) glutamate (150 mM) challenge; (c) H2O2 (600 pM) challenge was applied to the neuronal cells. Open bar: unchallenged cells; black bar: challenged without peptide treatment. Cells represented by colored bars with corresponding symbols were challenged and treated with N-terminally modified GLP-1R agonist derivatives shown in Table S6.Figure 6 A representative experiment of (a) serially diluted fenoterol incubated with HEK-293T cells transfection with plasmids outlined in “Fenoterol stimulated cAMP Luciferase Reporter Assay for Y2R agonism”. (b) A representative experiment of the concentration-response curves of the TC2 and TC3 analogues in this work suppressing cAMP formation through Y2R agonism, which was facilitated through the fenoterol stimulated cAMP luciferase reporter assay.Figure 7 (a) Analysis of the EC50 values of tirzepatide and TC4 in cAMP production by the luciferase reporter assay at the GLP-1R demonstrating no significance (p = 0.6259). (b) Analysis of the EC50 values of tirzepatide and TC4 in cAMP production by the luciferase reporter assay of tirzepatide and TC4 at the GIPR demonstrating a subtle difference in potency (p = 0.0186). (c) Analysis of the maximal P-arrestin-2 recruitment (maximal efficacy) to the GLP-1R induced by the analogue compared to the % maximal recruitment (maximal efficacy) of GLP-1. Data analysis was conducted on GraphPad Prism 10 where panels (a) and (b) were analyzed by Welch’s two-tailed T-tests and panel (c) was analyzed by ordinary one-way ANOVA. Significance determined if *P < 0.05, **P < 0.01, ****P < 0.0001.Figure 8 Despite TC3's potent glucagon receptor engagement in addition to GLP-1, GIP, and Y2R, it remains to be a strong glucose regulatory agent. Intraperitoneal Glucose Tolerance Test (IPGTT) of (a) high fat diet (HFD)-fed old female mice, (b) chow-fed young female mice, (c) HFD-fed young female mice, (d) extrapolated area under the curve analysis of all groups, and (e) blood glucose levels 1 hour post treatment of the compound and at t=0IP administration of glucose. Mice were treated subcutaneously with either vehicle (0.05% Tween-80 in PBS), or TC3 (30 nmol / kg) (t= -60’) followed by IP glucose (t= 0). Old mice (29-months-old) were fed HFD for 6 months and young mice (7-months-old) were fed HFD for 5 months. Compound TC3 was disolved in vehicle. Mice are wild-type C57BL / 6 (n = 4-5 per group), mean ± SEM. *P < 0.05 vs vehicle using two-way ANOVA with Tukey’s post-hoc analysis.Figure 9 Despite TC3c's potent glucagon receptor engagement in addition to GLP-1, GIP, and Y2R, it remains to be a strong glucose regulatory agent. Intraperitoneal Glucose Tolerance Test (IPGTT) of (a) chow-fed old female mice, (b) high fat diet (HFD)-fed old female mice, (c) chow-fed young female mice, and (d) HFD-fed young mice, (e) The cumulative area under the curve analysis of all female mouse groups tested with vehicle or TC3c demonstrates robust glucoregulation, (f) IPGTT of male young chow-fed mice and male old HFD-fed mice tested with vehicle or TC3c demonstrate that the tetra-agonist is effective in both genders of mice. Mice were treated subcutaneously with either vehicle (0.05% Tween-80 in PBS), or TC4 (30 nmol / kg) (t= -60) followed by IP glucose (t= 0). Old mice (29-months-old) were fed HFD for 6 months and young mice (7-months-old) were fed HFD for 5 months. Compounds TC4 was dissolved in vehicle. Mice are wild-type C57BL / 6, mean ± SEM. *P < 0.05 vs vehicle using two-way ANOVA with post-hoc Sidak's test.Figure 10 Despite TC4's potent glucagon receptor engagement in addition to GLP-1, GIP, and Y2R, it remains to be a strong glucose regulatory agent. Intraperitoneal Glucose Tolerance Test (IPGTT) of (a) chow-fed old female mice, (b) high fat diet (HFD)-fed old female mice, (c) chow-fed young female mice, (d) HFD-fed young mice, and the cumulative area under the curve analysis of all groups (right bar graph). Mice were treated subcutaneously with either vehicle (0.05% Tween-80 in PBS), or TC4 (30 nmol / kg) (t= -60) followed by IP glucose (t= 0). Old mice (29-months-old) were fed HFD for 6 months and young mice (7-months-old) were fed HFD for 5 months. Compound TC4 was dissolved in vehicle. Mice are wild-type C57BL / 6 (n = 4-5 per group), mean ± SEM. *P < 0.05 vs vehicle using two-way ANOVA with Tukey’s post-hoc analysis.Figure 11 TC4 decreases cumulative food intake in all groups. All female mice were fasted from 5pm the previous day to 7am. The following morning mice were treated subcutaneously with either vehicle (0.05% Tween-80 in PBS, open bar graph) or TC4 dissolved in vehicle (closed bar graph) at 30nmol / kg. This SC treatment occurred at 7am followed by immediate return of the chow diet. Cumulative food intake was measured at 1,4, 8, and 24-hours post TC4 tx. High fat diet (HFD)-fed old female mice, chow-fed old female mice, chow-fed young female mice, and HFD-fed young female mice were utilized in the study. Old mice (29-months-old) were fed either HFD or chow for >6 months and young mice (7-months-old) were fed HFD or chow for >5 months. Mice are wild-type C57BL / 6, mean ± SEM. *P < 0.05 vs vehicle using two-way ANOVA with Tukey’s post-hoc analysis.DETAILED DESCRIPTION

[0004] Disclosed are tetra-receptor agonist chimeras that are highly potent, efficacious, and accommodating to a series of lipid side chains with high therapeutic viability. Biased agonism was tested at the GLP-1 receptor to show a variety of compounds that exhibited a favorable cAMP signaling profile, with minimal P-arrestin recruitment.

[0005] Obesity and type 2 diabetes (T2D) have become a public health crisis in the United States, and they are a rapidly rising concern globally. These two metabolic syndromes are often linked, leading to the termed ‘diabesity’ concern. Prior studies have shown that a wide range of comorbidities are associated with obesity in particular, including cardiovascular disease, cancer, and numerous other conditions that may play a direct or indirect role in a higher mortality rate in people with this metabolic syndrome.1

[0006] The role of the glucagon-like peptide- 1 (GLP-1) receptor (GLP-1 R) agonists in improving glycemic control has been long-established. Stimulation of the GLP-1R leads to glucose-dependent insulin secretion from pancreatic P-cells, with various peripheral effects such as increased satiety and delayed gastric emptying.2Various GLP-1 constructs have been examined to elucidate methods of enhancing activity and exploring enzymatic stabilization, such as chemical strategies to eliminate dipeptidyl peptidase-4 (DPP4) catalyzed degradation, which is the front-line protease for the rapid degradation of the incretin hormones GLP-1 and the glucose-dependent insulinotropic polypeptide (GIP).3-7GLP-1R mono-agonists, such as semaglutide, have been successful in the treatment of T2D and foster significant weight loss. Semaglutide contains 2-aminoisobutyric acid (Aib, X) at the second position to provide stability against DPP4, and it contains a lipid diacid side chain that allows for a once- weekly injection due to strong affinity to serum albumin.8

[0007] With the interest that has emerged in GLP-1R agonists, other metabolic regulatory peptides such as GIP, glucagon (Gcg) and peptide YY (PYY) are growing in interest and potential therapeutic value. The other incretin hormone, GIP, metabolizes lipids and adipose tissues, and has centrally important actions alongside GLP-1 on pancreatic P-cells. Theglucagon (Gcg) peptide is most renowned for stimulating glucose production in hepatocytes, a mechanism protecting against hypoglycemia. However, the agonism of the Gcg receptor (GcgR) is also strongly linked to increased energy expenditure, making it a premier potential target for weight loss therapeutics. Many investigations show the glycemic control of GLP-1R and GIPR agonists when co-administered with GcgR agonists are still effective at correcting hyperglycemia.9

[0008] The GLP1R, GIPR, and GcgR are members of the class B family of GPCRs, and they bind their native ligands through a similar means. Because of this, a class of unimolecular chimeras have become widely sought after through the use of a structural blend of the structural homologies there are conserved in GLP-1, GIP, and Gcg (Fig. la, yellow highlights). A focal point to the initial excitement of the unimolecular chimeras was the development of a dual-agonist of the GLP-1R and GIPR, which broadly elicited glucose control and enhanced weight reduction compared to GLP-1R mono-agonists.10Tirzepatide, a clinically approved chimeric GLP-l / GIP dual agonist, can promote 15-20% weight loss in humans, consistently outperforming mono-agonist competitors.11 12In 2015, Finan and colleagues demonstrated that a dual agonist of GLP-1R and GIPR, when co-administered with a glucagon derivative with a similar circulation time, produced a significantly higher % weight loss in diet induced obese mice compared to the dual agonist alone.9This work evolved into the chemical derivatization of a peptide chimera that was capable of agonizing all three receptors, referred to as a triagonist (Fig. la).9 13 14Another triagonist, retatrutide (LY3437943), of GLP-1R, GIPR, and GcgR was recently developed by researchers at Eli Lilly (Fig. la). In a 24-week phase 2 clinical trial analysis, retatrutide was capable of providing a maximal 24% weight loss in obese and overweight individuals.9 15Although the clinical studies that elucidated the weight loss were performed in differing regiments, there is a clear semi-linear relationship between the number of receptors agonized and maximal weight loss regarding GLP-1R agonists that are also active at GIPR and GcgR.

[0009] The 36-mer PYY has recently entered the spotlight as another hormone that induces key therapeutically relevant effects in the body leading to weight loss.16 19PYY has two active circulating forms, the full length (1-36) and the DPP4-degraded form (3-36). The full length PYY is potent at multiple receptors within the neuropeptide Y (NPY) receptor family, while the PYY3-36 form is a selective agonist of the neuropeptide Y2 receptor (“Y2R”).20Selective agonists of Y2R are one some of the most abundantly studied in this family, due to their beneficial effect in weight loss promotion through satiety signaling in the brain, delayedgastric emptying in the stomach,21,22and lipolysis and thermogenesis.23,24Additionally, PYY3-36 combination treatments with GLP-1 show that Y2R agonism improves HbAlc levels, weight loss, and total insulin secretion from the pancreas in diet induced obese mice.25The NPY receptor family are class A GPCRs, which are agonized differently than GLP-1R, GIPR, and GcgR.20Analysis of the PYY3-36-Y2R complex illustrates that the binding interactions occur at the C-terminal end of PYY, which contrasts strongly with the N-terminal interaction necessity found in GLP-1R, GIPR, and GcgR agonists (Fig. lb). In past work conducted by Ostergaard and colleagues, it was demonstrated that only a small C-terminal portion of PYY is necessary to reach full agonism of Y2R.26This work demonstrated that a peptide hybrid containing the N-terminus of GLP-1 and the C-terminus of PYY was capable of agonizing both receptors, and demonstrated greater appetite suppression than treatment of GLP-1R agonists or Y2R agonists alone.26In other work on the peptide GEP44, which is an agonist of the GLP-1R and Y2R, it was observed that this peptide stimulated greater food intake reduction and produced less emetic episodes than exendin-4, which is an FDA-approved GLP-1R agonist.27,28A combination therapy study examining a long acting GIPR agonist and Y2R agonist corroborated the potency of Y2R agonism in inducing weight loss, but also demonstrates that the additional GIPR agonism contributed to a reduction in nausea of mice populations compared to Y2R agonist treatment alone.29With the consideration of past literature, it was hypothesized that the C-terminal PYY tail could be grafted onto carefully tuned chimeric multi-agonist scaffolds. The resulting series of tetra-receptor agonist chimeras (TC) produced in this work presents a novel class of tetra-agonists that are within a length accessible to solid-phase peptide synthesis (SPPS) and other scalable methods with high potency, efficacy, and therapeutic translatability (Fig. la-c).

[0010] To test the feasibility of generating a tetra-receptor agonist chimera, we begun by examining the reported triagonist from Finan and co-workers (Triagonist, Fig. la).9We elected to replace the lipidation at position 10, and insert the C-terminus of PYY24-36 at the 33rdposition. Past research by the work of Ostergaard and co-workers demonstrated that this length of the C-terminus was essential for maintaining activity at Y2R,26and Roth, Doyle, and colleagues have demonstrated that substitutions at the 33rdposition are optimal.27The resulting compound, TAI (Fig. 1c), provided good Y2R activity (6.6-fold loss), good relative activity at GcgR (10-fold loss), robust GLP-1R potency compared to GLP-1 (6.5-fold improvement), but, unfortunately, suffered poor GIPR activity (80-fold loss). This compoundwas considered a triagonist of the GLP-1R, GcgR, and Y2R, and although such a triagonist may provide useful future prospect, the pursuit of the tetra-agonist was continued (Table 1).

[0011] To repeat this process, a reported tri-agonist, retatrutide, was selected for chemical modification.30Of note, aside from the Aib at the second position for DPP4 stability, this scaffold contained two additional a-methyl-L-amino acids at the 13th(aMeL, L“) and 20th(Aib) positions (Fig. la). The issue with these two residues is their high cost and difficulty in optimal coupling yield in SPPS. Therefore, these two unnatural amino acids were replaced for natural counterparts that were postulated to be tolerated by the receptors with a dual L“isL and X20Q exchange to form RET1.Table Key: identity of the peptides in past literature, and this works reported constructs based on the triagonist and retatrutide from figure 1. Agonism at the GLP-1R, GIPR, and GcgR utilized the cAMP CREex-lucif erase reporter system, Y2R agonism was measured using the chimeric Gqi5 stimulated SRE-luciferase reporter system. All assays were performed using HEK293 cells.bModifications were conducted (shown on in parenthesize) on the prior specified construct. Lipid sidechain modifications (in brackets) are acylated on the lysine side chain at the designated position.cECso is the concentration of peptide required for half-maximal activity at the target receptor, and experiments not tested at the receptor are labeled (-), experiments where no agonism was detected are labeled (ND). A minimum of three separate experiments was performed for each peptide at each respective receptor.dEC5o of a compound with a two separate experiments.eThe fold-shift indicating whether the potency of the compound is better (f) or worse (|) the compound is compared to the native ligands’ potency at each receptor. A difference of < 1.5-fold is considered equally active at each receptor. Error in all compounds (SEM) was no more than 50% of the potency value with exceptions designated with (*).fThe native ligands used were GLP-1 for GLP-1R, GIP for GIPR, Gcg for GcgR, and PYY for Y2R. The EC50 + SEM of the values reported in Table 1 can be found in Table S3, with molecular weight characterization reported in Table S4 and sequences in Table S5.Table 1. Activities of GLP-1, GIP, glucagon, PYY, and the tetra-receptor chimera analogues.GLP-1 Receptor GIP Receptor Gcg Receptor Y2 Receptor EC50 (pM)cFold-Shift EC50 (pM)cFold-Shift EC5o(pM)cFold-Shift EC5o(pM)cFold-Shift Peptide" Modification^7(W)xe(Wxe(Wxe(WxeNative ligand^ 2.6 3.5 12 60 Semaglutide 0.81 $ 3.2 Tirzepatide 35 $ 13 2.6 equal Retatrutide 11 $ 4-2 2.3 $ 1.5 9.8rfequalGEP44 0.58 $ 4.5 12000^ $ 200 TAI Triagonist (Y10, 33- 0.4 $ 6.5 280 $ 80 120 $ 10 400 $ 6.7 PYY24-36)RET1 Retatrutide (LI 3, 36000 $ 14,000 10000* $ 2,900 3200* $ 270Q20)RET2 RET1 (K17) 3.1 equal 425* $ 120 550* $ 46TCI RET2 (33-PYY24-36) 0.4 $ 6.5 2.3 $ 1.5 130 $ 11 170rf$ 2.8 TC2 TCI (K10[3], V37, 2.1 equal 0.98 $ 3.6 30 $ 2.5 55 equal W39, L40)TC2a TC2 (K10[yE- 17 $ 6.5 120 $ 34 3200 $ 270 1200rf$ 20 C20DA])TC2b TC2a (Y10, K31[2]) 110 $ 42 210 $ 60 NA 160 $ 2.6 TC2c TC2b (K31[4]) 95 $ 37 330 $ 5.5 TC2d TC2c (K16[2], P31) 89 $ 34 39 $ 11 350* 440 $ 7.3 TC2e TC2d (K16, K17[l]) 91 $ 35 2.7 equal 140 $ 12 170 $ 2.8 TC2f TC2e (K17[2]) 89 $ 34 5.6 $ 1.6 250 $ 21 290 $ 4.8 TC2g TC2f (K17[4]) 55 $ 21 6.3 $ 1.8 140 $ 12 1700 $ 28 TC2h TC2g (K17[l], X20) 47rf$ 18TC2i TC2h (K17[O2X- 530* $ 200 87 $ 25 3100rf$ 52PA-YE-C18DA])Table 1 Cont.TC2j TC2j (K17[O-PA- 47 18 1.3 t 2.7 2irf1.8 1900 32\E-C18DA])TC3 TC2j (K17[5]) 1.8 equal 0.75 t 4.7 23 1.9 420 7 TC3a TC3 (K17, 4.7 1.8 1800rf30NMeR44)TC3b TC3a (K17[l]) 53 20TC3c TC3b (K17[5]) 20 7.7 1.1 t 3.2 29 2.4 16000 270 TC3d TC3c (L“13, K17) 1.1 J 2.4 0.50rfvTC3e TC3d (K17[l]) 21 j, 8.1 0.95 t 3.7 38rf3.2TC3f TC3e (K17[5]) 18 8 1.2 t 2.9 41 3.4 20000 330 TC4TC3 (R16, A20) 31 12 0.98 T 3.6 81 1 6.8 1100 18

[0012] To our surprise, we observed detrimental activity losses in activity at GLP-1R, GIPR, and GcgR through these two mutations (Table 1). Removal of the retatrutide lipid to a lysine (lipid 4, position 17) yielded RET2, which exhibited an encouraging revived activity at the three receptors (Table 1). Introduction of the PYY C-terminal tail at position 33 of RET2, provided a highly potent agonist at each receptor.31As a result, this resulting scaffold, TCI, was deemed the first tetra-receptor agonist chimera that future iterations were conducted on (Fig. 1c). TCI showed a 6.5-fold improvement at GLP-1R, near-equal potency at GIPR, a 11-fold loss in activity at GcgR, and a 2.8-fold loss in activity at Y2R (Fig. la, Table 1). This finding suggests that the presence of the exendin tail found in most multi-receptor agonists within the field of GLP-1R, GIPR, and GcgR agonism may not be an exclusive strategy for improvingactivity,9’13’30’32’33and the PYY c.t.’s addition could serve two functions; its addition could improve activity of an already established agonist of GLP-1R, GIPR, and potentially GcgR, and it can also provide a nearly equipotent agonist at Y2R compared to PYY.

[0013] Lipidation was next investigated for the TCI peptide scaffold as a means of providing serum albumin binding, which is known to increase circulation time in the body, thereby increasing half-life, and to a certain extent enzymatic stability.8,34The first lipid examined for introducing longer half-life was a yGlu (yE) directly conjugated to a lysine followed by palmitic acid (Cl 6 acyl) to form lipid 3, which is featured in the triagonist peptide and liraglutide (Fig. la, d, e).9This lipid has a demonstrated high affinity to albumin, giving the peptide improved pharmacokinetics (PK).8,35,36In follow up studies examining cryoEM of the triagonist peptide bound to GLP-1R, GIPR, and GcgR, it was postulated that the lipid 3 at position 10 may have cell membrane association in the bound state, which may also occur when placed in the TCI construct.37In addition to this lipids’ introduction, the C-terminal tail of the TC scaffold was modified with the L37V, L39W, and V40L substitutions to increase the peptide’s potency at Y2R, partially based on previously established literature.26This resulting construct with the modified PYY C-terminus and the lipid 3 acylation at position 10 formed TC2, which demonstrated encouraging potency and efficacy at each receptor. The TC2 peptide was relatively equipotent at GLP-1R, 3.6-fold greater in activity at GIPR, 2.5-fold worse at GcgR, and equally potent at Y2R, all compared to native ligands (Table 1, Fig.2a). Notably, the TC2 compound demonstrated improved activity at both GcgR and Y2Rcompared to TCI, likely owed to the lipid’s addition for the former and the C-terminal modifications for the latter.

[0014] Despite this large advancement in the TC design, the next focus became the advancement of the lipid protraction moiety to a lipid diacid. The lipid diacid is featured in many recent peptide hormone-based therapeutics due to its higher albumin affinity and greater determined in vivo protraction compared to lipid 3 and similar mono-acid moieties. Previous work by Lau and coworkers showed that semaglutide had a >3 fold longer half-life in mini-pigs via i.v. administration as compared to liraglutide, which may be partially correlated to the fact that it has a 5.6-fold greater affinity to albumin than liraglutide, as measured by analytical ultracentrifugation.8Accordingly, a series of positions on TC2 were scanned for lipid diacid (DA) tolerance. The first modification made was at the 10th position TC2, where the C16 acyl was replaced with the C20DA to form TC2a (KioyE-C2ODA). This change resulted in a large loss in activity at GIPR and GcgR, which may be attributed to the unfavorable proximity of the lipids terminal acid to the cell membrane when in the ligandreceptor bound state. Thus, a series of other positions were scanned for lipid diacid tolerance, with position 10 exchanged for a tyrosine for closer GIP and Gcg sequence homology. The 31st position of TC2 was examined for lysine conjugated tirzepatide (lipid 2, TC2b) and retatrutide (lipid 4, TC2c) lipid side chains. There is precedented work that shows that lipid diacid conjugation to PYY3-36 at this relative position to the C-terminus (position 22 of PYY, position 31 of TC2) was tolerated,34however, we observed major impacts to potency (Table 1). Our conclusion from this lipidation site was that the Y2R agonist region of the TC cannot accommodate a lipid side chain. Thus, position 16 was chosen as a lipidation site, as that region appears to be solvent exposed in cryoEM, and has precedent in bearing a lipid diacid in other triagonists of GLP-1R, GIPR, and GcgR.32In our hands, this position bearing the lipid 2 side chain (TC2d) was far better than position 31, but still presented a negative impact on most receptors, with potency losses at GLP-1R, GIPR, and GcgR (Table 1). These results encouraged the thought that the middle area of the GLP-1R, GIPR, GcgR agonist region of TC2 could potentially accommodate a lipid side chain, leading to position 17 being explored. This position is where retatrutide is lipidated and was a well-tolerated position in the development of liraglutide.30,38While this position was tolerated in the TC2 construct by GIPR and GcgR, with fluctuating Y2R activity based on linker design and lipid selection, the GLP-1R activity was consistently below desirable levels (TC2(e-g), Table 1).

[0015] To remedy this loss in GLP-1R activity, the Aib residue was introduced at the twentieth position of the peptide backbone to form a potentially improved scaffold. This position has a long history in chimeric multi-agonists as being a necessary region for chemically induced strong a-helical structure. DiMarchi and coworkers have developed numerous multi-agonist compounds that support this assertion through both lactam and Aib placement at this position.13 14,32To additionally test the lipid diacid tolerance of the TC2 modified construct, a series of lipid linkers were tested, such as y-L-glutamic acid (yGlu, yE), 8-amino-3,6-dioxaoctanoic acid (OEG, O), and P-alanine (PAla, PA) placement at various points on the 17th position of the scaffold. From the assessment of varying linker-conjugated lipid diacids (TC2(h-j)) it was found that the pA-O-yE-C18DA motif (lipid 5) was a standalone highly potent compound at the GLP-1R, in addition to the other receptors, which designated the new construct TC3. This TC3 scaffold demonstrated slightly greater potency at GLP-1R, 4.7-fold greater potency at GIPR, 1.9-fold worse potency at GcgR, and 7 -fold worse activity at Y2R (Fig. la, Table 1). The compound TC2j has P-alanine and OEG in reversed positions compared to TC3, yet it exhibited a worse activity profile at GLP-1R.

[0016] The positive finding in the TC3 scaffold led to additional exploration into enzymatically stabilizing factors. The N-methyl arginine (NMeR) motif was introduced at the second to last position to the C-terminus based on the work of Ostergaard and coworkers that illustrated its potential importance in improving stability in PYY analogues (Fig. 1c, f).34While this modification was reported to be minimally perturbative to Y2R activity in PYY analogues, this modification within the TC3(a-c) constructs reduced active at NPYR. The non-lipidated TC3a presented a 30-fold potency reduction compared to PYY, with the lipidated TC3c peptide (lipid 5 at position 17) suffering a 270-fold potent loss. In parallel to the exploration to the NMeR placement in the TC3 scaffold, the TC3(d-f) constructs was substituted with a aMeL residue (L“) at position 13 to restore a more similar structural motif to retatrutide. While there is evidence that this 13thposition may be degraded by neprilysin, and therefore placement of a-methyl amino acids may be an important stabilizing force, it was a surprise that no notable activity changes occurred.39The scaffolds TC3a and TC3d were found to be highly potent agonists of the GLP-1R. Attaching the semaglutide lipid side chain featured in TC3b and TC3e predictably resulted in a subtle loss in activity, as observed previously in TC2h, however, the conjugation of the previously optimized lipid 5 of TC3 did not recover activity as expected in the TC3d and TC3f peptides.

[0017] A final sequence design was examined as a possible peptide scaffold more adaptable to a scaled production using yeast or similar peptide synthesis technologies. Thus, the Aib residue in TC3 at position 20 was changed to alanine, and the lysine at position 16 of the structure was mutated to an arginine (X20A, K16R) to form TC4 (Fig. la). This TC4 scaffold may allow a hypothetical assembly comparable to semaglutide, which is assembled in yeast to the third position, acylated orthogonally with the lipid (to form lipid 1), and finally coupled with the first two N-terminal residues (His-Aib) to form the full-length drug. Although this resulting TC4 construct had tolerable activity at the four receptors (Table 1) its loss in activity at GcgR compared to TC3 to resemble the potency of TCI was expected (Table 1, Fig. 2a, c).

[0018] Compounds that can occupy and help populate different regions of the available conformational space when receptor-bound may trigger 'bias' in the signaling pathways associated with GPCR activation.40,41Signaling bias can tune down pathways linked to receptor internalization, thus promoting longer lasting agonism and consequently productive phenotypic outcomes. Indeed, a single amino acid change such as substitution at the second position from the N-terminus to valine in GLP-1 can dramatically change receptor signaling bias to favor the G protein-coupled pathway and reduce internalization mediated by P-arrestin recruitment.41,42The capability of tirzepatide to function as a biased agonist of GLP-1R to favor cAMP signaling may partially explain its utility as a therapeutic; it is internalized less, which may counteract its known potency loss at the GLP-1R compared to the native ligand.11

[0019] To examine the degree of bias between the cAMP-stimulatory signaling pathway and the recruitment of P-arrestin, we tested the P-arrestin-2 (PArr-2) construct employing a bioluminescence resonance energy transfer (BRET)-based bioassay to measure P-arrestin recruitment to the receptor. The GLPlR-RLuc8 and GFP2-P-arrestin-2 (R393E, R395E) fusion proteins were transiently transfected into HEK 293T cells following previously outlined protocols.42, 45These assays were normalized to the maximal and minimal activity of GLP-1, where the efficacy of agonists present were measured relative to the maximum to yield the max response (% GLP-1) reading (Table 2). Tirzepatide has proven to be a highly biased construct with an 18% relative maximal efficacy to GLP-1.11As expected, semaglutide was found to not exhibit significant bias, and retatrutide exhibited mild bias (58% maximal recruitment relative to GLP-1) which was in line with expectations.30As a prelude to analyzing the various lipid-bearing tetra- agonists, the TAI and TCI constructs were tested, with neither construct showing high degrees of bias. Analysis of the TC2compound showed a notably biased signaling profile, with slightly less than half of the maximal recruitment of the P-arrestin-2 protein at the GLP-1R while having equally potent cAMP production compared to GLP-1 (43% relative P-Arr2 recruitment, Table 2). Analysis of one of the next leading constructs with the lipid diacid, TC3, showed a contrasting story, with a now elevated recruitment of the P-arrestin-2 protein (120%, Table 2). These data demonstrate a stark difference between the TC2 to TC3 analogues. The single R44NMeR mutation of TC3c compared to TC3 was found to obstruct P-arrestin-2 recruitment (18% relative P-Arr2 recruitment, Table 2, Fig. 4a).

[0020] To examine this concept, we utilized the recently released AlphaFold 3 program to predict the binding interaction that takes place between TC3 and the GLP-1R sequence.46, 47Due to AlphaFold 3’s inability to process non-canonical amino acids, the Aib at position 2 and 20 was changed to an alanine, and the lipid at position 17 was removed for a free lysine (Fig. 3b). From this predicted structure we observed the expected binding interactions occurring from the first to the approximate 33rd position of our compound. However, the PYY C-terminus was shown not to have any receptor binding interactions. We believe that this visual interaction aids in understanding the oddity observed in the differential arrestin signaling of TC3c compared to TC3 (Fig. 3c). The strong bias of the TC3c molecule towards cAMP signaling verses P-arrestin-2 recruitment was reduced significantly by the additional incorporation of the aMeL at position 13 of TC3f (Fig. 7c). This residue was believed to makes important ligand-receptor interactions with mild solvent exposure, which may improve the ligands binding to the receptor and stabilize the conformational states that recruit arrestin (Fig. 3b, d). As previously noted, this TC3f analogue containing the aMeL residue had a nearly identical cAMP stimulatory effect compared to the TC3c analogue at the GLP-1R, however its maximal P-arrestin-2 recruitment was significantly higher. This finding led us to believe that the application of the a-methyl substituted residues may be applicable as a tool for tuning the bias in arrestin recruitment under certain situations (Fig. 3f). Analysis of the final construct, TC4, revealed a biased nature like tirzepatide and TC3c, simply through a Lysl6Arg and Aib20Ala mutation to the TC3 scaffold to produce a 14% relative P-Arr2 recruitment compared to GLP-1 (Fig. 3a, e, Table 2). This finding was surprising as it furthers the previous assertion that the TC4 construct has a strong resemblance to the in vitro pharmacology of tirzepatide regarding potency in cAMP production at the GLP-1R and GIPR, and signaling bias exhibited at the GLP-1 R (Fig. 7a-c). In addition, TC4 introduces additional GcgR and Y2R agonism.-ARRESTIN-2pEC5(? Max response (% nGLP-1)c-7.27 + 0.12 100 6-7.57 + 0.05 92 + 5 4NDe18 + 2 6-7.62 + 0.07 58 + 5 6-7.67 + 0.07 66 + 4 4-7.67 + 0.09 90 + 5 4-7.55 + 0.05 110 + 7 3-7.57 + 0.21 43 + 7 3-7.29 + 0.11 120 + 5 4NDe18 + 2 6 -7.51 + 0.06 43 + 2 4NDe14 + 2 6 identity of the peptides that were evaluated (Fig. 1, Table 1). Values reported are the mean + SEM of >3 independent experiments. P-arrestin-2 recruitment was measured through the BRET assay.bpEC5o = -log(EC5o) of independent experiments.cMaximal response was measured by the normalization of the analogue to the maximal response % of GLP-1. " Compounds that exhibited an unstable potency due to a poor R2 fitted values.

[0021] To investigate the potential biological impact of lipid acylation on the TC2 and TC3 constructs, we elected to measure the EC50 of our constructs with and without 2% (w / v) human serum albumin (HSA) at the GLP-1R, utilizing the cAMP luciferase reporter bioassay reported in prior studies.8 11,44A substantial decrease in potency at GLP-1R was observed when the lipidated agonist was co-incubated with 2% HSA, suggesting the formation of a nonsignaling HSA-construct complex that illustrates affinity of the peptide to albumin (Table SI). The observed change in activity in + 2% HSA incubation was the highest with semaglutide (1,200-fold), with the TC2 (130-fold) and TC3 (140-fold) constructs a less dramatic change in activity. This realization was not of high surprise, the original semaglutide paper did report that the linker regions in the lipid diacid played a role in their receptor binding ratio with + 2% HSA. This paper demonstrated that the C20 diacid and C18 diacid a large ratio difference in binding the GLP-1R + 2% HSA. However, ultracentrifugation of those two diacid lipids showed the same relative binding, and both of these diacid bearing constructs showed equal circulation time in rats.8Therefore, despite this shorter realized change in the EC50 + 2% HSA for TC3, we remained convinced that this analogue and its similar diacid bearing moieties produced in this work would allow for a comparable circulation time to the semaglutide, tirzepatide, and retatrutide compounds.

[0022] With the validation that the lipid side chain provided strong albumin binding (TC2 and TC3), we next investigated the stability of our compounds against DPP4. Studies haveshown that in addition to diacid incorporation, a DPP4 protective element is also necessary for long-acting analogues.8To investigate our constructs stability against this serine protease, we utilized the luciferase-based cAMP assay. This method is based on the observation that the truncated GLP-1 peptide (9-36 amide) suffers a >103-fold loss in potency at GLP-1R. Thus, incubating of GLP-1 and our constructs with either vehicle or with DPP4 will provide a fold-shift in potency that will inform whether significant DPP4-catalyzed degradation has occurred. Incubation of the GLP-1 peptide with DPP4 demonstrated a significant loss in potency (Fig. 4a, Table S2). Past work has demonstrated that the half-life GLP-1 to the 9-36 amide truncated product within the parameters of this assay occurs in less than a minute.7This assay demonstrates that the compounds TC2, TC3, and TC4 suffer no significant loss in potency with or without the enzyme, establishing their refractory nature to DPP4 (Fig. 4b-d, Table S2). This finding was not surprising, as it is widely known that Aib placement at the second position of DPP4 substrates (Pl residue to the scissile bond), such as GLP-1 and GIP, provides full enzymatic protection.

[0023] Previous studies have illustrated the clinical advancement of producing a single-agent peptide chimera that agonizes the GLP-1R, GIPR, and GcgR over dual-agonists that agonize GLP-1R with either GcgR or GIPR, or a monoagonist of GLP-1R.9,32Additional studies have shown that GLP-1R and Y2R dual-agonists can produce superior appetite suppression than GLP-1R agonists alone,26,27and GIPR agonist co-administration with Y2R agonists significantly reduce nausea,29which is known to plague GLP-1R and Y2R mono-agonists. Collectively, this information suggests that a single-agent tetra-receptor agonist of GLP-1R, GIPR, GcgR, and Y2R is a highly therapeutically interesting chemical species, that until now has never been reported. Our work has illustrated that our derived scaffolds can be accommodative to a variety of lipid acylation positions and types to delay renal clearance in vivo. We have also shown that our scaffold can maintain acceptable activity at each receptors without the necessity of unnatural amino acids found within the binding region that other multi-agonists rely on.30,33,45This finding furthers the translatability of our work as this processing technology could be applied to scaffolds greater than the general SPPS limit of 50 amino acids, allowing the C-terminus of TC4 to be potentially applied to longer C-terminal sequence elements. Additionally, the field of metabolic disease is quite broad, in certain situations one of the four receptors agonized by our construct may not be desirable, thus we are actively working on various tri-and dual-agonists that are capable of agonizing a variety of receptor combinations.

[0024] In some aspects, the present invention provides a peptide having at least 85% sequence identity to Formula A:XaaiXaa2Xaa3GTXaaeXaa7 SDXaai oSXaai 2Xaai 3 Xaa 14Xaai 5 Xaa16 X aa 17 X aa 1 sXaai 9 X aa2oX a a2iFXaa23Xaa24Xaa25Xaa26Xaa27Xaa28GGXaa3iSXaa33RXaa35Xaa36Xaa37 NXaa39Xaa4oTRX aa43Xaa44Y -NH-RFormula A;wherein:Xaai is selected from:wherein R1is selected from hydrogen, alkyl, fluoroalkyl, and alkyl-heteroaryl; Xaa2 is selected from A, Aib, AzaA, G and V;Xaa3 is selected from Q, E, H, aMeE and aMeQ;Xaae is selected from F, aMeF and a-Me-2-fluorophenylalanine;Xaa? is selected from T and I;Xaaio is selected from Y, L, K and K;Xaai2 is selected from I, K and K;Xaai3 is selected from L, Y, aMeL, Aib, K and K;Xaai4 is selected from L and K;Xaais is selected from D and E;Xaaie is selected from E, R, K and K:;Xaan is selected from R, K and K;Xaais is selected from A, Y and R;Xaai9 is selected from Q and A;Xaa2o is selected from Q, Aib, A, K and K;Xaa2i is selected from E, D, Aib, K, K:and A;Xaa23 is selected from I and V;Xaa24 is selected from E and Q;Xaa25 is selected from W, Y and aMeY;Xaa26 is selected from L, K, and K,Xaa27 is selected from K, K, L and I;Xaa28 is selected from K, K, E, A and D;Xaasi is selected from P, K and K:;Xaa33 is selected from L, D-proline and aMeL;Xaa35 is selected from H and 3-(4-pyridyl)alanine;Xaa36 is selected from Y and 3 -cyclohexylalanine;Xaa37 is selected from L, V, Y, aMeL, Aib and aMeY;Xaa39 is selected from W, L, K, aMeL, Aib and aMeY;Xaa4o is selected from V, L and aMeL;Xaa43 is selected from Q and aMeQ;Xaa44 is selected from R and NMeR;each K:is independentlyHbEpLinkerlIRLinker2iRLinker3\TwhereinRLinker1, RLinker2and RLinker3are independently selected from a linker group and a covalent bond;RTcomprises a lipid moiety or an oligosaccharide moiety; andR2is selected from hydrogen, alkyl and fluoroalkyl;provided that the peptide is not:Retatrutide: YXQGTFTSDYSIαLDK4AQXAFIEYLLEGGPSSGAPPPS–NH2; Tirzepatide: YXEGTFTSDYSIXLDKIAQ2AFVQWLIAGGPSSGAPPPS–NH2; Triagonist: HXQGTFTSD3SKYLDERAAQDFVQWLLDGGPSSGAPPPS-NH2; Analogue 19: HXEGTFTSDVSSYLEGQALRHYINWLTRQRY-NH2;Compound 16: HXHGTFTSDYSIYLEQKYAXEFVQWLLEGGPSSGAPPPS- NH2;GEP44: HsQGTFTSDLSKYLEEEAVREFIAWLKNGGPSRHYLNLVTRQRY- NH2; orSAR441255: HXHGTFTSDLSKL(][EEQRQXEFIEWLKAaGPPSXKPPPK-NH2;wherein:□ is Lysine acylated with sLys-sLys-yGlu-C O diacid;[ is Lysine acylated with yGl u-yGl u-C 16 acyl;s is D-serine;a is D-alanine;4 is Lysine acylated with OEG-y-Glu-C20 diacid;3 is Lysine acylated with y-Glu-C16 acyl;2 is Lysine acylated with OEG-OEG-y-Glu-C20 diacid; anda is a-methyl-L- Leucine, also referred to as (aMeL, L“).

[0025] In some aspects, the present invention provides a peptide having at least 85% sequence identity to Formula A:XaaiXaa2Xaa3GTFTSDXaaioSXaai2Xaai3Xaai4Xaai5Xaai6Xaai7Xaai8Xaai9Xaa2oXaa2iFX aa23Xaa24Xaa25Xaa26Xaa27Xaa2sGGXaa3iSLRHYXaa37NXaa39Xaa4oTRQXaa44Y-NH-R2Formula A;wherein:Xaai is selected from:wherein R1is selected from hydrogen, alkyl, fluoroalkyl, and alkyl-heteroaryl; Xaa2 is selected from A, Aib, AzaA, G and V;Xaa3 is selected from Q, E and H;Xaaio is selected from Y, L and K;Xaai2 is selected from I, K and K;Xaai3 is selected from L, Y, aMeL, K and K;Xaai4 is selected from L and K;Xaais is selected from D and E;Xaaie is selected from E, R, K and K:;Xaan is selected from K and K;Xaais is selected from A, Y and R;Xaai9 is selected from Q and A;Xaa2o is selected from Q, X, A, K and K;Xaa2iis selected from E and D;Xaa23 is selected from I and V;Xaa24 is selected from E and Q;Xaa25 is selected from W and Y;Xaa26 is selected from L, K, and K,Xaa27 is selected from K, K, L and I;Xaa28 is selected from K, K, E, A and D;Xaasi is selected from P, K and K:;Xaas? is selected from L and V;Xaa39 is selected from W and L;Xaa4o is selected from V and L;Xaa44 is selected from R and NMeR;each K:is independentlyH NHN^RLinkerlRLinker2LinkersRTwhereinj^Lmkeri, j^Lmker2 anj RLinker3arejn(jepencien11 y selected from a linker group and a covalent bond;RTcomprises a lipid moiety or an oligosaccharide moiety; andR2is selected from hydrogen, alkyl and fluoroalkyl;provided that the peptide is not:Retatrutide: YXQGTFTSDYSIαLDK4AQXAFIEYLLEGGPSSGAPPPS–NH2; Tirzepatide: YXEGTFTSDYSIXLDKIAQ2AFVQWLIAGGPSSGAPPPS–NH2; Triagonist: HXQGTFTSD3SKYLDERAAQDFVQWLLDGGPSSGAPPPS-NH2; Analogue 19: HXEGTFTSDVSSYLEGQALRHYINWLTRQRY-NH2;Compound 16: HXHGTFTSDYSIYLEQKYAXEFVQWLLEGGPSSGAPPPS- NH2;GEP44: HsQGTFTSDLSKYLEEEAVREFIAWLKNGGPSRHYLNLVTRQRY- NH2; orSAR441255: HXHGTFTSDLSKL(][EEQRQXEFIEWLKAaGPPSXKPPPK-NH2; wherein:□ is Lysine acylated with sLys-sLys-yGlu-C20 diacid;[ is Lysine acylated with yGl u-yGl u-C 16 acyl;s is D-serine;a is D-alanine;4 is Lysine acylated with OEG-y-Glu-C20 diacid;3 is Lysine acylated with y-Glu-C16 acyl;2 is Lysine acylated with OEG-OEG-y-Glu-C20 diacid; anda is a-methyl-L- Leucine, also referred to as (aMeL, L“)., FC 0 >

[0026] In certain embodiments, R is selected front hydrogen,

[0027] In certain embodiments, R1is hydrogen.

[0028] In certain embodiments, R2is hydrogen. In certain embodiments, R2is alkyl or aralkyl. In certain embodiments, R2is selected from ethyl, isopropyl, isobutyl, benzyl,

[0029] In certain embodiments, R2is fluoroalkyl. In certain embodiments, R2is selected from 1,1,1 -trifluoroethyl and 1,1,1,2,2-pentafluoropropyl.

[0030] In certain embodiments, RLinker1is selected from a covalent bond and:wherein n is 1-24.

[0031] In certain embodiments, RLinker1is selected from a covalent bond and

[0032] In certain embodiments, RLinker2is selected from a covalent bond and:wherein n is 1-24.

[0033] In certain embodiments, RLinker2is selected from a covalent bond and

[0034] In certain embodiments, RLinker3is selected from a covalent bond and:wherein n is 1-24.

[0035] In certain embodiments, RLinker3is selected from a covalent bond andMa.<>->. A x..Hand S

[0036] In certain embodiments, RTis selected from:Of MO:;VA Av...--_anjwherein RSis selected from CH3, CO2H, CO2R$$, P(O)(OH)2, SO3H, tetrazole,....... Jj* / ’ KOH QO X4, and Hwherein R$$is selected from:O',, and R$$$ js seiected from:wherein R&&is selected from:wherein R&&&is selected from, andV-H V^nwherein R&&&&is selected from:, and ',@wherein R&&&&&isselected from:, and *,<s,,zOH v^@wherein R&&&&&&sselected from:, and;provided that one and only one of R&, R&&, R&&&, R***&*ANC|comprises - @Y@wherein R#is selected from: and,Owherein -@ represents the point of attachment to the remainder of the molecule; a is 1-24; andm is 6-24.

[0037] In certain embodiments, RTis:

[0038] In certain embodiments, RSis CH3 or CO2H.

[0039] In certain embodiments, RTis:wherein x is 1-20.

[0040] In certain embodiments, RLinker1is a covalent bond orRL1nker3& covalent bond OroR$is Me or CO2H;n is 1-4; andm is 14-18.

[0041] In certain embodiments, at least one of Xaaio, Xaai3, Xaaie, Xaai7, Xaa2o, Xaa26, Xaa27, Xaa28 and Xaa3i is Kt In certain embodiments, at least one of Xaaio, Xaaie, Xaai7 and Xaa2o is Kt In certain embodiments, Xaai is Y. In certain embodiments, Xaa2 is Aib. In certain embodiments, Xaas is Q.

[0042] In certain embodiments, the peptide has at least 90% sequence identity to Formula A. In certain embodiments, the peptide has at least 95% sequence identity to Formula A. In certain embodiments, the peptide has Formula A.

[0043] In certain embodiments, the peptide is an agonist of at least one receptor selected from GLP-1R, GIPR, GcgR and Y2R. In certain embodiments, the peptide is an agonist of Y2R. In certain embodiments, the peptide is an agonist of at least 2 receptors selected from GLP-1R, GIPR, GcgR and Y2R. In certain embodiments, the peptide is an agonist of GLP-1R and Y2R. In certain embodiments, the peptide is an agonist of GIPR and Y2R. In certain embodiments, the peptide is an agonist of at least 3 receptors selected from GLP-1R, GIPR, GcgR and Y2R. In certain embodiments, the peptide is an agonist of GLP-1R, GIPR and Y2R. In certain embodiments, the peptide is an agonist of GLP-1R, GIPR, GcgR and Y2R.

[0044] In certain embodiments, the peptide is selected from:YAQGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;YAEGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;HAHGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;YXQGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;HXQGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;BAQGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;ZAQGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;YXQGTFTSD3SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY;YGQGTFTSD3SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY; YVQGTFTSD3SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY; BAQGTFTSD3SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY; JAQGTFTSD3SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY; YUQGTFTSD3SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLDKKAQQAFIEYLLEGG4SLRHYVNWLTRQRY; YXQGTFTSDYSILLDKKAQQAFIEYLLEGG2SLRHYVNWLTRQRY; YXQGTFTSDYSILLDK1AQQAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLDK2AQQAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLDK4AQQAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLD2KAQQAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSD5SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLDK1AQXAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLDK6AQXAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLDK7AQXAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLDK8AQXAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLDKKAQXAFIEYLLEGGPSLRHYVNWLTRQAY; YXQGTFTSDYSILLDK1AQXAFIEYLLEGGPSLRHYVNWLTRQAY; YXQGTFTSDYSILLDK8AQXAFIEYLLEGGPSLRHYVNWLTRQAY; YXQGTFTSDYSIaLDKKAQXAFIEYLLEGGPSLRHYVNWLTRQAY; YXQGTFTSDYSIaLDKlAQXAFIEYLLEGGPSLRHYVNWLTRQAY; YXQGTFTSDYSIaLDK8AQXAFIEYLLEGGPSLRHYVNWLTRQAY; YXQGTFTSDYSILLDR8AQAAFIEYLLEGGPSLRHYVNWLTRQRY; YXEGTFTSDYSILLDR8AQAAFIEYLLEGGPSLRHYVNWLTRQRY; HAHGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; YAQGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; YAEGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; HXHGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; YXQGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; YXEGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; JAHGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; YAEGTFTSDYSILLDKIAQ9AFVQWLIAGGPSLRHYLNWVTRQRY; YAEGTFTSDYSILLDKIAQ1AFVQWLIAGGPSLRHYLNWVTRQRY;YXEGTFTSDYSILLDKIAQKAFVQWLIAGGPSLRHYLNLVTRQRY;HXEGTFTSDYSILLDKIAQKAFVQWLIAGGPSLRHYLNLVTRQRY;HAQGTFTSDYSILLDKIAQKAFVQWLIAGGPSLRHYLNLVTRQRY;JAQGTFTSDYSILLDR8AQAAFIEYLLEGGPSLRHYVNWLTRQRY;HXQGTFTSDYSKYLDERAAQDFVQWLLDGGPSLRHYLNLVTRQRY;HAQGTFTSDYSKYLDERAAQDFVQWLLDGGPSLRHYLNLVTRQRY;HAHGTFTSDLSKLKEEQRQQEFIEWLKAGGPSLRHYLNWVTRQRY;YAQGTFTSDLSKLKEEQRQQEFIEWLKAGGPSLRHYLNWVTRQRY;HAQGTFTSDLSKLKEEQRQQEFIEWLKAGGPSLRHYLNWVTRQRY;HXHGTFTSDYSILLDK

[0010] AQXAFIEYLLEGGPSLRHYLNWaTR[aMeQ]RY;YXQGTFTSDYSILLDK

[0010] AQXAFIE[aMeY]LLEGGPSaRHYLNWLTR[aMeQ]RY; YXQGTFTSDYSILLDK

[0010] AQXAFIEYLLEGGPSLRHYLNWaTRQAY; yXQGTFTSDYSILLDR

[0010] AQAAFIEYLLEGGPSLRHYLNWLTRQRY;[11-Y]AQGTFTSDYSILLDR[1O]AQAAFIEYLLEGGPSLRHYLNWLTRQRY;[Ac-Y]AQGTFTSDYSILLDR

[0010] AQAAFIEYLLEGGPSLRHYLNWLTRQRY;FXQGTFTSDYSILLDR

[0010] AQAAFIEYLLEGGPSLRHYLNWLTRQRY; fXQGTFTSDYSILLDR

[0010] AQAAFIEYLLEGGPSLRHYLNWLTRQRY;[Ac-F]AQGTFTSDYSILLDR

[0010] AQAAFIEYLLEGGPSLRHYLNWLTRQRY;YXQGTFTSDYSILLDK

[0010] AQXAFIEYLLEGGPSpR[Pyr(4)][Cha]XNKVTRQRY- NH2;YXQGTFTSDYSILLDK

[0010] AQXAFIEYLLEGGPSpR[Pyr(4)][Cha]XNWLTRQRY- NH2;YXQGTFTSDYSIaLDK

[0010] AQXAFIE[aMeY]LLEGGPSaRHYLNWLTR[aMeQ]RY; YXQGTFTSDYSIaLDK

[0010] AQXAFIE[aMeY]LLEGGPSaRHYLNWLTRQAY;[ll-Y]AQGTFISDYSIALDR

[0010] AQQDFVQWLLAGGPSLRHYLNWLTRQRY;YXEGTFTSDYSILLDR

[0010] AQAAFVQYLIAGGPSLRHYLNWLTRQRY;YXEGTFTSDYSILLDK

[0010] AQXAFVQYLIAGGPSLRHYLNWLTRQAY;YXEGTFTSDYSIaLDK

[0010] AQXAFVQYLIAGGPSLRHYLNWLTRQAY;YXEGTFTSDYSILLDRIAQ

[0010] AFVQYLIAGGPSLRHYLNWLTRQRY; yAEGTFTSDYSILLDRIAQ

[0010] AFVQYLIAGGPSLRHYLNWLTRQRY;[ll-Y]AEGTFTSDYSILLDRIAQ

[0010] AFVQWLLAGGPSLRHYLNWLTRQRY;[ 11 - Y] AEGTFTSD YSILLDR

[0010] AQAAFVQWLLAGGPSLRHYLNWLTRQRY;YXEGTFTSDYSIaLDK

[0010] AQXAFVQWLLAGGPSaRHYLNWLTRQRY;YXEGTFTSDYSIaLDK

[0010] AQXAFVQWLLAGGPSLRHYLNWLTRQAY; YXEGTFTSDYSIaLDKIAQ

[0010] AFVQWLLAGGPSaRHYLNWLTRQRY; and yXEGTFTSDYSILLDR

[0010] AQAEFIEYLIAGGPSLRHYLNWLTRQRY; wherein:B is [2,2,2-triflouroethyl -Y];J is [2,2,2-triflouroethyl -H];Zis [Im-Y];X is Aib;3 is Lysine acylated with y-Glii-C 16 acyl;U is Aza-alanine;4 is Lysine acylated with OEG-y-Glu-C20 diacid;2 is Lysine acylated with OEG-OEG-y-Glu-C20 diacid;1 is Lysine acylated with OEG-OEG-y-Glu-C18 diacid;5 is Lysine acylated with y-Glu-C20 diacid;6 is Lysine acylated with OEG-OEG-PAla-y-Glu-C18 diacid;7 is Lysine acylated with OEG-PAla-y-Glu-C18 diacid;8 is Lysine acylated with pAla-OEG-y-Glu-C18 diacid;a is a-methyl-L- Leucine, also referred to as (aMeL, L“);9 is Lysine acylated with OEG-y-Glu-C18 diacid;0 (zero) is Lysine acylated with OEG-OEG-OEG-OEG-y-Glu-C18 diacid;* is Lysine acylated with OEG-OEG-C18 diacid;# is Lysine acylated with C16 acyl;Ais NMeR (N-terminally methylated arginine);10 is Lysine acylated with pAla-OEG-y-Glu-C18 diacid;aMeQ is a-methyl-L-glutamine;aMeE is a-methyl-L-glutamic acid;aMeF is a-methyl-L-phenylalanine;aMeY is a-methyl-L-tyrosine;Pyr(4) is 3-(4-pyridyl)alanine;Cha is 3-cyclohexylalanine;Ac-Y is N-terminally acylated L-tyrosine;Ac-y is N-terminally acylated D-tyrosine;Ac-F is N-terminally acylated L-phenylalanine;Ac-f is N-terminally acylated D-phenylalanine;11-Y is ((lH-imidazol-5-yl)methyl)-L-tyrosine;y is D-tyrosine;f is D-phenylalanine;p is D-proline;NMeY is N-terminally methylated tyrosine; andaMeF(2F) is a-Me-2-flourophenylalanine.

[0045] In some aspects, the present invention provides peptide having at least 85% sequence identity to Formula B:XaaiXaa2Xaa3GTXaaeTSDXaai oSXaai 2Xaai 3 Xaa i 4Xaai sXaai eXaai? Xaai sXaai 9 X aa 2oXaa2iFXaa23Xaa24Xaa25Xaa26Xaa27RXaa29Xaa3oXaa3iNXaa33Xaa34TRXaa37 Xaa38 Y-NH-R2Formula B;wherein:Xaai is selected from:wherein R1is selected from hydrogen, alkyl, fluoroalkyl, and alkyl-heteroaryl; Xaa2 is selected from A, Aib and AzaA;Xaa3 is selected from Q, E, H, aMeE and aMeQ;Xaae is selected from F, aMeF and a-Me-2-fluorophenylalanine;Xaaio is selected from Y, K and K;Xaai2 is selected from I and K;Xaai3 is selected from L, Y, K, K, Aib and aMeL;Xaai4 is selected from L and K;Xaais is selected from D and E;Xaaie is selected from E, K, K^and R;Xaan is selected from K, and R;Xaais is selected from A, Y and R;Xaai9 is selected from Q and A;Xaa2o is selected from Q, Aib, K and K;Xaa2i is selected from A, D, Aib, K, K:and E;Xaa23 is selected from I and V;Xaa24 is selected from E and Q;Xaa25 is selected from W, Y and aMeY;Xaa26 is selected from L and aMeL;Xaa27 is selected from L, D-proline and aMeL;Xaa29 is selected from H and 3-(4-pyridyl)alanine;Xaaso is selected from Y and 3 -cyclohexylalanine;Xaa3i is selected from L, V, Y, aMeL, Aib and aMeY;Xaa33 is selected from W, L, K, aMeL, Aib and aMeY;Xaa34 is selected from V, L and aMeL;Xaa37 is selected from Q and aMeQ;Xaa38 is selected from R and NMeR;each K:is independently^^'pLinkerlI RLinker2iRLinker3\Twhereinj^Linkerl, j^Linker2anJ j^Linker3arejnc|epenc|ent|y selected from a linker group and a covalent bond;RTcomprises a lipid moiety or an oligosaccharide moiety; andR2is selected from hydrogen, alkyl and fluoroalkyl;provided that the peptide is not:Retatrutide: YXQGTFTSDYSIαLDK4AQXAFIEYLLEGGPSSGAPPPS–NH2;Tirzepatide: YXEGTFTSDYSIXLDKIAQ2AFVQWLIAGGPSSGAPPPS–NH2;Triagonist: HXQGTFTSD3SKYLDERAAQDFVQWLLDGGPSSGAPPPS-NH2;Analogue 19: HXEGTFTSDVSSYLEGQALRHYINWLTRQRY-NH2; orPeptide 19: YXEGTFTSDYSIYLDKQAAXEFVNWLLAGGPSSGAPPPS#-NH2;wherein:4 is Lysine acylated with OEG-y-Glu-C20 diacid;3 is Lysine acylated with y-Glu-C 16 acyl;2 is Lysine acylated with OEG-OEG-y-Glu-C20 diacid;# is Lysine acylated with C16 acyl; and

[0046] a is a-methyl-L- Leucine, also referred to as (aMeL, L“).

[0047] In some aspects, the present invention provides a peptide having at least 85% sequence identity to Formula B:XaaiXaa2Xaa3GTFTSDXaaioSXaai2Xaai3Xaai4Xaai5Xaai6Xaai7AXaai9Xaa2oXaa2iFXaa23Xaa24Xaa25LLRHYXaa3iNXaa33Xaa34TRQRY-NH-R2Formula B;wherein:Xaai is selected from:wherein R1is selected from hydrogen, alkyl, fluoroalkyl, and alkyl-heteroaryl; Xaa2is selected from A and X;Xaa3 is selected from Q, E and H;Xaaio is selected from Y, K and K;Xaai2is selected from I and K;Xaai3 is selected from L, Y, K and K;Xaai4 is selected from L and K;Xaais is selected from D and E;Xaaie is selected from E, K and K;Xaan is selected from K and K;Xaai9 is selected from Q and A;Xaa2o is selected from Q, K and K;Xaa2i is selected from A and D;Xaa23 is selected from I and V;Xaa24 is selected from E and Q;Xaa25 is selected from W and Y;Xaasi is selected from L and V;Xaa33 is selected from W and L;Xaa34 is selected from V and L;each K:is independentlyHN-RLinkerlIRLinker2RLinker3\TwhereinRLinker1, RLinker2and RLinker3are independently selected from a linker group and a covalent bond;RTcomprises a lipid moiety or an oligosaccharide moiety; andR2is selected from hydrogen, alkyl and fluoroalkyl;provided that the peptide is not:Retatrutide: YXQGTFTSDYSIαLDK4AQXAFIEYLLEGGPSSGAPPPS–NH2; Tirzepatide: YXEGTFTSDYSIXLDKIAQ2AFVQWLIAGGPSSGAPPPS–NH2; Triagonist: HXQGTFTSD3SKYLDERAAQDFVQWLLDGGPSSGAPPPS-NH2; Analogue 19: HXEGTFTSDVSSYLEGQALRHYINWLTRQRY-NH2; or Peptide 19: YXEGTFTSDYSIYLDKQAAXEFVNWLLAGGPSSGAPPPS#-NH2; wherein:4 is Lysine acylated with OEG-y-Glu-C20 diacid;3 is Lysine acylated with y-Glii-C 16 acyl;2 is Lysine acylated with OEG-OEG-y-Glu-C20 diacid;# is Lysine acylated with C16 acyl; anda is a-methyl-L- Leucine, also referred to as (aMeL, L“).

[0049] In certain embodiments, R1is hydrogen.

[0050] In certain embodiments, R2is hydrogen. In certain embodiments, R2is alkyl or aralkyl. In certain embodiments, R2is selected from ethyl, isopropyl, isobutyl, benzyl,

[0051] In certain embodiments, R2is fluoroalkyl. In certain embodiments, R2is selected from 1,1,1 -trifluoroethyl and 1,1,1,2,2-pentafluoropropyl.

[0052] In certain embodiments, RLinker1is selected from a covalent bond and:wherein n is 1-24.

[0053] In certain embodiments, RLinker1is selected from a covalent bond and

[0054] In certain embodiments, RLinker2is selected from a covalent bond and:wherein n is 1-24.

[0055] In certain embodiments, RLinker2is selected from a covalent bond and

[0056] In certain embodiments, RLinker3is selected from a covalent bond and:wherein n is 1-24.

[0057] In certain embodiments, RLinker3is selected from a covalent bond andMa.<>->. A x..Hand S

[0058] In certain embodiments, RTis selected from:Of MO:;VA Av...-- _anjwherein RSis selected from CH3, CO2H, CO2R$$, P(O)(OH)2, SO3H, tetrazole,....... Jj* / ’ KOH QO X4, and Hwherein R$$is selected from:O',, and R$$$ js seiected from:wherein R&&is selected from:wherein R&&&is selected from, andV-H V^nwherein R&&&&is selected from:, and ',@wherein R&&&&&isselected from:, and *,<s,,zOH v^@wherein R&&&&&&sselected from:, and;provided that one and only one of R&, R&&, R&&&, R***&*ANC|comprises - @Y@wherein R#is selected from: and,Owherein -@ represents the point of attachment to the remainder of the molecule; a is 1-24; andm is 6-24.

[0059] In certain embodiments, RTis:

[0060] In certain embodiments, RSis CH3 or CO2H.

[0061] In certain embodiments, RTis:wherein x is 1-20.

[0062] In certain embodiments, RLinker1is a covalent bond orf' IT 'KRL1nker3& covalent bond OFC>oR$is Me or CO2H;n is 1-4; andm is 14-18.

[0063] In certain embodiments, at least one of Xaaio, Xaai3, Xaaie, Xaai7, Xaa2o is Kt In certain embodiments, at least one of Xaaio and Xaai7 is Kt In certain embodiments, Xaai is Y. In certain embodiments, Xaa2 is Aib. In certain embodiments, Xaai9 and Xaa2o are both Q.

[0064] In certain embodiments, the peptide has at least 90% sequence identity to Formula B. In certain embodiments, the peptide has at least 95% sequence identity to Formula B. In certain embodiments, the peptide has Formula B.

[0065] In certain embodiments, the peptide is an agonist of at least one receptor selected from GLP-1R, GIPR, GcgR and Y2R. In certain embodiments, the peptide is an agonist of Y2R. In certain embodiments, the peptide is an agonist of at least 2 receptors selected from GLP-1R, GIPR, GcgR and Y2R. In certain embodiments, the peptide is an agonist of GLP-1R and Y2R. In certain embodiments, the peptide is an agonist of GIPR and Y2R. In certain embodiments, the peptide is an agonist of at least 3 receptors selected from GLP-1R, GIPR, GcgR and Y2R. In certain embodiments, the peptide is an agonist of GLP-1R, GIPR and Y2R. In certain embodiments, the peptide is an agonist of GLP-1R, GIPR, GcgR and Y2R.

[0066] In certain embodiments, the peptide is selected from:YAEGTFTSD3SIYLEKQAQQDFVQWLLRHYVNWLTRQRY;YAQGTFTSDYSILLDKKAQQAFIEYLLRHYINWLTRQRY;YAEGTFTSDYSKYLDERAQQDFVQWLLRHYLNLVTRQRY;HXHGTFTSDYSKYLDERAQQDFVQWLLRHYLNLVTRQRY;YXEGTFTSD3SKYLDERAQQDFVQWLLRHYVNWLTRQRY;YXQGTFTSD3SKYLDERAQQDFVQWLLRHYVNWLTRQRY;YAQGTFTSDYSILLDKOAQQAFIEYLLRHYINWLTRQRY;YAQGTFTSDYSILLDK1AQQAFIEYLLRHYINWLTRQRY;YAEGTFTSDKSIYLEKQAQQDFVQWLLRHYVNWLTRQRY;HAQGTFTSDYSKYLDERAQQDFVQWLLRHYLNLVTRQRY;YAEGTFTSD3SIYLEKQAQQDFVQWLLRHYVNWLTRQRY;HXHGTFTSD5SIYLEKQAQQDFVQWLLRHYVNWLTRQRY;YAEGTFTSDYSILLDKKAQKAFVQWLLRHYLNWLTRQRY;YAEGTFTSDYSILLDK*AQKAFVQWLLRHYLNWLTRQRY;YAEGTFTSDYSILLDK1AQKAFVQWLLRHYLNWLTRQRY;YAEGTFTSDYSILLDK#AQKAFVQWLLRHYLNWLTRQRY;YAEGTFTSDKSIYLEKQAQQDFVQWLLRHYVNWLTRQRY;YXEGTFTSDYSILLDR

[0010] AQXEFVQWLLRHYLNWLTRQRY;[ll-Y]AEGTFTSDYSILLD

[0010] RAQAEFVQWLLRHYLNWLTRQRY;[ 11 - Y] AEGTFTSD YSILLDR

[0010] AQAEFVQWLLRHYLNWLTRQRY; yAEGTFTSDYSILLDK

[0010] AQXEFVQWLLRHYLNWLTRQRY;YXEGTFTSDYSILLDK

[0010] AQXEFVQWLLRHYLNWLTRQAY;[11-Y]AEGTFTSDYSILLDR[2]AQAEFVQWLLRHYLNWLTRQRY;YXEGTFTSDYSILLDR[2]AQAEFVQWLLRHYLNWLTRQRY;YXEGTFTSDYSILLDR[2]AQAEFVQYLLRHYLNWLTRQRY;HXHGTFTSDYSIYLE

[0010] KYAXEFVQWLLRHYLNWLTRQRY;YXQGTFTSDYSIaLDK

[0010] AQXAFIE[aMeY]LLRHYLNWLTRQAY;YXQGTFTSDYSIaLDK

[0010] AQXAFIEYLLRHYaNWLTRQAY;YXEGTFTSDYSILLDR

[0010] AQXEFVQWLpR[Pyr(4)][Cha]XNWLTRQRY; YXEGTFTSDYSILLDR

[0010] AQXEFVQWLpR[Pyr(4)][Cha]XNKVTRQRY; [ll-Y]AQGTFISDYSIALDR

[0010] AQADFVQYLLRHYLNWLTRQRY;[Ac-Y]AEGTFTSDYSILLDR[2]AQAEFVQWLLRHYLNWLTRQRY;[ 11 - Y] AEGTFTSD YSILLDR

[0010] AQAEFVQWLLRHYLNWLTRQAY;[11-Y]AEGTFTSDYSILLDR[2]AQAEFVQWLLRHYLNWLTRQAY;YXQGTFTSDYSIaLDK

[0010] AQXAFIE[aMeY]LLRHYaNWLTRQAY;YXEGTFTSDYSIaLDKKAQ[2]AFIEYLLRHYaNWLTRQAY;YXEGTFTSDYSKLDKKAQ[2]AFIEYLLRHYXNWLTRQAY;YXEGTFTSDYSILLDR

[0010] AQAAFIEYLLRHYLNWLTRQRY;YXEGTFTSDYSEXLDK

[0010] AQXAFIEYLLRHYLNWLTR[aMeQ]RY;YXEGTFTSDYSEXLDK

[0010] AQXAFIEYLLRHYXNWLTR[aMeQ]RY;YXEGTFTSDYSIaLDK[2]AQXAFIE[aMeY]LLRHYXNWLTR[aMeQ]RY; andHXHGTFTSDYSIaLDK[2]AQXAFIE[aMeY]LLRHYXNWLTR[aMeQ]RY wherein:B is [2,2,2-triflouroethyl -Y];J is [2,2,2-triflouroethyl -FI];Zis [Im-Y];X is Aib;3 is Lysine acylated with y-Glii-C 16 acyl;U is Aza-alanine;4 is Lysine acylated with OEG-y-Glu-C20 diacid;2 is Lysine acylated with OEG-OEG-y-Glu-C20 diacid;1 is Lysine acylated with 0EG-0EG-y-Glu-C18 diacid;5 is Lysine acylated with y-Glu-C20 diacid;6 is Lysine acylated with 0EG-0EG-PAla-y-Glu-C18 diacid;7 is Lysine acylated with 0EG-PAla-y-Glu-C18 diacid;8 is Lysine acylated with pAla-0EG-y-Glu-C18 diacid;a is a-methyl-L- Leucine, also referred to as (aMeL, L“);9 is Lysine acylated with OEG-y-Glu-C18 diacid;

[0067] 0 (zero) is Lysine acylated with OEG-OEG-OEG-OEG-y-Glu-C18 diacid; * is Lysine acylated with OEG-OEG-C18 diacid;# is Lysine acylated with C16 acyl;Ais NMeR (N-terminally methylated arginine);10 is Lysine acylated with pAla-OEG-y-Glu-C18 diacid;aMeQ is a-methyl-L-glutamine;aMeE is a-methyl-L-glutamic acid;aMeF is a-methyl-L-phenylalanine;aMeY is a-methyl-L-tyrosine;Pyr(4) is 3-(4-pyridyl)alanine;Cha is 3-cyclohexylalanine;Ac-Y is N-terminally acylated L-tyrosine;Ac-y is N-terminally acylated D-tyrosine;Ac-F is N-terminally acylated L-phenylalanine;Ac-f is N-terminally acylated D-phenylalanine;11-Y is ((lH-imidazol-5-yl)methyl)-L-tyrosine;y is D-tyrosine;f is D-phenylalanine;p is D-proline;NMeY is N-terminally methylated tyrosine; andaMeF(2F) is a-Me-2-flourophenylalanine.

[0068] In some aspects, the present invention provides a peptide having at least 85% sequence identity to Formula C:XaaiXaa2Xaa3GTXaaeXaa7 SDXaai oSXaai 2Xaai 3LX aa i sXaai eXaai? Xaai sXaai 9 R X a a2iXaa22Xaa23NXaa25Xaa26TRXaa29Xaa3oY-NH-R2Formula C;wherein:Xaai is selected from:wherein R1is selected from hydrogen, alkyl, fluoroalkyl, and alkyl-heteroaryl; Xaa2 is selected from A and Aib;Xaa3 is selected from Q, E, H, aMeE and aMeQ;Xaae is selected from F, aMeF and a-Me-2-fluorophenylalanine;Xaa? is selected from T and I;Xaaio is selected from K and K;Xaai2 is selected from K and I;Xaai3 is selected from Y, Aib, L, NMeL, K and K;Xaais is selected from D and E;Xaaie is selected from E, R, K and K:;Xaan is selected from R, K and K;Xaais is selected from A, Aib, K and K;Xaai9 is selected from L, NMeL K and K;Xaa2i is selected from H and 3-(4-pyridyl)alanine;Xaa22 is selected from Y and 3 -cyclohexylalanine;Xaa23 is selected from L, V, Y, aMeL, Aib, and aMeY;Xaa25 is selected from W, L, K, aMeL, Aib, and aMeY;Xaa26 is selected from V, L and aMeL;Xaa29 is selected from Q and aMeQ;Xaaso is selected from R and NMeR;each K:is independentlyHN-RLinker1IRLinker2RLinker3\TwhereinRLinker1, RLinker2and RLinker3are independently selected from a linker group and a covalent bond;RTcomprises a lipid moiety or an oligosaccharide moiety; andR2is selected from hydrogen, alkyl and fluoroalkyl;provided that the peptide is not:[written from N- to C-terminus]Triagonist: HXQGTFTSD3SKYLDERAAQDFVQWLLDGGPSSGAPPPS-NH2; or Analogue 19: HXEGTFTSDVSSYLEGQALRHYINWLTRQRY-NH2; wherein:3 is Lysine acylated with y-Glii-C 16 acyl.

[0069] In some aspects the present invention provides a peptide having at least 85% sequence identity to Formula C:XaaiAXaa3GTFXaa7SDXaaioSKXaai3LDXaai6Xaai7ALRHYVNWLTRQRY-NH-R2Formula C;wherein:Xaai is selected from:wherein R1is selected from hydrogen, alkyl, fluoroalkyl, and alkyl-heteroaryl;Xaas is selected from Q and E;Xaa? is selected from T and I;Xaaio is selected from K and K;Xaai3 is selected from Y, K and K;Xaaie is selected from E, K and K;Xaan is selected from R, K and K;each K:is independentlyHN-RLinker1iRLinker2RLinker3\TwhereinRLinker1, RLinker2and RLinker3are independently selected from a linker group and a covalent bond;RTcomprises a lipid moiety or an oligosaccharide moiety; andR2is selected from hydrogen, alkyl and fluoroalkyl;provided that the peptide is not:[written from N- to C-terminus]Triagonist: HXQGTFTSD3SKYLDERAAQDFVQWLLDGGPSSGAPPPS-NH2; or Analogue 19: HXEGTFTSDVSSYLEGQALRHYINWLTRQRY-NH2; wherein:3 is Lysine acylated with y-Glu-C 16 acyl.

[0070] In certain embodiments, R1is selected from hydrogen,

[0071] In certain embodiments, R1is hydrogen.

[0072] In certain embodiments, R2is hydrogen. In certain embodiments, R2is alkyl or aralkyl. In certain embodiments, R2is selected from ethyl, isopropyl, isobutyl, benzyl,

[0073] In certain embodiments, R2is fluoroalkyl. In certain embodiments, R2is selected from 1,1,1 -trifluoroethyl and 1,1,1,2,2-pentafluoropropyl.

[0074] In certain embodiments, RLinker1is selected from a covalent bond and:wherein n is 1-24.

[0075] In certain embodiments, RLinker1is selected from a covalent bond and

[0076] In certain embodiments, RLinker2is selected from a covalent bond and:wherein n is 1-24.

[0077] In certain embodiments, RLinker2is selected from a covalent bond and

[0078] In certain embodiments, RLinker3is selected from a covalent bond and:wherein n is 1-24.

[0079] In certain embodiments, RLinker3is selected from a covalent bond andHand o

[0080] In certain embodiments, RTis selected from:HO, and wherein RSis selected from CH3, CO2H, CO2R$$, P(O)(OH)2, SO3H, tetrazole,, and wherein R$$is selected from:, and R$$$ js seiected from:wherein R&&&is selected from:, andwherein R&&&&is selected from:$, and ',\.-Hy@wherein R&&&&&isselected from:, and,wherein R&&&&&&sselected from:, andprovided that one and only one of R&, R&&, R&&&, R***&*ANC|comprises - @wherein R#is selected from:and,wherein -@ represents the point of attachment to the remainder of the molecule;a is 1-24; andm is 6-24.

[0081] In certain embodiments, RTis:

[0082] In certain embodiments, RSis CH3 or CO2H.

[0083] In certain embodiments, RTis:wherein x is 1-20.

[0084] In certain embodiments, RLinker1is a covalent bond orHNy OEG;HO......., RLlnker2a C()va|entbond or is selected from:and ©RLlnker3a covalent bond OroRTis mR$is Me or CO2H;n is 1-4; andm is 14-18.

[0085] In certain embodiments, at least one of Xaaio, Xaai3, Xaaie, Xaai7, Xaa2o is t In certain embodiments, at least one of Xaaio and Xaai7 is Kt In certain embodiments, Xaai is Y. In certain embodiments, Xaa3 is Q. In certain embodiments, Xaa? is I.

[0086] at least one of Xaaio, Xaai3, Xaaie, Xaai7, Xaa2o is Kt In certain embodiments, at least one of Xaaio and Xaan is Kt In certain embodiments, Xaai is Y. In certain embodiments, Xaa2 is Aib. In certain embodiments, Xaai9 and Xaa2o are both Q.

[0087] In certain embodiments, the peptide has at least 90% sequence identity to Formula C. In certain embodiments, the peptide has at least 95% sequence identity to Formula C. In certain embodiments, the peptide has Formula C.

[0088] In certain embodiments, the peptide is an agonist of at least one receptor selected from GLP-1R, GIPR, GcgR and Y2R. In certain embodiments, the peptide is an agonist of Y2R. In certain embodiments, the peptide is an agonist of at least 2 receptors selected from GLP-1R, GIPR, GcgR and Y2R. In certain embodiments, the peptide is an agonist of GLP-1R and Y2R. In certain embodiments, the peptide is an agonist of GIPR and Y2R. In certain embodiments, the peptide is an agonist of at least 3 receptors selected from GLP-1R, GIPR, GcgR and Y2R. In certain embodiments, the peptide is an agonist of GLP-1R, GIPR and Y2R. In certain embodiments, the peptide is an agonist of GLP-1R, GIPR, GcgR and Y2R.

[0089] In certain embodiments, the peptide is selected from:HAQGTFTSDKSKYLDERALRHYVNWLTRQRY;YAQGTFISDKSKYLDERALRHYVNWLTRQRY;YAEGTFISDKSKYLDERALRHYVNWLTRQRY; HXEGTFTSDKSILLEK

[0010] XLR[Pyr( 4)] [Cha]XNWLTRQRY;HXEGTFTSDKSILLE

[0010] KXLR[Pyr(4)][Cha]XNWLTRQRY;YXEGTFTSDYSIaLDK

[0010] XLRHYXNWLTRQRY;YXEGTFTSDYSIaLDK

[0010] XLRHYXNWLTRQRY;YXEGTFTSDYSIaLDK

[0010] XLRHYaNWLTR[aMeQ]RY;HXEGTFTSD

[0010] SSaLDKKALRHYaNWLTR[aMeQ]RY;HXEGTFTSD

[0010] SSaLDKKALRHYaNWLTR[aMeQ]RY;HXHGTFTSDYSIaLDK

[0010] XLRHYaNWLTRQAY;HXEGTFTSDYSI

[0010] LDKKALRHYaNWLTR[aMeQ]RY;HXEGTFTSDKSIaLEK

[0010] XLRHYLN[aMeY]LTRQRY;HXEGTFTSDKSI[2]LEKKXLRHYLN[aMeY]LTRQRY;HXEGTFTSD

[0010] SSaLDKKALRHYaNWLTR[aMeQ]RY;HXEGT[aMeF]TSD

[0010] SSaLDKKALRHYaNWLTR[aMeQ]RY;HXEGT[aMeF]TSD

[0010] SSaLDKKALRHYaNWLTRQAY;HXHGT[aMeF]TSDYSSaLDE

[0010] XLRHYaNWLTRQAY;HXHGT[aMeF]TSDYSIaLDK

[0010] XLRHYaNWLTRQAY;HXHGT[aMeF]TSD[3]SIaLDK[3]XLRHYaNWLTRQAY;HXHGT[aMeF]TSD[3]SIaLD[3]KXLRHYaNWLTRQAY; HXEGT[aMeF]TSDKSI

[0010] LEKKXLR[Pyr(4)][Cha]XNWLTRQRY;HXEGT[aMeF]TSDKSI

[0010] LEKKXLR[Pyr(4)][Cha]XNWLTR[aMeQ]RY;[ll-Y]AEGT[aMeF]TSDKSIaLEK

[0010] XLRF[Cha]XNWLTR[aMeQ]RY;[11-Y]AHGTFTSDYSILLDR[1O]ALRHYLNWLTRQRY; and HXHGTFTSDYSIXLDK

[0010] ALRHYXNWLTRQRYwherein:B is [2,2,2-triflouroethyl -Y];J is [2,2,2-triflouroethyl -H];Zis [Im-Y];X is Aib;3 is Lysine acylated with y-Glu-C 16 acyl;U is Aza-alanine;4 is Lysine acylated with OEG-y-Glu-C20 diacid;2 is Lysine acylated with OEG-OEG-y-Glu-C20 diacid;1 is Lysine acylated with OEG-OEG-y-Glu-C18 diacid;5 is Lysine acylated with y-Glu-C20 diacid;6 is Lysine acylated with OEG-OEG-PAla-y-Glu-C18 diacid;7 is Lysine acylated with OEG-PAla-y-Glu-C18 diacid;8 is Lysine acylated with pAla-OEG-y-Glu-C18 diacid;a is a-methyl-L- Leucine, also referred to as (aMeL, L“);9 is Lysine acylated with OEG-y-Glu-C18 diacid;0 (zero) is Lysine acylated with OEG-OEG-OEG-OEG-y-Glu-C18 diacid; * is Lysine acylated with OEG-OEG-C18 diacid;# is Lysine acylated with C16 acyl;Ais NMeR (N-terminally methylated arginine);10 is Lysine acylated with pAla-OEG-y-Glu-C18 diacid;aMeQ is a-methyl-L-glutamine;aMeE is a-methyl-L-glutamic acid;aMeF is a-methyl-L-phenylalanine;aMeY is a-methyl-L-tyrosine;Pyr(4) is 3-(4-pyridyl)alanine;Cha is 3-cyclohexylalanine;Ac-Y is N-terminally acylated L-tyrosine;Ac-y is N-terminally acylated D-tyrosine;Ac-F is N-terminally acylated L-phenylalanine;Ac-f is N-terminally acylated D-phenylalanine;11-Y is ((lH-imidazol-5-yl)methyl)-L-tyrosine;y is D-tyrosine;f is D-phenylalanine;p is D-proline;NMeY is N-terminally methylated tyrosine; andaMeF(2F) is a-Me-2-flourophenylalanine.

[0090] In further aspects, disclosed herein are methods of:a) treating or preventing type 2 diabetes, hyperglycemia, impaired glucose tolerance, or non-insulin dependent diabetes, and / or obesity;b) reducing body weight and / or food intake, and / or inducing satiety;c), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), metabolic dysfunction-associated liver disease (MASLD), and / or nonalcoholic fatty liver disease (NAFLD);d) treating chronic kidney disease;e) treating or preventing emesis;f) treating or preventing effects of aging;g) support of islet transplant survival in Type 1 diabetes; and / orh) treating or preventing arthritis and related diseases, for example, Osteoarthritis, Rheumatoid arthritis, Gout, Ankylosing spondylitis, Psoriatic arthritis, Juvenile arthritis, Fibromyalgia, Infectious arthritis, Spondyloarthritis, Sjogren's syndrome, Scleroderma, and / or Polymyalgia rheumatica;comprising administering to a subject in need thereof an effective amount of a peptide disclosed herein.

[0091] In yet further aspects, disclosed herein are methods of treating cardiovascular disease and / or hypertension, comprising administering to a subject in need thereof an effective amount of a peptide disclosed herein.

[0092] In yet further aspects, disclosed herein are methods of treating a neurodegenerative disease (e.g., Alzheimer’s, Parkinsons, other forms of dementia, traumatic brain injury),comprising administering to a subject in need thereof an effective amount of a peptide of any one of a peptide disclosed herein.

[0093] In yet further aspects, disclosed herein are methods of treating alcohol use disorder, substance use disorder or smoking addiction, comprising administering to a subject in need thereof an effective amount of a peptide of a peptide disclosed herein.

[0094] In yet further aspects, disclosed herein are methods of treating inflammation, comprising administering to a subject in need thereof an effective amount of a peptide of any one of a peptide disclosed herein.

[0095] In yet further aspects, disclosed herein are methods of treating diabetes, comprising administering to a subject in need thereof an effective amount of a peptide of a peptide disclosed herein.

[0096] In yet further aspects, disclosed herein are methods of treating obesity, comprising administering to a subject in need thereof an effective amount of a peptide a peptide disclosed herein.

[0097] In yet further aspects, the subject was not responsive to or did not adequately tolerate a previous course of therapy with a mono- or multiagonist.

[0098] In certain embodiments the peptide impacts or increases cAMP signaling more than it impacts or increases beta-arrestin recruitment and internalization of the receptor or receptor:peptide complex.Definitions

[0099] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well-known and commonly used in the art.

[0100] The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N. Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman& Co., N. Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0101] Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C. A. (1985).

[0102] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.

[0103] It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[0104] As used herein, the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2. Preferably, “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.

[0105] Articles such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includesembodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0106] As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C1-C10 branched-chain alkyl groups. Preferably, the “alkyl” group refers to Ci-Ce straight-chain alkyl groups or Ci-Ce branched-chain alkyl groups. Most preferably, the “alkyl” group refers to C1-C4 straight-chain alkyl groups or C1-C4 branched-chain alkyl groups. Examples of “alkyl” include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1 -pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1 -hexyl, 2-hexyl, 3-hexyl, 1 -heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl and the like. The “alkyl” group may be optionally substituted.

[0107] The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0108] The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0109] The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0110] The term “alkoxy” refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

[0111] The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0112] The term “alkyl” refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl- substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., Ci-30 for straight chains, C3-30 for branched chains), and more preferably 20 or fewer.

[0113] Moreover, the term “alkyl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.

[0114] The term “Cx.y” or “Cx-Cy”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that containfrom x to y carbons in the chain. Coalkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. A Cnealkyl group, for example, contains from one to six carbon atoms in the chain.

[0115] The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.

[0116] The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0117] The term “amide”, as used herein, refers to a group0yR10

[0118] wherein R9and R10each independently represent a hydrogen or hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0119] The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented byR9R9|— N or <j— N-R10R10RW

[0120] wherein R9, R10, and R10’ each independently represent a hydrogen or a hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0121] The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.

[0122] The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

[0123] The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0124] The term “carbamate” is art-recognized and refers to a group0 0R9R9

[0125] wherein R9and R10independently represent hydrogen or a hydrocarbyl group.

[0126] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0127] The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0128] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0129] The term “carbonate” is art-recognized and refers to a group -OCO2-.

[0130] The term “carboxy”, as used herein, refers to a group represented by the formula -CO2H.

[0131] The term “ester”, as used herein, refers to a group -C(O)OR9wherein R9represents a hydrocarbyl group.

[0132] The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.

[0133] The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0134] The terms “hetaralkyl” and “hetero aralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.

[0135] The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cyclo alkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

[0136] The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0137] The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

[0138] The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0139] The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbonhydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms.Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[0140] The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

[0141] The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[0142] The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

[0143] The term “sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0144] The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae

[0145] wherein R9and R10independently represents hydrogen or hydrocarbyl.

[0146] The term “sulfoxide” is art-recognized and refers to the group-S(O)-.

[0147] The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0148] The term “sulfone” is art-recognized and refers to the group -S(O)2-.

[0149] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamide, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or hetero aromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0150] The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.

[0151] The term “thioester”, as used herein, refers to a group -C(O)SR9or -SC(O)R9.

[0152] wherein R9represents a hydrocarbyl.

[0153] The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

[0154] The term “urea” is art-recognized and may be represented by the general formulaO

[0155] wherein R9and R10independently represent hydrogen or a hydrocarbyl.

[0156] The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.

[0157] The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0158] ‘ ‘Salt” is used herein to refer to an acid addition salt or a basic addition salt.

[0159] Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01 / 062726.

[0160] Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers.Some of the compounds may also exist in tautomeric forms. Such forms, although not explicitly indicated in the formulae described herein, are intended to be included within the scope of the present disclosure.

[0161] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0162] “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0163] The term “pharmaceutically acceptable cation” refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like (see, e. g., Berge, et al., J. Pharm. Sci. 66 (1): 1-79 (January 77).

[0164] “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0165] “Pharmaceutically acceptable metabolically cleavable group” refers to a group which is cleaved in vivo to yield the parent molecule of the structural formula indicated herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONRR and -CH2OR radicals, where R is selected independently at each occurrence from alkyl, trialkylsilyl, carbocyclic aryl or carbocyclic aryl substituted with one or more of alkyl, halogen, hydroxy or alkoxy. Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl and trimethylsilyl groups.

[0166] “Prodrugs” refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Suchexamples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkylesters or (alkoxycarbonyl)oxy)alkylesters. Particularly the Ci-Cs alkyl, C2-Cs alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.

[0167] “Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g., in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non- stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0168] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle aged adult or senior adult) and / or a non- human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0169] An “effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to effect such treatment orprevention. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. A “therapeutically effective amount” refers to the effective amount for therapeutic treatment. A “prophylatically effective amount” refers to the effective amount for prophylactic treatment.

[0170] “Preventing” or “prevention” or “prophylactic treatment” refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject not yet exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.

[0171] The term “prophylaxis” is related to “prevention,” and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization, and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0172] “Treating” or “treatment” or “therapeutic treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

[0173] As used herein, the term “isotopic variant” refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an “isotopic variant” of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium (2H or D), carbon- 13 (13C), nitrogen- 15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be “2H / D, any carbon may be13C, or any nitrogen may be15N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instancefor example, where the resulting compounds may be used for drug and / or substrate tissue distribution studies. The radio-active isotopes tritium, i.e.,3H, and carbon- 14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such asnC,18F,15O and13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.

[0174] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”

[0175] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R - and S - sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)- isomers, respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0176] “Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of it electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0177] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound andis, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0178] As used herein and unless otherwise indicated, the term “enantiomerically pure R-compound” refers to at least about 95% by weight R-compound and at most about 5% by weight S-compound, at least about 99% by weight R-compound and at most about 1% by weight S-compound, or at least about 99.9 % by weight R-compound and at most about 0.1% by weight S-compound. In certain embodiments, the weights are based upon total weight of compound.

[0179] As used herein and unless otherwise indicated, the term “enantiomerically pure S-compound” or “S-compound” refers to at least about 95% by weight S-compound and at most about 5% by weight R-compound, at least about 99% by weight S-compound and at most about 1% by weight R-compound or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound. In certain embodiments, the weights are based upon total weight of compound.

[0180] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0181] The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.

[0182] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0183] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.

[0184] Abbreviations: Glucagon-like peptide- 1 (GLP-1), Glucose-dependent insulinotropic polypeptide (GIP), glucagon (Gcg), Peptide YY (PYY), neuropeptide Y2 receptor (Y2R), dipeptidyl peptidase-4 (DPP4), 2-aminoisobutyric acid (Aib, X), a-methyl-L-Leucine (aMeL, L“), type 2 diabetes (T2D), tetra-receptor chimera (TC), diacid (DA), N-methyl arginine (NMeR), lysine conjugated via acylation (Z), y-L-glutamic acid (yGlu, yE), 8-amino-3,6-dioxaoctanoic acid (OEG, O), P-alanine (PAla, PA). Lipid side chain abbreviations are lysine side chain acylated, such as OEG-OEG-yGlu-C18DA (lipid 1), OEG-OEG-yGlu-C20DA (lipid 2), yGlu-C16 acyl (lipid 3), OEG-yGlu-C18DA (lipid 4), OEG-OEG-Pala-yGlu-C18DA (O2x-PA-yE-C18DA), OEG-Pala-yGlu-C18DA (O-pA-yE-C18DA), and Pala-OEG-yGlu-C18DA (lipid 5).EXAMPLES

[0185] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, compositions, materials, device, and methods provided herein and are not to be construed in any way as limiting their scope.General

[0186] Mass spectra (MS) were obtained using a Finnigan LTQ ESI TOF Mass Spectrometer. Liquid chromatography mass spectrometry (LC-MS) was performed using an Agilent 6230 LC ESLMS. All C-terminally amidated peptides were synthesized on Rink amide resin (Novabiochem, preloaded with 0.66 mmol NH2 eq. / g). All Fmoc-protected amino acids, Boc-Tyr(tBu)-OH, Tetrakis (triphenylphosphine)palladium (0), O-(7-azabenzotriazol-l-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU), and piperidine were purchased from Chem-Impex. Solvents used were obtained from Fisher Scientific. N, N-diisopropylethylamine were purchased from TCI America, Biograde trifluoroacetic acid was procured from Halocarbon.Solid-phase peptide synthesis

[0187] Peptide backbone elongation was done with a fast-flow method for rapid assembly as developed by Pentelute and colleagues.1Standard peptide coupling was performed in dry DMF using 4 eq of Fmoc-amino acid (Fmoc-AA-OH), 3.6 eq of HATU (0.36 M), and 8 eq of DIPEA (relative to -NH2 eqs. on resin). Coupling of the Fmoc-amino acids were completed in 45 minutes of shaking the resin. The coupling of Fmoc-Aib-OH took place for a 60 minute period. The deprotection of Fmoc was achieved by shaking the resin with 20% piperidine in DMF for 5 minutes, and then with drained solution a fresh batch of 20% piperidine in DMF was added for an additional 15 minutes. Lipid side chain appendages were incorporated into peptides on resin from precedented protocols.2Peptide Purification

[0188] The reacted peptide on resin was washed with DMF (3 x 5 mL), CH₂Cl₂ (3 x 5 mL), and MeOH (3 x 5 mL) and then dried in vacuo. Peptides were cleaved from the resin in a cleavage cocktail of trifluoroacetic acid (TFA), triisopropylsilane (TIPS), and H2O (95:2.5:2.5). After 90 minutes, the TFA was removed by rotary evaporation, and the peptides were precipitated in cold ether. Crude peptides were lyophilized and purified by reversephase high-performance liquid chromatography (RP-HPLC) with solvent A (99:1:0.1, H2O:acetonitrile: TFA) and solvent B (10:90:0.07, H2O:acetonitrile: TFA) pre-warmed to 50 °C. A semiprep C18 column (Higgins Analytical, C18 Proto 200, 250 X 10mm, 5 micron) was used for purification at a flow rate of 2.5 mL / min. Purification was conducted at a 30-50% B gradient for 30 minutes for all non-lipidated analogues, and 40-60% B for the lipidated analogues. The purity (> 95%) was analyzed by analytical C18 column (Higgins Analytical, C18 Proto 200, 250 X 4.6 mm, 5 micron) at a flow rate of 1.0 mL / min monitoring an absorbance at 230 nm unless otherwise specified. The presence of the peptides was confirmed via electrospray ionization mass spectroscopy (ESLMS) with consistent ESI parameters (Ispray voltage, 4.52 kV; spray current, 0.17 p A; capillary voltage, 23 V; capillary temp 275 °C; tube lens, 89.7 V; N2 carrier gas). Concentrations of peptides were determined by tyrosine or tryptophan absorbance at 280 nm in neat DMSO.cAMP Luciferase Reporter Assay for GLP-1R agonism

[0189] HEK-293C34L cells stably transfected with GLP-1R and CREex-luciferase were plated in a 96-wells with a 0.2K population per well with an additional quantity of HEK-293QB1 bystander cells at 4.8K population per well. Concentration-response curves were made by the incubation of peptide for a 4-hour period followed by addition of steadylite plus® reagent and an immediate analysis of chemiluminescence.cAMP Luciferase Reporter Assay for GIPR and GcgR agonism

[0190] Transient transfection protocols have been outlined in previously described work.3-5Briefly, HEK-293T cells were plated into 96-wells with a 10K population per well and were transfected with GIPR or GcgR, CREex-luciferase, and P-galactosidase vectors. Concentration-response curves were generated by the incubation of peptide for a 4-hour period followed by steadylite plus® reagent addition and immediate chemiluminescence measurement. Subsequent correction of the transfection was achieved by the addition of ortho-nitrophenyl-β-galactosidase and monitoring of absorbance at 420 nm at t = 0 min and t = 5 min.Serum Response Element (SRE)-Luciferase Reporter Assay for Y2R agonism

[0191] Briefly, HEK-293T cells were plated into 96-wells with a 10K population per well and were transfected with Y2R (5 ng / well receptor cDNA), Gqi56(10 ng / well receptor cDNA) SRE-luciferase (50 ng / well receptor cDNA), and P-galactosidase(5 ng / well receptor cDNA). Concentration-response curves were generated by the incubation of peptide for a 4-hour period followed by steadylite plus® reagent addition and immediate chemiluminescence measurement. Subsequent correction of the transfection was achieved by the addition of ortho-nitrophenyl-β-galactosidase and monitoring of absorbance at 420 nm at t = 0 min and t = 10 min.Fenoterol stimulated cAMP Luciferase Reporter Assay for Y2R agonism

[0192] Transient transfection protocols have been outlined in previously described work.3-5Briefly, HEK-293T cells were plated into 96-wells with a 10K population per well and were transfected with Y2R (10 ng / well), CREex-luciferase (5 ng / well), and P-galactosidase vectors (50 ng / well). Fenoterol is an agonist of the P(2)-adrenoreceptor that is found on the HEK 293T cells. A concentration-response curve of fenoterol was obtained by the incubation of peptide for a 4-hour period followed by steadylite plus® reagent addition and immediate chemiluminescence measurement. The potency of Y2R agonists was obtained through their incubation, and subsequent addition of fenoterol, held at its ECss concentration (73 pM),followed by a 4-hour incubation and subsequent chemiluminescence analysis. Correction of the transfection was achieved by the addition of ortho-nitrophenyl-β-galactosidase and monitoring of absorbance at 420 nm at t = 0 min and t = 5 min.cAMP Assay in the Presence of Human Serum Albumin (HSA)

[0193] This procedure followed the cAMP Luciferase Reporter Assay for GLP-1R agonism with an additional step performed. Prior to the incubation of peptide with the cells, the plate was aspirated and 50 pL well serum-free expression medium (with L-Gln and pen / strep) alone or 4% HSA (w / v) was added. Serially diluted peptide was added 50 pL / well to bring the final volume of 2% HSA, which was incubated with cells for 4 h followed by the addition of steadylite plus® reagent and analysis of chemiluminescence.β-Arrestin-2 Recruitment Assay at the GLP-1R

[0194] Similar protocols utilizing these plasmid constructs have been reported in past work.7HEK-293T cells were seeded in a 6-well plate at a cell density of 250K population per well. After a 24-hour incubation, to each well was transfected 100 ng GLP-1R-Rluc8 and 3000 ng GFP2-β-Arrestin-2 (R393E, R395E), using a 1:4 cDNA / lipofectamine ratio in opti-mem. After 6 hours of incubation, each well was diluted 2-fold with a 20% FBS, 2% L-glutamine pre-warmed to 37°C DMEM solution. Following an additional 12-hour incubation, these cells washed gently with HBSS and then were trypsinized and plated in 96-well plates at a population of 10K per well. After 24 hours, the media was aspirated from the wells, and the cells were incubated with D-PBS for 1 hour, then incubated with serially diluted peptide for 20 minutes, followed the addition of coelenterazine 400a, and 10 minutes later, the bioluminescence resonance energy transfer (BRET) data was collected at 395 nm and 510 nm, where the ratio of 395 / 510 was derived, and all analogues activity were normalized to the activity of GLP-1.Table SI. Potency at the GLP-1R of GLP-1, Semaglutide, TC2, and TC3 with and without 2% HSA.aGLP- 1 R POTENCY (EC50. PM ±_ SEM) _PEPTIDE0% HSA 2% HSA ratio 2% / 0% HSA nGLP-1 0.46 + 0.06 0.95 + 0.22 2.1 3 SEMAGLU 0.84 + 0.07 1100 + 160 1300 3TIDE TC2 0.51 + 0.04 65 + 21 130 3TC3 0.17 + 0.08 23 + 11 140 3aGLP-l receptor potency at 0% or 2% concentrations of human serum albumin (HSA) using HEK-293C34L cells stably expressing the GLP-1R and CRE6x-luciferase. Each experiment (n) was conducted with the analogue present on the same plate with or without the additionof HSA at 2%. Prior to peptide addition, the wells designated for HSA incubation were aspirated and the HSA-containing media was added. Incubation with the cells took place over a 4-hour period.Table S2. Potency at the GLP-IRa of GLP-1, TC2, TC3, and TC4 with vehicle or DPP4.bGLP- 1 R POTENCY (EC50. PM ±SEM)PEPTIDE - DPP4 + DPP4 ratio (+ DPP4) / (- nDPP4) GLP-1 1.4 ± 0.3 870 + 210 620 3 TC2 21 + 10 27 + 12 1.3 3 TC3 2.0 + 0.71 4.6 + 0.71 2.3 3 TC4 41 75 1.8 1aGLP-l receptor potency with or without incubation with DPP4 using HEK-293C34L cells stably expressing the GLP-1R and CRE6x-luciferase. Each experiment (n) was conducted with the analogue present on the same plate where the day prior it was incubated with vehicle or with DPP4 enzyme.bPrior work has established the conditions of the 18-hour incubation prior to the GLP-1R bioassay.5In brief, peptides (0.1 mM) incubated at 37 °C with and without DPP4 (4 nM) were placed in reaction buffer (20 mM TRIS, 100 mM NaCl, 1 mM EDTA, pH 8.0). After 18 hours, the reactions were centrifuged, serially diluted in serum-free DMEM, and subjected to the outlined experiment “cAMP Luciferase Reporter Assay for GLP-1R agonism”.Table S3. In vitro human GLP-1R, GIPR, GcgR, and Y2R potencies of analogues tested in table 1.Table S4. Molecular weight characterization of synthesized peptides.Peptide" MW (Calculated)'' MW (Found)' PYY 4309.81 4309.22GLP-1 3297.68 3296.70GIP 4983.60 4983.51 Glucagon 3482.80 3482.07 GEP44 5197.81 5197.78TAI 5330.81 5331.59RET1 4760.93 4760.46RET2 4161.53 4162.08TCI 5281.90 5282.74TC2 5687.95 5688.00TC2a 5774.95 5774.51TC2b 6130.01 6130.125TC2c 5985.41 5985.36TC2d 6098.95 6099.595TC2e 6070.95 6071.64TC2f 6099.41 6100.00TC2g 5954.35 5954.03TC2h 6027.82 6028.69TC2i 6099.82 6100.27TC2j 5954.82 5954.85TC3 5954.82 5955.39TC3a 5326.63 5326.67TC3b 6042.63 6042.66TC3c 5969.63 5969.24TC3d 5340.47 5340.81TC3e 6056.47 6056.72TC3f 5983.47 5982.68TC4 5968.91 5968.19aAll peptides were identified to be >95% pure by analytical RP-HPLC using a C18 column (Higgins, 5 micron, 4.6 mm x 250 mm). Mobile phases are shown for each peptide using a linear gradient of solvent B (10% H2O, 90% CH3CN, 0.07% TFA) in solvent A (99% H2O, 1% CH3CN, 0.1% TFA) over 20 minutes at a flow rate of 1 mL / min with an absorbance monitored at 230 nm.bMolecular weights (Da) of the synthesized peptides were calculated from average masses using Peptide Mass Calculator v3.2 (Katholieke Univeriteit, Leuven, Belgium). cExperimental molecular weights were detected by electrospray ionization-mass spectrometry (ESLMS) using direct infusion methods of purified peptides dissolved in 50% H2O / CH3CN and 0.1% TFA. Semaglutide (NNC-0113-0217; Ozempic) and tirzepatide (LY3298176; Mounjaro) were purchased from Invivochem. Retatrutide (LY3437943) was purchased from Medchemexpress.Table S5. Sequences of synthesized peptides. _ TC peptide Sequence"TCI YXQGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY TC2 YXQGTFTSD[K-lipid 3]SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY TC2a YXQGTFTSD[K-γGlu-C20DA]SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY TC2b YXQGTFTSDYSILLDKKAQQAFIEYLLEGG[K-lipid 2]SLRHYVNWLTRQRY TC2c YXQGTFTSDYSILLDKKAQQAFIEYLLEGG[K-lipid 4]SLRHYVNWLTRQRY TC2d YXQGTFTSDYSILLD[K-lipid 2]KAQQAFIEYLLEGGPSLRHYVNWLTRQRY TC2e YXQGTFTSDYSILLDK[K-lipid 1]AQQAFIEYLLEGGPSLRHYVNWLTRQRY TC2f YXQGTFTSDYSILLDK[K-lipid 2]AQQAFIEYLLEGGPSLRHYVNWLTRQRY TC2g YXQGTFTSDYSILLDK[K-lipid 4]AQQAFIEYLLEGGPSLRHYVNWLTRQRY TC2h YXQGTFTSDYSILLDK[K-lipid 1]AQXAFIEYLLEGGPSLRHYVNWLTRQRY TC2i YXQGTFTSDYSILLDK[K-OEG-OEG-0Ala-YGlu- C18DA]AQXAFIEYLLEGGPSLRHYVNWLTRQRYTC2j YXQGTFTSDYSILLDK[K-OEG-0Ala-YGlu- C18DA]AQXAFIEYLLEGGPSLRHYVNWLTRQRYTC3 YXQGTFTSDYSILLDK[K-lipid 5]AQXAFIEYLLEGGPSLRHYVNWLTRQRY TC3a YXQGTFTSDYSILLDKKAQXAFIEYLLEGGPSLRHYVNWLTRQ(NMeR)Y TC3b YXQGTFTSDYSILLDK[K-lipid l]AQXAFIEYLLEGGPSLRHYVNWLTRQ(NMeR)YTC3c YXQGTFTSDYSILLDK[K-lipid 5]AQXAFIEYLLEGGPSLRHYVNWLTRQ(NMeR)YTC3d YXQGTFTSDYSIL(L«)DKKAQXAFIEYLLEGGPSLRHYVNWLTRQ(NMeR)Y TC3e YXQGTFTSDYSIL(L«)DK[K-Lipid l]AQXAFIEYLLEGGPSLRHYVNWLTRQ(NMeR)YTC3f YXQGTFTSDYSIL(L«)DK[K-lipid5]AQXAFIEYLLEGGPSLRHYVNWLTRQ(NMeR)YTC4 YXQGTFTSDYSILLDR[K-Lipid_ 5 ] AQAAFIEYLLEGGPSLRHYVNWLTRQRY _aSequences of the corresponding tetra-receptor agonist chimera (TC) peptides written from N-terminus to C-terminus. All peptides reported in this table have a free N-terminal amine and are C-terminal amides. Lipidations (in brackets) correlate to the structures described in Figure Id, e, and the unnatural amino acids (X, L“, NMeR) were described in Figure If.Table S6. Sequences of GLP-1R agonist peptides reported in Figure 5.Peptide Molecular Sequence"weight C2CF3 GLP-1 3379.7 JAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2C2CF3 LIR (Octaose) 4763.9 JAEGTFTSDVSSYLEGQAA[Kt-RT(x =6)]EFIAWLVRGRG-OHC2CF3 LIR (Trios) 3954.2 JAEGTFTSDVSSYLEGQAA[Kt-RT(x =1)]EFIAWLVRGRG-OHC2CF3 Liraglutide 3833.3 JAEGTFTSDVSSYLEGQAA3EFIAWLVRGRG-OHaSequences of the corresponding to the GLP-1R agonist peptides reported in Figure 5. “J” represents a 2,2,2-trifluoroethyl alkylated histidine, “| K -RT|” represents lysine sidechain N- functionalized with an oligosaccharide RT:“3” represents a lysine residue acylated with the γGlu-C16 acyl moiety.REFERENCES CITED(1) Guh, D. P.; Zhang, W.; Bansback, N.; Amarsi, Z.; Birmingham, C. L.; Anis, A. 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DOI: 10.1021 / acs.jmedchem.0c01783.INCORPORATION BY REFERENCE

[0195] All U. S. and PCT patent publications and U. S. patents mentioned herein are hereby incorporated by reference in their entirety as if each individual patent publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.OTHER EMBODIMENTS

[0196] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

We claim:

1. A peptide having at least 85% sequence identity to Formula A:XaaiXaa2Xaa3GTXaaeXaa7 SDXaai oSXaai 2Xaai 3X aa 14Xaai 5 X aa 1 eXaai? Xaai sXaai 9 Xaa2oXaa2iFXaa23Xaa24Xaa25Xaa26Xaa27Xaa2sGGXaa3iSXaa33RXaa35Xaa36Xaa37N Xaa39Xaa4oTRXaa43Xaa44Y -NH-R2Formula A;wherein:Xaai is selected from:wherein R1is selected from hydrogen, alkyl, fluoroalkyl, and alkylheteroaryl;Xaa2 is selected from A, Aib, AzaA, G and V;Xaas is selected from Q, E, H, aMeE and aMeQ;Xaae is selected from F, aMeF and a-Me-2-fluorophenylalanine;Xaa? is selected from T and I;Xaaio is selected from Y, L, K and K;Xaai2 is selected from I, K and K;Xaai3 is selected from L, Y, aMeL, Aib, K and K;Xaai4 is selected from L and K;Xaais is selected from D and E;Xaaie is selected from E, R, K and K:;Xaan is selected from R, K and K;Xaais is selected from A, Y and R;Xaai9 is selected from Q and A;Xaa2o is selected from Q, Aib, A, K and K;Xaa2i is selected from E, D, Aib, K, K:and A;Xaa23 is selected from I and V;Xaa24 is selected from E and Q;Xaa25 is selected from W, Y and aMeY;Xaa26 is selected from L, K, and K,Xaa27 is selected from K, K, L and I;Xaa28 is selected from K, K, E, A and D;Xaasi is selected from P, K and K:;Xaa33 is selected from L, D-proline and aMeL;Xaa35 is selected from H and 3-(4-pyridyl)alanine;Xaa36 is selected from Y and 3 -cyclohexylalanine;Xaa37 is selected from L, V, Y, aMeL, Aib and aMeY;Xaa39 is selected from W, L, K, aMeL, Aib and aMeY;Xaa4o is selected from V, L and aMeL;Xaa43 is selected from Q and aMeQ;Xaa44 is selected from R and NMeR;each K:is independentlyHN^pLinkerlIRLinker2iRLinker3\TwhereinRLinker1, RLinker2and RLinker3are each independently selected from alinker group and a covalent bond;RTcomprises a lipid moiety or an oligosaccharide moiety; andR2is selected from hydrogen, alkyl and fluoroalkyl;provided that the peptide is not:Retatrutide: YXQGTFTSDYSIαLDK4AQXAFIEYLLEGGPSSGAPPPS–NH2;Tirzepatide: YXEGTFTSDYSIXLDKIAQ2AFVQWLIAGGPSSGAPPPS–NH2;Triagonist: HXQGTFTSD3SKYLDERAAQDFVQWLLDGGPSSGAPPPS-NH2;Analogue 19: HXEGTFTSDVSSYLEGQALRHYINWLTRQRY-NH2;Compound 16: HXHGTFTSDYSIYLEQKYAXEFVQWLLEGGPSSGAPPPS-NH2; GEP44: HSQGTFTSDLSKYLEEEAVREFIAWLKNGGPSRHYLNLVTRQRY-NH2; or SAR441255: HXHGTFTSDLSKL¶EEQRQXEFIEWLKAaGPPSXKPPPK-NH2;wherein:Ω is Lysine acylated with εLys-εLys-γGlu-C20 diacid;¶ is Lysine acylated with γGlu-γGlu-C16 acyl;s is D-serine;a is D-alanine;4 is Lysine acylated with OEG-y-Glu-C20 diacid;3 is Lysine acylated with y-Glu-C16 acyl;2 is Lysine acylated with OEG-OEG-y-Glu-C2() diacid; and a is a-methyl-L- Leucine, also referred to as (aMeL, L“).

2. The peptide of claim 1, wherein R1is selected from hydrogen,3. The peptide of claim 1, wherein R1is hydrogen.

4. The peptide of any one of claims 1-3, wherein R2is hydrogen.

5. The peptide of any one of claims 1-3, wherein R2is alkyl or aralkyl.

6. The peptide of claim 5, wherein R2is selected from ethyl, isopropyl, isobutyl,benzyl,and7. The peptide of any one of claims 1-3, wherein R2is fluoroalkyl.

8. The peptide of claim 7, wherein R2is selected from 1,1,1 -trifluoroethyl and 1,1,1,2,2-pentafluoropropyl.

9. The peptide of any one of claims 1-8, wherein RLinker1isselected from a covalent bond and:wherein n is 1-24.

10. The peptide of claim 9, wherein RLinker1isselected from a covalent bond and11. The peptide of any one of claims 1-10, wherein RLinker2isselected from a covalent bond and:wherein n is 1-24.

12. The peptide of claim 11, wherein RLinker2is selected from a covalent bond and13. The peptide of any one of claims 1-12, wherein RLinker3isselected from a covalent bond and:wherein n is 1-24.

14. The peptide of claim 13, wherein RLinker3is selected from a covalent bond and6anci615. The peptide of any one of claims 1-14, wherein RTis selected from:wherein R$is selected from CH3, CO2H, CCTR55. P(O)(OH)2, SO3H, tetrazole,, and N wherein R$$is selected from:, and, andwherein R&is selected from, andwherein R&&is selected from:• H y@wherein R&&&is selected from:, and 'wherein R&&&&is selected from:■,, and ',wherein R&&&&&isselected from:, and ',\.Z, H <5 x @ wherein R&&&&&&isselected from:, and '; provided that one and only one of R&, R&&, R&&&, R***&*ANC|comprises - @y@wherein R#is selected from: ' and,wherein -@ represents the point of attachment to the remainder of the molecule; a is 1-24; andm is 6-24.

16. The peptide of claim 15, wherein RTis:ORtzm17. The peptide of claim 16, wherein RSis CH3 or CO2H.

18. The peptide of any one of claims 1-14, wherein RTis:wherein x is 1-20.

19. The peptide of any preceding claim, wherein:Y Y" RLlnker2a covaient bond or is selected from:S andRL1nker3 •s a covalent bond Or &:oR$is Me or CO2H;n is 1-4; andm is 14-18.

20. The peptide of any one of the preceding claims, wherein at least one of Xaaio, Xaai3, Xaaie, Xaai7, Xaa2o, Xaa26, Xaa27, Xaa28 and Xaa3i is Kt21. The peptide of claim 20, wherein at least one of Xaaio, Xaaie, Xaai7 and Xaa2o is Kt22. The peptide of any one of claims 1-21, wherein Xaai is Y.

23. The peptide of any one of claims 1-22, wherein Xaa2 is Aib.

24. The peptide of any one of claims 1-23, wherein Xaa? is Q.

25. The peptide of any one of claims 1-24, wherein the peptide has at least 90% sequence identity to Formula A.

26. The peptide of any one of claims 1-24, wherein the peptide has at least 95% sequence identity to Formula A.

27. The peptide of any one of claims 1-24, wherein the peptide has a sequence of Formula A.

28. The peptide of any one of claims 1-27, wherein the peptide is an agonist of at least one receptor selected from GLP-1R, GIPR, GcgR and Y2R.

29. The peptide of any one of claims 1-28, wherein the peptide is an agonist of Y2R.

30. The peptide of any one of claims 1-29, wherein the peptide is an agonist of at least 2 receptors selected from GLP-1R, GIPR, GcgR and Y2R.

31. The peptide of any one of the preceding claims, wherein the peptide is an agonist of GLP-1R and Y2R.

32. The peptide of any one of the preceding claims, wherein the peptide is an agonist of GIPR and Y2R.

33. The peptide of any one of the preceding claims, wherein the peptide is an agonist of at least 3 receptors selected from GLP-1R, GIPR, GcgR and Y2R.

34. The peptide of any one of the preceding claims, wherein the peptide is an agonist of GLP-1R, GIPR and Y2R.

35. The peptide of any one of the preceding claims, wherein the peptide is an agonist of GLP-1R, GIPR, GcgR and Y2R.

36. The peptide of claim 1, wherein the peptide is selected from:YAQGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;YAEGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;HAHGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;YXQGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;HXQGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;BAQGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;ZAQGTFTSDYSILLDKKAQQAFIEYLLEGGPSLRHYLNLVTRQRY;YXQGTFTSD3SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY;YGQGTFTSD3SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY;YVQGTFTSD3SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY;BAQGTFTSD3SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY;JAQGTFTSD3SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY;YUQGTFTSD3SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY;YXQGTFTSDYSILLDKKAQQAFIEYLLEGG4SLRHYVNWLTRQRY;YXQGTFTSDYSILLDKKAQQAFIEYLLEGG2SLRHYVNWLTRQRY;YXQGTFTSDYSILLDK1AQQAFIEYLLEGGPSLRHYVNWLTRQRY;YXQGTFTSDYSILLDK2AQQAFIEYLLEGGPSLRHYVNWLTRQRY;YXQGTFTSDYSILLDK4AQQAFIEYLLEGGPSLRHYVNWLTRQRY;YXQGTFTSDYSILLD2KAQQAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSD5SILLDKKAQQAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLDK1AQXAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLDK6AQXAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLDK7AQXAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLDK8AQXAFIEYLLEGGPSLRHYVNWLTRQRY; YXQGTFTSDYSILLDKKAQXAFIEYLLEGGPSLRHYVNWLTRQAY; YXQGTFTSDYSILLDK1AQXAFIEYLLEGGPSLRHYVNWLTRQAY; YXQGTFTSDYSILLDK8AQXAFIEYLLEGGPSLRHYVNWLTRQAY; YXQGTFTSDYSIaLDKKAQXAFIEYLLEGGPSLRHYVNWLTRQAY; YXQGTFTSDYSIaLDKlAQXAFIEYLLEGGPSLRHYVNWLTRQAY; YXQGTFTSDYSIaLDK8AQXAFIEYLLEGGPSLRHYVNWLTRQAY; YXQGTFTSDYSILLDR8AQAAFIEYLLEGGPSLRHYVNWLTRQRY; YXEGTFTSDYSILLDR8AQAAFIEYLLEGGPSLRHYVNWLTRQRY; HAHGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; YAQGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; YAEGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; HXHGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; YXQGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; YXEGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; JAHGTFTSDYSIYLEKKYAAEFVQWLLEGGPSLRHYLNWVTRQRY; YAEGTFTSDYSILLDKIAQ9AFVQWLIAGGPSLRHYLNWVTRQRY; YAEGTFTSDYSILLDKIAQ1AFVQWLIAGGPSLRHYLNWVTRQRY; YXEGTFTSDYSILLDKIAQKAFVQWLIAGGPSLRHYLNLVTRQRY; HXEGTFTSDYSILLDKIAQKAFVQWLIAGGPSLRHYLNLVTRQRY; HAQGTFTSDYSILLDKIAQKAFVQWLIAGGPSLRHYLNLVTRQRY; JAQGTFTSDYSILLDR8AQAAFIEYLLEGGPSLRHYVNWLTRQRY;HXQGTFTSDYSKYLDERAAQDFVQWLLDGGPSLRHYLNLVTRQRY;HAQGTFTSDYSKYLDERAAQDFVQWLLDGGPSLRHYLNLVTRQRY;HAHGTFTSDLSKLKEEQRQQEFIEWLKAGGPSLRHYLNWVTRQRY;YAQGTFTSDLSKLKEEQRQQEFIEWLKAGGPSLRHYLNWVTRQRY;HAQGTFTSDLSKLKEEQRQQEFIEWLKAGGPSLRHYLNWVTRQRY;HXHGTFTSDYSILLDK[10]AQXAFIEYLLEGGPSLRHYLNWaTR[aMeQ]RY; YXQGTFTSDYSILLDK[10]AQXAFIE[aMeY]LLEGGPSaRHYLNWLTR[aMeQ ]RY;YXQGTFTSDYSILLDK[10]AQXAFIEYLLEGGPSLRHYLNWaTRQAY; yXQGTFTSDYSILLDR[10]AQAAFIEYLLEGGPSLRHYLNWLTRQRY;[11-Y]AQGTFTSDYSILLDR[1O]AQAAFIEYLLEGGPSLRHYLNWLTRQRY;[Ac-Y]AQGTFTSDYSILLDR[10]AQAAFIEYLLEGGPSLRHYLNWLTRQRY; FXQGTFTSDYSILLDR[10]AQAAFIEYLLEGGPSLRHYLNWLTRQRY; fXQGTFTSDYSILLDR[ 10] AQAAFIEYLLEGGPSLRHYLNWLTRQRY;[Ac-F]AQGTFTSDYSILLDR[10]AQAAFIEYLLEGGPSLRHYLNWLTRQRY; YXQGTFTSDYSILLDK[10]AQXAFIEYLLEGGPSpR[Pyr(4)][Cha]XNKVTRQR Y-NH2;YXQGTFTSDYSILLDK[10]AQXAFIEYLLEGGPSpR[Pyr(4)][Cha]XNWLTRQR Y-NH2;YXQGTFTSDYSIaLDK[10]AQXAFIE[aMeY]LLEGGPSaRHYLNWLTR[aMeQ ]RY;YXQGTFTSDYSIaLDK[10]AQXAFIE[aMeY]LLEGGPSaRHYLNWLTRQAY;[ll-Y]AQGTFISDYSIALDR[10]AQQDFVQWLLAGGPSLRHYLNWLTRQRY; YXEGTFTSDYSILLDR[10]AQAAFVQYLIAGGPSLRHYLNWLTRQRY;YXEGTFTSDYSILLDK[10]AQXAFVQYLIAGGPSLRHYLNWLTRQAY;YXEGTFTSDYSIaLDK[10]AQXAFVQYLIAGGPSLRHYLNWLTRQAY;YXEGTFTSDYSILLDRIAQ[10]AFVQYLIAGGPSLRHYLNWLTRQRY; yAEGTFTSDYSILLDRIAQ[10]AFVQYLIAGGPSLRHYLNWLTRQRY;[ll-Y]AEGTFTSDYSILLDRIAQ[10]AFVQWLLAGGPSLRHYLNWLTRQRY;[ 11 - Y] AEGTFTSD YSILLDR[ 10] AQAAFVQWLLAGGPSLRHYLNWLTRQRY; YXEGTFTSDYSIaLDK[10]AQXAFVQWLLAGGPSaRHYLNWLTRQRY; YXEGTFTSDYSIaLDK[10]AQXAFVQWLLAGGPSLRHYLNWLTRQAY; YXEGTFTSDYSIaLDKIAQ[10]AFVQWLLAGGPSaRHYLNWLTRQRY; and yXEGTFTSDYSILLDR[ 10] AQAEFIEYLIAGGPSLRHYLNWLTRQRY;wherein:B is [2,2,2-triflouroethyl -Y];J is [2,2,2-triflouroethyl -H];Zis [Im-Y];X is Aib;3 is Lysine acylated with y-Glu-C 16 acyl;U is Aza-alanine;4 is Lysine acylated with OEG-y-Glu-C20 diacid;2 is Lysine acylated with OEG-OEG-y-Glu-C20 diacid;1 is Lysine acylated with OEG-OEG-y-Glu-C18 diacid;5 is Lysine acylated with y-Glu-C20 diacid;6 is Lysine acylated with OEG-OEG-PAla-y-Glu-C18 diacid;7 is Lysine acylated with OEG-PAla-y-Glu-C18 diacid;8 is Lysine acylated with pAla-OEG-y-Glu-C18 diacid;a is a-methyl-L- Leucine, also referred to as (aMeL, L“);9 is Lysine acylated with OEG-y-Glu-C18 diacid;0 (zero) is Lysine acylated with OEG-OEG-OEG-OEG-y-Glu-C18 diacid; * is Lysine acylated with OEG-OEG-C18 diacid;# is Lysine acylated with C16 acyl;Ais NMeR (N-terminally methylated arginine);10 is Lysine acylated with pAla-OEG-y-Glu-C18 diacid;aMeQ is a-methyl-L-glutamine;aMeE is a-methyl-L- glutamic acid;aMeF is a-methyl-L-phenylalanine;aMeY is a-methyl-L-tyrosine;Pyr(4) is 3-(4-pyridyl)alanine;Cha is 3-cyclohexylalanine;Ac-Y is N-terminally acylated L-tyrosine;Ac-y is N-terminally acylated D-tyrosine;Ac-F is N-terminally acylated F-phenylalanine;Ac-f is N-terminally acylated D-phenylalanine;11-Y is ((lH-imidazol-5-yl)methyl)-F-tyrosine;y is D-tyrosine;f is D-phenylalanine;p is D-proline;NMeY is N-terminally methylated tyrosine; andaMeF(2F) is a-Me-2-flourophenylalanine.

37. A method of:a) treating or preventing type 2 diabetes, hyperglycemia, impaired glucose tolerance, or non-insulin dependent diabetes, and / or obesity;b) reducing body weight and / or food intake, and / or inducing satiety;c), nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), metabolic dysfunction-associated liver disease (MASFD), and / or nonalcoholic fatty liver disease (NAFFD);d) treating chronic kidney disease;e) treating or preventing emesis;f) treating or preventing effects of aging;g) support of islet transplant survival in Type 1 diabetes; and / orh) treating or preventing arthritis and related diseases, for example, Osteoarthritis, Rheumatoid arthritis, Gout, Ankylosing spondylitis, Psoriatic arthritis, Juvenile arthritis,Fibromyalgia, Infectious arthritis, Spondyloarthritis, Sjogren's syndrome, Scleroderma, and / or Polymyalgia rheumatica;comprising administering to a subject in need thereof an effective amount of a peptide of any one of claims 1-36.

38. A method of treating cardiovascular disease and / or hypertension, comprising administering to a subject in need thereof an effective amount of a peptide of any one of claims 1-36.

39. A method of treating a neurodegenerative disease (e.g., Alzheimer’s, Parkinsons, other forms of dementia, traumatic brain injury), comprising administering to a subject in need thereof an effective amount of a peptide of any one of claims 1-36.

40. A method of treating alcohol use disorder, substance use disorder or smoking addiction, comprising administering to a subject in need thereof an effective amount of a peptide of any one of claims 1-36.

41. A method of treating inflammation, comprising administering to a subject in need thereof an effective amount of a peptide of any one of claims 1-36.

42. A method of treating diabetes, comprising administering to a subject in need thereof an effective amount of a peptide of any one of claims 1-36.

43. A method of treating obesity, comprising administering to a subject in need thereof an effective amount of a peptide of any one of claims 1-36.

44. The method of any one of claims 37-43, wherein the subject was not responsive to or did not adequately tolerate a previous course of therapy with a mono- or multiagonist.

45. The peptide of any one of claims 1-36, wherein the peptide impacts or increases cAMP signaling more than it impacts or increases beta-arrestin recruitment and internalization of the receptor or receptor:peptide complex.

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