Agonist peptides, compositions and methods thereof

Abstract

The present disclosure provides agonist peptides against incretin hormone receptors for the management of metabolic disorders including Type 2 Diabetes, Obesity, and / or co-morbidities. Also provided are compositions and methods for treatment and management of Type 2 Diabetes, Obesity, and / or co-morbidities.

Description

AGONIST PEPTIDES, COMPOSITIONS AND METHODS THEREOF FIELD OF INVENTION

[0001] The present disclosure broadly relates to the field of peptidomimetics. In particularly, the invention relates to peptides having agonist activity on receptors. The present invention also relates to compositions having agonist peptides, and method of preparation and use thereof.BACKGROUND OF INVENTION

[0002] Peptidomimetics, such as GLP-1 agonists and other incretin analogues, have recently emerged as promising platforms in treatment of metabolic disorders including diabetes, obesity, and related co-morbidities, etc. Incretins play an essential role in the regulation of blood glucose levels, energy expenditure and fat deposition. These hormones stimulate the β-cells in pancreas to release insulin upon sensing the presence of excess glucose in the intestinal lumen. Incretin mimetics have been developed to activate receptor leading to increased insulin secretion, reduced glucagon release, delayed gastric emptying, and suppressed appetite, ultimately improving blood sugar control and aiding in weight management for individuals with type 2 diabetes and obesity.

[0003] Type 2 Diabetes Mellitus (T2DM), characterized by insulin resistance and relative insulin deficiency, frequently coexists with obesity, marked by excessive adiposity with about two thirds of the T2DM cases diagnosed already having obesity. Historically, managing T2DM and obesity has relied on lifestyle modifications, pharmacotherapy, and, in severe cases, bariatric surgery. However, existing interventions exhibit limitations in efficacy, tolerability, and long-term adherence. Weight loss alone through medication or lifestyle changes is not enough to reduce the progression of T2DM and Obesity. Consequently, there is a burgeoning interest in innovative therapeutic approaches targeting the intricateinterplay between T2DM and obesity. Exogeneous insulin therapy was one promising approach to overcome hyperglycemia, but it led to weight gain.

[0004] Incretin mimetics having mono agonist and dual agonist activity have previously been developed. However, there is a need for effective, stabilized, and long-acting peptides and therapeutic approaches for treatment and management of metabolic disorders, obesity, and related co-morbidities.SUMMARY OF THE INVENTION

[0005] In an initial aspect of the present disclosure, there is provided an agonist peptide comprising a peptide having an amino acid sequence of: SEQ ID NO. 1, wherein X1is selected from Histidine (H) or Tyrosine (Y), X2is selected from Glycine (G), Serine (S), or a non-natural amino acid, X3and X21 are, independently, selected from selected from Alanine (A), Glutamine (Q), or Glutamic acid (E), X12is selected from Lysine (K), Glutamic acid (E), or Isoleucine (I), X13is selected from Tyrosine (Y) or a non-natural amino acid, X16, X17, and X28are, independently, selected from selected from Lysine (K), Glutamic acid (E), Arginine (R), or Isoleucine (I), X20is selected from lysine, an acylated lysine or a non-natural amino acid, X23is selected from Isoleucine (I), Valine (V), or Leucine (L), X24is selected from Asparagine (N), Glutamic acid (E), or Valine (V), X25 is selected from Tyrosine (Y), Tryptophan (W), or Phenylalanine (F), and X26 and X27 are, independently, selected from selected from Leucine (L), or Isoleucine (I), and X29, X30, X31, X33, X34 and X35 are, independently, selected from Glycine (G), Proline (P), Alanine (A), or non-natural amino acids; or a pharmaceutically acceptable salt thereof.

[0006] In another aspect of the present disclosure, there is provided a composition comprising the agonist peptide as disclosed herein, and at least one pharmaceutically acceptable carrier.

[0007] In yet another aspect of the present disclosure, there is provided a method for modulating incretin receptors and / or glucagon receptors, comprising: providing an effective amount of the agonist peptide or the composition as disclosed herein.

[0008] In an aspect of the present disclosure, there is provided a method for treatment and / or management of obesity in a subject, comprising providing an effective amount of the agonist peptide as disclosed herein, to the subject.

[0009] In an aspect of the present disclosure, there is provided a method for treatment and / or management of metabolic disorders in a subject, comprising providing an effective amount of the agonist peptide as disclosed herein, to the subject.

[0010] In an aspect of the present disclosure, (a) synthesizing the peptide by solidphase peptide synthesis and optionally including at least one non-natural amino acid; (b) optionally incorporating at least one modified amino acid residue; and (c) cleaving and recovering the peptide to obtain the peptide as claimed in claim 1.

[0011] These and other features, aspects, and advantages of the present subject matter will be better understood with reference to the following description and appended claims. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS

[0012] The following drawings form a part of the present specification and are included to further illustrate aspects of the present disclosure. The disclosure may be better understood by reference to the drawings in combination with the detailed description of the specific embodiments presented herein.

[0013] Figure 1 depicts a schematic representation of the amino acid structures of the exemplary peptides, in accordance with the embodiments herein.

[0014] Figure 2 shows the results of a Surface Plasmon Resonance (SPR) sensorgram showing immobilisation of GIPR onto a CM5 chip (Fc=l) via amine coupling, with sequential baseline, EDC / NHS activation, receptor injection, and post-immobilisation stabilisation phases, in accordance with the embodiments herein.

[0015] Figure 3 shows (A) the results of a single-concentration binding SPR sensorgram of LY (positive control) at 50 pM and 5 pM injected over immobilized GIPR, and (B) the results of multi-concentration kinetic SPR sensorgram of LY (0, 4.1, 12, 37, 111, 333, 1000 nM) binding to immobilized GIPR, with 1:1 Langmuir fitting used to determine ka, kd, and KD (B), in accordance with the embodiments herein.

[0016] Figure 4 shows (A) the results of a single-concentration binding sensorgram of Peptide 20 at 50 pM and 5 pM injected over immobilized GIPR, and (B) shows the results of multi-concentration kinetic sensorgram of Peptide 20 (20, 61, 185, 555, 1666, 5000 nM) binding to immobilized GIPR, in accordance with the embodiments herein.

[0017] Figure 5 shows (A) the results of single-concentration binding sensorgram of ND-MC-ZB-50b at 50 pM and 5 pM injected over immobilized GIPR, and (B) the results of multi-concentration kinetic sensorgram of ND-MC-ZB-50b (0, 15.5, 31.25, 62.5, 250, 500 nM) binding to immobilized GIPR in accordance with the embodiments herein.

[0018] Figure 6 shows (A) the results of single-concentration binding sensorgram of ND-MC-ZB-50c at 50 pM and 5 pM injected over immobilized GIPR, and (B) the results of multi-concentration kinetic sensorgram of ND-MC-ZB-50c (0, 15.5, 31.25, 62.5, 250, 500 nM) binding to immobilized GIPR in accordance with the embodiments herein.

[0019] Figure 7 shows (A) the results of single-concentration binding sensorgram of ND-MC-ZB-50d at 50 pM and 5 pM injected over immobilized GIPR, and (B) the results of multi-concentration kinetic sensorgram of ND-MC-ZB-50d (0, 15.5, 31.25, 62.5, 250, 500 nM) binding to immobilized GIPR in accordance with the embodiments herein.

[0020] Figure 8 shows (A) the results of single-concentration binding sensorgram of ND-MC-ZB-50e at 50 pM and 5 pM injected over immobilized GIPR, and (B) the results of multi-concentration kinetic sensorgram of ND-MC-ZB-50e (0, 15.5,31.25, 62.5, 250, 500 nM) binding to immobilized GIPR in accordance with the embodiments herein.

[0021] Figure 9 shows the results of a SPR sensorgram showing immobilisation of GLP-1R onto a CM5 chip (Fc=3) via amine coupling, with sequential baseline, EDC / NHS activation, receptor injection, and post-immobilisation stabilisation phases, in accordance with the embodiments herein.

[0022] Figure 10 shows the results of multi-concentration kinetic sensorgram of LY (positive control; 4.1, 12, 37, 111, 333, 1000 nM) binding to immobilized GLP-1R, in accordance with the embodiments herein.

[0023] Figure 11 shows the results of multi-concentration kinetic sensorgram of Peptide 20 (0, 20, 61, 185, 555, 1666, 5000 nM) binding to immobilized GLP-1R, in accordance with the embodiments herein.

[0024] Figure 12 shows the results of multi-concentration kinetic sensorgram of ND-MC-ZB-50b (0, 31.25, 62.5, 125, 250, 500, 1000 nM) binding to immobilized GLP-1R, in accordance with the embodiments herein.

[0025] Figure 13 shows the results of multi-concentration kinetic sensorgram of ND-MC-ZB-50c (0, 31.25, 62.5, 125, 250, 500, 1000 nM) binding to immobilized GLP-1R, in accordance with the embodiments herein.

[0026] Figure 14 shows the results of multi-concentration kinetic sensorgram of ND-MC-ZB-50d (0, 31.25, 62.5, 125, 250, 500, 1000 nM) binding to immobilized GLP-1R, in accordance with the embodiments herein.

[0027] Figure 15 shows the results of multi-concentration kinetic sensorgram of ND-MC-ZB-50e (0, 31.25, 62.5, 125, 250, 500, 1000 nM) binding to immobilized GLP-1R, in accordance with the embodiments herein.

[0028] Figure 16 shows the results of a SPR sensorgram showing immobilisation of GCGR (GCGR-lig 3) onto a CM5 chip (Fc=l) via amine coupling, withsequential baseline, EDC / NHS activation, receptor injection, and postimmobilisation stabilisation phases, in accordance with the embodiments herein.

[0029] Figure 17 shows the results of multi-concentration kinetic sensorgram of LY (positive control; 0, 156, 312.5, 625, 1250, 2500, 5000 nM) binding to immobilized GCGR, in accordance with the embodiments herein.

[0030] Figure 18 shows the results of multi-concentration kinetic sensorgram of Peptide 20 (0, 156, 312.5, 625, 1250, 2500, 5000 nM) binding to immobilized GCGR. The low maximal binding response (~8 RU) is indicative of weak binding affinity to this receptor, in accordance with the embodiments herein.

[0031] Figure 19 shows the results of multi-concentration kinetic sensorgram of ND-MC-ZB-50b (0, 156, 312.5, 625, 1250, 2500, 5000 nM) binding to immobilized GCGR, in accordance with the embodiments herein.

[0032] Figure 20 shows the results of multi-concentration kinetic sensorgram of ND-MC-ZB-50c (0, 312, 625, 1250, 2400, 5000 nM) binding to immobilized GCGR, in accordance with the embodiments herein.

[0033] Figure 21 shows the results of multi-concentration kinetic sensorgram of ND-MC-ZB-50d (0, 156, 312.5, 625, 1250, 2500, 5000 nM) binding to immobilized GCGR, in accordance with the embodiments herein.

[0034] Figure 22 shows the results of multi-concentration kinetic sensorgram of ND-MC-ZB-50e (0, 156, 312.5, 625, 1250, 2500, 5000 nM) binding to immobilized GCGR, in accordance with the embodiments herein.

[0035] Figure 23 depicts results of cAMP based in-vitro assay for peptide induced receptor activation for GLP-IR(A), GIPR (B), and GCGR (C). Plots shown depict the activation of the receptors in presence of the positive control peptide Retatrutide, in accordance with the embodiments herein.

[0036] Figure 24 depicts results of cAMP based in-vitro assay for peptide induced receptor activation for GLP-1R (A), and GIPR (B). Plots shown depict theactivation of the receptors in presence of the positive control peptide Tirzepatide, in accordance with the embodiments herein.

[0037] Figure 25 depicts results of cAMP based in-vitro assay for peptide induced receptor activation for GLP-1R (A), GIPR (B), and GCGR (C). Plots shown depict the activation of the receptors in presence of the peptide ND-MC-ZB-50(b) (SEQ ID NO. 19), in accordance with the embodiments herein.

[0038] Figure 26 depicts results of cAMP based in-vitro assay for peptide induced receptor activation for GLP-1R (A), GIPR (B), and GCGR (C). Plots shown depict the activation of the receptors in presence of the peptide ND-MC-ZB-50(c) (SEQ ID NO. 20), in accordance with the embodiments herein.

[0039] Figure 27 depicts results of cAMP based in-vitro assay for peptide induced receptor activation for GLP-1R (A), GIPR (B), and GCGR (C). Plots shown depict the activation of the receptors in presence of the peptide ND-MC-ZB-50(d) (SEQ ID NO. 21), in accordance with the embodiments herein.

[0040] Figure 28 depicts results of cAMP based in-vitro assay for peptide induced receptor activation for GLP-1R (A), GIPR (B), and GCGR (C). Plots shown depict the activation of the receptors in presence of the peptide ND-MC-ZB-50(e) (SEQ ID NO. 22), in accordance with the embodiments herein.DETAILED DESCRIPTION OF THE INVENTION

[0041] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such steps, features, compositions, and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any or more of such steps or features. Definitions

[0042] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are delineated here. Thesedefinitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.

[0043] The articles “a”, “an” and “the” are used to refer to one or more than one (i.e., to at least one) of the grammatical object of the article.

[0044] The terms “comprise” or “contain” and “comprising” or “containing” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.

[0045] The term "at least one" is used to mean one or more and thus includes individual components as well as mixtures / combinations.

[0046] Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.

[0047] The term “including” is used to mean “including but not limited to”, “including” and “including but not limited to” are used interchangeably.

[0048] The term “peptide”, as used herein, broadly refers to a molecule having two or more amino acids residues joined together by peptide bonds. The term “peptide” and “polypeptide” are used interchangeably herein.

[0049] The term “agonist”, as used herein, refers to a substance which promotes the biological activity of another. The term agonist encompasses substances that bind to receptors and substances which promote receptor function without binding thereto. For example, a Glucagon-like peptide- 1 (GLP-1) analogue binds to GLP-1 receptor (GLP-1R) to agonize GLP-1R.

[0050] Amino acid residues are generally represented by single letter and three letter abbreviations, for example “Alanine” is represented by single letter code “A”and three letter code “ala” or “Ala”. The expression “X” as used in amino acid sequences refers to any amino acid residue, including natural, non-natural, and modified / acylated amino acid residues. In the expression “Xi”, the number ‘ 1 ’ refer to the position of X amino acid in the amino acid sequence of the peptide. For example, “Xi”, denotes X amino acid at position 1, “X2” denotes X amino acid at position 2, and so on. Such representations are generally used and well understood by a person skilled in the art. The present disclosure in describing the present invention employs such representations or phrases which is intended to mean the generally acceptable meaning in the art.

[0051] The term “peptide staple” refers to a brace, including a covalent or non-covalent bond, positioned in a peptide to link two amino acids including natural or non-natural amino acids in the peptide. The term “stapled peptide” or “cyclized peptide” refers to a peptide stabilized by a peptide staple. It refers to a peptide wherein side chains of two amino acids including natural or non-natural amino acids in the peptide are linked. The term “hydrocarbon staple” refers to a peptide staple between hydrocarbon side chains of two non-natural amino acids in the peptide. Peptide stapling is a technique capable of promoting secondary structure formation, and / or stabilizing secondary structure of peptide. Peptide staples help promote and stabilize alpha-helical secondary structure in peptides. Peptide staples may be suitably positioned to link natural or non-natural amino acids in peptides between various positions such as i, i+4; i, i+7, etc. The terms “i,” and “i+4”, as used herein, refers to the positions of the natural or non-natural amino acids within the peptide that become linked to one another upon stapling. The “i” position refers to the position of the amino acid that is nearest to the N-terminal of the peptide. The “i+4” position is 4 amino acids downstream, i.e. 4 amino acids towards the C-terminal of the peptide.

[0052] Embodiments herein disclose agonist peptides for therapeutic application. The agonist peptides, according to embodiments herein, are peptide mimetics having agonist activity on receptors including glucagon and incretin receptors. The term “incretin”, as used herein, broadly refers to group of metabolic hormonesincluding glucagon-like peptide- 1 (GLP-1) and glucose dependent insulinotropic peptide (GIP). Incretin hormones are naturally-occurring peptide hormones. Embodiments herein provide peptides that are capable of mimicking the activity of incretin hormones. Embodiments herein provide peptide mimetics capable of mimicking the incretin and glucagon molecules. The peptide mimetics, according to embodiments herein, have agonist activity on receptors, particularly incretin hormone receptors and / or glucagon receptors, including glucagon-like peptide- 1 receptor (GLP-1R), gastric inhibitory polypeptide receptor GIPR, and glucagon receptor GCGR. In a preferred embodiment, the agonist peptides as disclosed herein are agonists which exhibit agonist activity on at least three receptors including glucagon-like peptide-1 receptor (GLP1R), gastric inhibitory polypeptide receptor GIPR, and glucagon receptor GCGR. Further, the embodiments herein provide compositions comprising the agonist peptides as disclosed herein. Also disclosed herein are methods for use and preparation of the agonist peptides disclosed herein. The agonist peptides, according to embodiments herein, are capable of regulating blood glucose and body weight in subjects. Accordingly, embodiments herein include methods for modulating receptors including GLP-1R, GIPR and GCGR, methods for treating and / or management of metabolic disorders including diabetes, obesity, and / or co-morbidities.

[0053] The present inventors have, by application of computational structural biology, designed unimolecular agonist peptides capable of agonist activity on at least three receptors. With the application of the machine learning (ML), molecular modelling and molecular dynamics simulations (MD), and classical physics based binding free energy calculations, the fine intricacies of peptide- receptor complex formation and protein-protein interactions were studied. This was instrumental in enhancing the binding efficiency and agonistic properties of the designed peptides with the three receptors, i.e. GLP-1R, GIPR and GCGR. Accordingly, the present inventors have been able to achieve agonist peptides having improved properties.

[0054] The agonist peptides, according to embodiments herein, are capable of binding and having selectivity to incretin hormone receptors and / or glucagonreceptors. The agonist peptides, as disclosed herein, are long acting with good serum half-life and stability. In some embodiments, the agonist peptides have stabilized alpha-helix, comprising non-natural amino acids linked by a peptide staple, preferably hydrocarbon staple. The agonist peptides have amino acid sequences comprising non-natural amino acids which help in promoting and maintaining secondary structure, particularly alpha helical secondary structure, in some embodiments. In general, serum half-life is mainly determined by the two critical factors viz. clearance rate by the kidney and enzyme mediated degradation. It is observed that the agonist peptides of the present invention have increased stability and solubility, showing enhanced activation of GLP-1R, reduced clearance rate, and lower chances of enzyme mediated degradation.Peptides

[0055] Embodiments herein disclose agonist peptides. The agonist peptides, according to embodiments herein, have specificity for incretin hormone receptors and / or glucagon receptors. The agonist peptides, as disclosed herein, comprise peptides having an amino acid sequences comprising natural, non-natural, and / or acylated / modified amino acid residues. In some embodiments, the non-natural amino acids may further include side chains that facilitate peptide stapling. The peptides, as disclosed herein, is such that it exhibits enhanced stability, specificity and binding affinity to incretin receptors, and prolonged serum half-life of the peptides.

[0056] In an embodiment, the agonist peptide comprises a peptide having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to an amino acid sequence as set forth in SEQ ID NO. 1. In an embodiment, the peptide has an amino acid sequence as set forth in SEQ ID NO. 1:X1X2X3GTFTSDX10SX12X13LDX16X17AQX20X21FX23X24X25X26X27X28X29X30X31 SX33X34X35PPPS(SEQ ID NO. 1),wherein, X1, X2, X3, X10, X12, X13, X16, X17, X20, X21, X23, X24, X25, X26, X27, X28, X29, X30, X31, X33, X34, and X35are, independently, amino acids selected from natural, non-natural, or modified / acylated amino acid residues. Examples of natural, non-natural, and modified amino acid residues include, but are not limited to, histidine (H), tyrosine (Y), lysine (K), arginine (R), isoleucine (I), alanine (A), glutamic acid (E), glutamine (Q), Leucine (L), aspartic acid (D), serine (S), Tryptophan (W), Phenylalanine (F), Valine (V), Alpha-aminobutyric acid (Aib), Alpha-MethylLeucine (αMeL), HomoSerine (hSer), Norvaline (nVal), NorLeucine (nLeu), Diaminopimelic acid (DAP), alpha-4-pentenyl alanine, Bis-Pentenyl glycine, S-octenyl alanine, R-octenyl alanine, (S)-N-Fmoc-a-(4-pentenyl)alanine, Methionine sulfoxide (MetO), Selenocysteine (Sec), Methylalanine, or acylated forms thereof. Acylated forms include amino acids having at least one acyl group conjugated to the amino acid.

[0057] In an embodiment, the peptide has an amino acid sequence as set forth in SEQ ID NO. 1, wherein Xi, X2, X3, X12, Xi6, X17, X21, X28, X23, X24, X25, X26, and X27 are amino acids selected from a group consisting of Histidine (H), Tyrosine (Y), Alanine (A), Glutamine (Q), Glutamic acid (E), Lysine (K), Isoleucine (I), Lysine (K), Arginine (R), Valine (V), Leucine (L), Asparagine (N), Tryptophan (W), and Phenylalanine (F).

[0058] In an embodiment, the agonist peptide comprises a peptide having an amino acid sequence as set forth in SEQ ID NO. 1, wherein X1is selected from Histidine (H) or Tyrosine (Y), X2is selected from Glycine (G), Serine (S), or a non-natural amino acid, X3and X21 are, independently, selected from selected from Alanine (A), Glutamine (Q), or Glutamic acid (E), Xio is selected from lysine (K), Tyrosine (Y) or modified lysine (Km), X12is selected from Lysine (K), Glutamic acid (E), or Isoleucine (I), X12is selected from Lysine (K), Glutamic acid (E), or Isoleucine (I), Xi3is selected from Tyrosine (Y) or a non-natural amino acid, Xi6, X17, and X28are, independently, selected from selected from Lysine (K), Glutamic acid (E),Arginine (R), or Isoleucine (I), X20 is selected from lysine, an acylated lysine or a non-natural amino acid, X23 is selected from Isoleucine (I), Valine (V), or Leucine (L), X24 is selected from Asparagine (N), Glutamic acid (E), or Valine (V), X25 is selected from Tyrosine (Y), Tryptophan (W), or Phenylalanine (F), and X26andX27 are, independently, selected from selected from Leucine (L), or Isoleucine (I), and X29, X30, X31, X33, X34 and X35 are, independently, selected from Glycine (G), Proline (P), Alanine (A), or non-natural amino acids; or a pharmaceutically acceptable salt thereof.

[0059] In another embodiment, there is provided an agonist peptide having a peptide, wherein the peptide has an amino acid sequence selected from the group consisting of: SEQ ID NO. 2, SEQ ID NO. 3, and SEQ ID NO. 4; or a pharmaceutically acceptable salt thereof.

[0060] In another embodiment, there is provided an agonist peptide having a peptide, wherein the peptide has an amino acid sequence as set forth in (SEQ ID NO. 2):X1X2QGTFTSDYSX12X13LDX16X17AQX20EFLVFLLKGGPSSGAPPPS(SEQ ID NO. 2),whereinXi is selected from Histidine (H) or Tyrosine (Y), X2is selected from Glycine (G), Serine (S), or a non-natural amino acid, X12is selected from Lysine (K), or Glutamic acid (E), X13is selected from Tyrosine (Y) or a non-natural amino acid, preferably Aib, Xi6 is selected from selected from Glutamic acid (E), or Arginine (R), X17 is selected from selected from Isoleucine (I), or Glutamic acid (E), and X20 is selected from lysine, or an acylated lysine;

[0061] In another embodiment, there is provided an agonist peptide having a peptide, wherein the peptide has an amino acid sequence as set forth in (SEQ ID NO. 3):X1X2EGTFTSDYSIX13LDEIAQX20EFVNWLIKGGPSSGAPPPS(SEQ ID NO. 3)wherein X1is selected from Histidine (H) or Tyrosine (Y), X2 is a non-natural amino acid, X13is selected from Tyrosine (Y) or a non-natural amino acid, preferably Aib, X20is selected from lysine, or an acylated lysine.

[0062] In another embodiment, there is provided an agonist peptide having a peptide, wherein the peptide has an amino acid sequence as set forth in (SEQ ID NO. 4):X1X2QGTFTSDYSIX13LDKX17AQX20AFIEYLLEGGX31SSGX35PPPS(SEQ ID NO. 4),wherein X1is selected from Histidine (H) or Tyrosine (Y), X2is selected from Glycine (G) or Serine (S), X13 is a non-natural amino acid, preferably a-methylated amino acid, more preferably Alpha-Methyl Leucine (crMeL), X17 is selected from lysine, or an acylated lysine, X2ois a non-natural amino acid, preferably Aib, X31 andX35 are, independently, selected from Proline (P) or non-natural amino acids.Modifications

[0063] The agonist peptides, according to embodiments herein, include peptides having acylated / modified amino acid residues, particularly acylated amino acids. The term “acylated amino acid”, as used herein, refers to an amino acid that have at least one acyl group attached to the amino acid. The acylated amino acid may be attached to the acyl group by one or more linker and / or spacers. Accordingly, the term “acylated lysine” or “modified lysine”, used interchangeably herein, refers to lysine having at least one acyl group (for eg: lipid) attached to, preferably via one or more linker and / or spacers. The acyl group may be fatty acid or fatty diacid. The modification, as disclosed herein, facilitate in improving the serum half-life, solubility, and stability of the peptide. In an embodiment, the amino acid residue is acylated by conjugating with a lipid (also referred to herein as “lipid tail”) via alinker and a spacer. The lipid tail may bind (reversibly) to serum albumin which increases the serum half-life of the peptide.

[0064] The term “lipid”, as used herein, broadly refers to organic compounds that are soluble in non-polar solvents. The term lipid includes fatty acids and fatty diacids, and their substituted or unsubstituted forms. The term “lipid tail” and “lipid” are used interchangeably herein, and include, substituted or unsubstituted, tail of a fatty acid moiety or tail of a diacid moiety. In an embodiment, the lipid is selected from C8- C22fatty acids or diacids. Examples of fatty acid or diacid include, but are not limited to, caprylic acid (C8), capric acid (C10), lauric acid (C12), myristic acid (C14), palmitic acid (C16), stearic acid (C18), arachidic acid (C20), dodecanedioic acid (C12), tridecanedioic acid (C13), tetradecanedioic acid (C14), pentadecanoic acid (C15), hexadecanedioic acid (C16), heptadecanedioic acid (C17), octadecanedioic acid (C18), eicosanedioic Acid (C20), and Docosanedioate (C22). In an embodiment, the lipid is selected from a compound of Formula (a) to (i) depicted in Table 1. In an embodiment, the lipid is selected from a compound of Formula (a), (b), (c), (d), (e), (f), (g), (h), and (i) depicted in Table 1. In an embodiment, the acylated lysine comprises a fatty acid conjugated to the lysine residue via at least one linker and / or spacer, wherein the fatty acid is selected from a Cs- C22 fatty acid or diacid. The lipid / acyl group may be attached to the amino acid via a linker and / or spacer, in accordance with the embodiment herein.

[0065] The lipid, in various embodiments herein, may comprise a compound of Formula I. In an embodiment, the lipid is a compound of Formula I.CO2H-(CH2)a-CO- Formula Iwherein ‘a’ is in the range of 8 to 22, preferably 12 to 20, more preferably 16 to 18.

[0066] The lipid, in various embodiments herein, may comprise a compound of Formula I(i). In an embodiment, the lipid is a compound of Formula I(i).CH3-(CH2)a-CO- Formula I(i)wherein ‘a’ is in the range of 8 to 22, preferably 12 to 20.

[0067] In an embodiment, the lipid is a compound of Formula I or Formula I(i).

[0068] The linker, in one embodiment herein, is attached to the lipid, preferably at the hydroxyl end of the lipid at one end and a spacer at the other end. The linker, in another embodiment herein, is attached to the lipid, preferably at the hydroxyl end of the lipid, at one end and the amino acid residue at the other end. Examples of linkers include, but are not limited to, one or more gamma-glutamic acid (yGlu) moieties, and Gamma-aminobutyric acid (GABA). In an embodiment, the linker is selected from one or more yGlu moieties, Gamma-aminobutyric acid (GABA), or combination thereof. The linker may comprise of one or more moieties of yGlu. In alternate embodiments, the linker may be one or more moieties selected from benzyl-PAla, yGlu, or alpha-aminobutyric acid-yGlu (Abu-yGlu). The yGlu may be D-yGlu or L-yGlu. Accordingly, in an embodiment, the linker is at least one yGlu linker. In an embodiment, the linker is a compound of Formula (1) depicted in Table 1. In an embodiment, the linker comprises a yGlu linker, wherein the lipid is preferably attached to the yGlu linker at its a -amino group. In another embodiment, the linker comprises two yGlu moieties, wherein the lipid is preferably attached to the a -amino group of one yGlu moiety which is further attached at the carboxyl end to another yGlu moiety. Similarly, the linker may comprise two or more yGlu moieties. The linker is further attached to a spacer.

[0069] The spacer, in some embodiments herein, may be attached to the linker at one end and the amino acid residue at the other end. In other embodiment, the spacer may be attached to the lipid, preferably at the hydroxyl end of the lipid, at one end and the amino acid residue at the other end. Examples of spacers include, but are not limited to, Aminoethylethanolamine (AEEA) moieties, GGGGS repeats, one or more y-Carboxylate moieties, and one or more PEG moieties. In an embodiment, the spacer comprises a moiety selected from Aminoethylethanolamine (AEEA), GGGGS repeats, one or more y-Carboxylate moieties, one or more polyethylene glycol (PEG) moieties, or combination thereof.

[0070] The term “PEG”, as used herein, refers to any water-soluble polyethylene oxide). The term “PEG” encompasses “Oligo(ethylene glycol)” or “OEG”, and is used interchangeably herein. Typically, PEG comprises the following structure — (OCH2CH2)b —, (also represented herein as (PEG)b ), wherein ‘b’ ranges from 1 to 4000. In an embodiment herein, PEG comprises the following structure — (PEG)b — wherein ‘b’ is in the range of 1 to 8, 2 to 8, preferably 2 to 6.

[0071] The spacer, in various embodiments herein, may comprise a compound of Formula II. In an embodiment, the spacer is a compound of Formula II.-(amino-(PEG / AEEA)b-CH2CO2H)c- Formula II

[0072] In an embodiment, the spacer is a compound selected from(i) -(amino-(PEG)b-CH2CO2H)c-; or (ii) -(amino-(AEEA)b-CH2CO2H)c-, wherein ‘b’ is in the range of 1 to 10, preferably 2 to 10, more preferably 2 to 8, and ‘c’ is in the range of 1 to 10, preferably 1 to 8, more preferably 1 to 5.

[0073] In an embodiment, the spacer is selected from a compound of Formula (j) to (k) depicted in Table 1.

[0074] Examples of AEEA moieties include, but is not limited to, Aminoethylethanolamine, 17-Amino-10-oxo-3,6,12,15-tetraoxa- 9azaheptadecanoic acid, etc.

[0075] The spacer, according to embodiments herein, is covalently attached to the amino acid residue. In an embodiment, the amino acid residue is lysine (K). The spacer is attached to the epsilon amino group of the lysine side chain. Accordingly, in an embodiment, the modified lysine (Km) is lysine (K) attached to a lipid by a linker and spacer at the s-amino group of the lysine side chain. In a preferable embodiment, the modified lysine is lysine (K) attached to a lipid, preferably a diacid of Formula I, by at least one yGlu linker and a spacer of Formula II.

[0076] The term “linker and spacer”, as used herein, refers to the combination of linker and spacer according to embodiments herein. In an embodiment, the linkerand spacer is selected from yGlu-PEG, D-yGlu-(PEG)2, (PEG)2- yGlu, γGlu-(PEG)8, γGlu-(PEG)8, benzyl-PAla-(PEG)2, (yGlu)2-(PEG)2, (yGlu) 3-(PEG)2, Abu-yGlu-PEG, Abu-(yGlu)2-PEG, or Abu-(PEG)2.

[0077] In an embodiment, the linker and spacer is selected from a compound of Formula (m) to (x) depicted in Table 1. In an embodiment, the linker and spacer is selected from a compound of Formula (m), (n), (o), (p), (q), (r), (s), (t), (u), (v), (w) and (x) depicted in Table 1.

[0078] In an embodiment, the acylated amino acid is acylated lysine of Formula III.Formula III

[0079] In another embodiment, the acylated amino acid is acylated lysine of Formula IV.Formula IV

[0080] In another embodiment, the acylated amino acid is acylated lysine of Formula V.Formula V

[0081] The acylated amino acid, preferably acylated lysine (Km), may be present at one or more positions in the peptide. In an embodiment, the acylated amino acid may be present at a position selected from a group consisting of 2, 10, 12, 17, 20, 21, 28, 30, and 32. In an embodiment, the acylated amino acid is modified lysine (Km) present at a position selected from a group consisting of 2, 10, 12, 17, 20, 21, 28, 30, and 32.

[0082] In an embodiment, the acylated amino acid is acylated lysine (Km) present at a position selected from a group consisting of 17 and 20. In an embodiment, the peptide comprises acylated lysine (Km) at position 17 of the peptide, wherein the acylated lysine is lysine (K) attached to a lipid, preferably a diacid, by a linker and a spacer, wherein the linker is selected from one or more yGlu moieties, Gamma-aminobutyric acid (GABA), or combination thereof, and wherein the spacer comprises a moiety selected from Aminoethylethanolamine (AEEA), y-Carboxylate moieties, GGGGS repeats, one or more PEG moieties, combination thereof. In another embodiment, the peptide comprises acylated lysine (Km) at position 20 of the peptide, wherein the acylated lysine is lysine (K) attached to a lipid, preferably a diacid, by a linker and a spacer, wherein the linker is selected from one or more yGlu moieties, Gamma-aminobutyric acid (GABA), or combination thereof, and wherein the spacer comprises a moiety selected from Aminoethylethanolamine (AEEA), y-Carboxylate moieties, GGGGS repeats, one or more PEG moieties, combination thereof.Non-natural amino acid

[0083] The peptides, according to embodiments herein, include one or more nonnatural amino acids. The non-natural amino acid helps decrease / avoid enzyme mediated degradation of the peptide, thereby contributing to improve serum halflife of the peptide. Examples of non-natural amino acids include, but are not limited to, Alpha-aminobutyric acid (Aib), a-methylated amino acid, Alpha-MethylLeucine (aMeL), HomoSerine (hSer), Norvaline (nVal), NorLeucine (nLeu), Diaminopimelic acid (DAP), Methionine sulfoxide (MetO), Selenocysteine (Sec), Methylalanine, alpha-4-pentenyl alanine or derivatives thereof, Bis-Pentenyl glycine, S-octenyl alanine, and R-octenyl alanine, (S)-N-Fmoc-a-(4-pentenyl)alanine, or derivatives thereof. Accordingly, in an embodiment, the peptide comprises a non-natural amino acid selected from a group consisting of Alpha-aminobutyric acid (Aib), Alpha-MethylLeucine (αMeL), HomoSerine (hSer), Norvaline (nVal), NorLeucine (nLeu), Diaminopimelic acid (DAP), Methionine sulfoxide (MetO), Selenocysteine (Sec), Methylalanine, alpha-4-pentenyl alanine or derivatives thereof, Bis-Pentenyl glycine, S-octenyl alanine, and R-octenyl alanine, (S)-N-Fmoc-a-(4-pentenyl)alanine. In an embodiment, the peptide comprises a non-natural amino acid selected from a group consisting of Alpha-aminobutyric acid (Aib), Alpha-MethylLeucine (αMeL), HomoSerine (hSer), Norvaline (nVal), NorLeucine (nLeu), Diaminopimelic acid (DAP), Methionine sulfoxide (MetO), Selenocysteine (Sec), and Methylalanine, In a preferred embodiment, the non-natural amino acid is Aib. In another preferred embodiment, the non-natural amino acid is a-methylated amino acid, preferably Alpha-Methyl Leucine (aMeL). In an embodiment, the non-natural amino acid is selected from Aib, or aMeL. In an embodiment, the peptide comprises a non-natural amino acid at a position selected from 2, 13, or combination thereof. In an embodiment, the peptide comprises a non-natural amino acid at a position selected from 2 and / or 13, wherein the non-natural amino acid is selected from Aib and / or Alpha-Methyl Leucine (aMeL). In an embodiment, the peptide comprises a non-natural amino acid at position 2, wherein the non-natural amino acid is Aib. In an embodiment, the peptide comprises a non-natural amino acid at position 13, wherein the non-natural amino acid is Aib or aMeL.

[0084] In an embodiment, the peptide has an amino acid sequence selected from SEQ ID NO. 1, wherein X₂ is Aib. In an embodiment, the peptide has an amino acid sequence selected from SEQ ID NO. 1, wherein X₂ and X₁₃ are Aib. In an embodiment, the peptide has an amino acid sequence selected from SEQ ID NO. 1, wherein X₁₃ is αMeL.Peptide stapling

[0085] The peptides, according to embodiments herein, include a peptide staple. The peptide staple in the peptide, according to embodiments herein, may be positioned to link the amino acids including natural or non-natural amino acids in the peptide. The peptide staple, in an embodiment, is a brace that links the amino acids residues to promote and maintain secondary structure of the peptide. The peptide staple may be positioned at a suitable position in the peptide. In an embodiment, the peptide comprises a stabilized alpha-helix with the non-natural amino acids linked by a peptide staple, preferably hydrocarbon staple. In an embodiment, the peptide staple links non-natural amino acids in the peptide. In another embodiment, the peptide staple links or is positioned to link non-natural amino acids at positions i, i+4, preferably the non-natural amino acids at positions 30 and 34; 31 and 35; or 29 and 33. Accordingly, in an embodiment, the peptide has an amino acid sequence selected from SEQ ID NO. 1, wherein a peptide staple, preferably hydrocarbon staple, is positioned to link non-natural amino acids at positions i, i+4 in the peptide.

[0086] These peptide staple may be positioned to promote and maintain secondary structure of peptide, particularly alpha-helical secondary structure.

[0087] In an embodiment, there is provided an agonist peptide comprising a peptide having an amino acid sequence selected from SEQ ID NO. 1 or SEQ ID NO.4, wherein the peptide comprises a stabilized alpha-helix, and comprises non-natural amino acids linked by a peptide staple, preferably hydrocarbon staple, positioned to link the non-natural amino acids at positions i, i+4, in the peptide.

[0088] In an embodiment, there is provided an agonist peptide comprising a peptide having an amino acid sequence selected from SEQ ID NO. 1 or SEQ ID NO.4, wherein a peptide staple, preferably hydrocarbon staple, is positioned to link nonnatural amino acids at positions 31 and 35. Accordingly, in an embodiment, the peptide has an amino acid sequence selected from SEQ ID NO. 4, SEQ ID NO. 9, SEQ ID NO. 10, SEQ ID NO. 15, and SEQ ID NO. 16, wherein a peptide staple, preferably hydrocarbon staple, is positioned to link non-natural amino acids at positions i, i+4 in the peptide.

[0089] The non-natural amino acids for peptide stapling, according to embodiments herein, may be selected from alpha-4-pentenyl alanine or derivatives thereof, Bis-Pentenyl glycine, S-octenyl alanine, and R-octenyl alanine, (S)-N-Fmoc-a-(4-pentenyl)alanine, Lactam bridge, Copper catalyzed azide-alkyne cycloaddition (CuAAC), or Triazole-based cyclization.

[0090] In an embodiment, the non-natural amino acids at positions i, i+4, preferably the non-natural amino acids at positions 30 and 34; 31 and 35; or 29 and 33, are selected from alpha-4-pentenyl alanine, Bis-Pentenyl glycine, or S-octenyl alanine, (S)-N-Fmoc-a-(4-pentenyl)alanine, and R-octenyl alanine, preferably (S)-N-Fmoc-a-(4-pentenyl)alanine.

[0091] In an embodiment, the non-natural amino acids for peptide stapling, according to embodiments herein, is alpha-4-pentenyl alanine or (S)-N-Fmoc-a-(4-pentenyl)alanine, preferably of Formula IV.Formula IV

[0092] Further, the agonist peptide, as disclosed herein, is amidated at the C-terminal end. The agonist peptide having amino acid sequence as set forth in SEQ ID NO. 1 comprises a serine residue at the C-terminal end which is amidated, to preferably eliminate the negative charge and stabilize the peptide. The term “amidation”, as used herein, refers to a modification of the C-terminus of a peptide to include an amine group. Amidation may be performed by methods generally known in the field including: Rink Amide Resin-Based Approach, Pre-Functionalized Resins based approach, or On-Resin Amidation via Carbodiimide Coupling. In an embodiment, the peptide has an amino acid sequence as set forth in SEQ ID NO. 1, wherein the serine residue at position 39 is amidated at the C-terminal end.

[0093] In an embodiment, the peptide has an amino acid sequence selected from the group consisting of:YAibQGTFTSDYSKYLDERAQKmEFLVFLLKGGPSSGAPPPS (SEQ ID NO.5);YAibQGTFTSDYSKAibLDEIAQKmEFLVFLLKGGPSSGAPPPS (SEQ ID NO.6);YAibQGTFTSDYSEAibLDRIAQKmEFLVFLLKGGPSSGAPPPS (SEQ ID NO.7); andYAibQGTFTSDYSEYLDRRAQKmEFLVFLLKGGPSSGAPPPS (SEQ ID NO.8).

[0094] In an embodiment, the peptide has an amino acid sequence as set forth inYAibEGTFTSDYSIAibLDEIAQKmEFVNWLIKGGPSSGAPPPS (SEQ ID NO.9).

[0095] In an embodiment, the peptide has an amino acid sequence selected from the group consisting of:YSQGTFTSDYSI αMeLLDKKAQAibAFIEYLLEGGX₃₁SSGX₃₅PPPS (SEQ ID NO. 10); andYGQGTFTSDYSI αMeLLDKKAQAibAFIEYLLEGGX₃₁SSGX₃₅PPPS (SEQ ID NO. 11),wherein X31 and X35 are, independently, non-natural amino acids selected from alpha-4-pentenyl alanine, (S)-N-Fmoc-a-(4-pentenyl)alanine, Bis-Pentenyl glycine, S-octenyl alanine, and R-octenyl alanine, preferably (S)-N-Fmoc-a-(4- pentenyl)alanine.

[0096] In another embodiment, the peptide has an amino acid sequence selected from the group consisting of:YGQGTFTSDYSI αMeLLDKKAQAibAFIEYLLEGGX₃₁SSGX₃₅PPPS (SEQ ID NO. 11);YAibQGTFTSDKmSIaMeLLDKKAQAibAFIEYLLEGGPSSGAPPPS-NH2 (SEQ ID NO. 19);YAibQGTFTSDKmSIYLDKKAQAibAFIEYLLEGGPSSGAPPPS-NH2 (SEQ ID NO. 20);YAibQGTFTSDKmSKYLDKKAQAibAFIEYLLEGGPSSGAPPPS-NH2 (SEQ ID NO. 21);YAibQGTFTSDYSIaMeLLDKKAQAibAFIEYLLEGGPSSGAPPPSKm-NH2 (SEQ ID NO. 22).

[0097] In an embodiment, the peptide has an amino acid is selected from the group consisting of:Y X2QGTFTSDX10SX12X13LDKKAQ Aib AFIEYLLEGG X31SSG X35PPPS (SEQ ID NO. 23); andY X₂ QGTFTSDX₁₀SX₁₂X₁₃LDKKAQ Aib AFIEYLLEGG X₃₁SSG X₃₅PPPSKm (SEQ ID NO. 24)wherein X2is selected from Glycine (G), Serine (S), or a non-natural amino acid, X10 is selected from lysine (K), Tyrosine (Y) or modified lysine (Km), Xi2 is selected from Lysine (K), Glutamic acid (E), or Isoleucine (I), X13is selected from Tyrosine (Y) or a non-natural amino acid, and X31 and X35 are, independently, selected from Glycine (G), Proline (P), Alanine (A), or non-natural amino acids.

[0098] In an embodiment, the peptide as set forth in SEQ ID NO. 23 and SEQ ID NO. 24, wherein the non-natural amino acid at position 2 and 13 are, independently, non-natural amino acids selected from Aib and / or Alpha-Methyl Leucine (aMeL) and wherein X31 and X35 are, independently, non-natural amino acids selected from alpha-4-pentenyl alanine, (S)-N-Fmoc-a-(4-pentenyl)alanine, Bis-Pentenyl glycine, S-octenyl alanine, and R-octenyl alanine, preferably (S)-N-Fmoc-a-(4-pentenyl)alanine.

[0099] In an embodiment, the peptide has an amino acid sequence as disclosed herein, wherein the amino acid residue at the C-terminal end of the peptide is amidated.

[0100] In an embodiment, there is provided an agonist peptide comprising a peptide having an amino acid sequence selected from the group consisting of: SEQ ID NO. 5; SEQ ID NO. 6; SEQ ID NO. 7; SEQ ID NO. 8; SEQ ID NO. 9; SEQ ID NO.10; SEQ ID NO. 11; SEQ ID NO. 12; SEQ ID NO. 13; SEQ ID NO.14; SEQ ID NO. 15; SEQ ID NO. 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 19, SEQ ID NO. 21, and SEQ ID NO. 22.

[0101] Table 1Formula Description Structurea Ci6 fatty acidb Cis fatty acid — - — - — — " — - — —c C20 fatty acidd C₁₂ diacide C₁₄ diacidf C₁₆ diacid?9iI!'Xg Cis diacidh C20 di acidi C22 diacidj -PEG- k -(PEG)2-1 YGIUm yGlu-PEGn YG1U-(PEG)20 DyGlu-(PEG)2P (PEG)2-? G1Uq γGlu-(PEG)₃r γGlu-(PEG)₈s benzyl-βAla-(PEG)₂t (γGlu)₂-(PEG)₂u (γGlu)₃-(PEG)₂v Abu-γGlu-PEGw Abu-(γGlu)₂-PEGX Abu-(PEG)2

[0102] Various embodiments of the peptide are disclosed herein. In an embodiment, the peptide has an amino acid sequence selected from the group consisting of SEQ ID NO. 2; SEQ ID NO. 3; SEQ ID NO.4; SEQ ID NO. 5, SEQ ID NO. 6; SEQ ID NO. 7, SEQ ID NO. 8; SEQ ID NO. 9; SEQ ID NO.10; SEQ ID NO. 11; SEQ ID NO. 12; SEQ ID NO. 13; SEQ ID NO. 14; SEQ ID NO. 15; and SEQ ID NO. 16.

[0103] Table 2 depicts the amino acid sequences of peptides in accordance with the embodiments herein.SEQ ID Type SequencesNOsSEQ ID peptide XlX2X3GTFTSD¥SX12X13LDXl6X17AQX20X21FX23X24X25X26X NO: 1 27X28 X29X30X31SX33X34X35PPPSSEQ ID NO: 2 peptide X₁X₂QGTFTSDYSX₁₂X₁₃LDX₁₆X₁₇AQX₂₀EFLVFLLKGGPSSGAPPPSSEQ ID peptide X1X2EGTFTSDYSIX13LDEIAQX20EFVNWLIKGGPSSGAPP NO: 3 PSSEQ ID NO: 4 peptide X₁X₂QGTFTSDYSIX₁₃LDKX₁₇AQX₂₀AFIEYLLEGGX₃₁SSGX₃₅PPPSSEQ ID peptide YAibQGTFTSDYSKYLDERAQKmEFLVFLLKGGPSSGAPP NO: 5 PSSEQ ID peptide YAibQGTFTSDYSKAibLDEIAQKmEFLVFLLKGGPSSGAPP NO: 6 PSSEQ ID peptide YAibQGTFTSDYSEAibLDRIAQKmEFLVFLLKGGPSSGAPP NO: 7 PSSEQ ID peptide YAibQGTFTSDYSEYLDRRAQKmEFLVFLLKGGPSSGAPPP NO: 8 SSEQ ID peptideNO: 9 YAibEGTFTSDYSIAibLDEIAQKmEFVNWLIKGGPSSGAPP PS SEQ ID NO: 10 peptide YSQGTFTSDYSIαMeLLDKKAQAibAFIEYLLEGGX₃₁SSGX₃₅PPPSSEQ ID NO: 11 peptide YGQGTFTSDYSIαMeLLDKKAQAibAFIEYLLEGGX₃₁SSGX₃₅PPPSSEQ ID peptide YAibQGTFTSDYSKYLDERAQKmEFLVFLLKGGPSSGAPP NO: 12 PS-NH2SEQ ID peptide YAibQGTFTSDYSKAibLDEIAQKmEFLVFLLKGGPSSGAPP NO: 13 PS-NH2SEQ ID peptide YAibQGTFTSDYSEAibLDRIAQKmEFLVFLLKGGPSSGAPP NO: 14 PS-NH2SEQ ID peptide YAibQGTFTSDYSEYLDRRAQKmEFLVFLLKGGPSSGAPPP NO: 15 S-NH2SEQ ID peptide YAibEGTFTSDYSIAibLDEIAQKmEFVNWLIKGGPSSGAPP NO: 16 PS-NH2SEQ ID NO: 17 peptide YSQGTFTSDYSIαMeLLDKKAQAibAFIEYLLEGGX₃₁SSGX₃₅PPPS-NH2SEQ ID NO: 18 peptide YGQGTFTSDYSIαMeLLDKKAQAibAFIEYLLEGGX₃₁SSGX₃₅PPPS-NH2SEQ ID YAib QGTFTSDKmSIaMeLLDKKAQpeptideNO: 19 AibAFIEYLLEGGPSSGAPPPS-NH2SEQ ID YAib QGTFTSDKmSIYLDKKAQ AibpeptideNO: 20 AFIEYLLEGGPSSGAPPPS-NH2SEQ ID YAib QGTFTSDKmSKYLDKKAQ AibpeptideNO: 21 AFIEYLLEGGPSSGAPPPS-NH2SEQ IDpeptide Y Aib QGTFTSDYSIaMeL LDKKAQ AibNO: 22 AFIEYLLEGGPS SGAPPPSKm-NH2SEQ ID peptide Y X2QGTFTSDXioSXi2Xi3LDKKAQ Aib AFIEYLLEGGNO: 23 X3ISSG X35PPPSSEQ ID peptide Y X2QGTFTSDXIOSXI2XI3LDKKAQ Aib AFIEYLLEGGNO: 24 X3iSSGX35PPPSKmCompositions

[0104] Embodiments herein provide compositions comprising the agonist peptides as disclosed herein. In an embodiment, the composition comprises at least one agonist peptide; and at least one pharmaceutically acceptable excipient. The excipient may be a carrier, diluent, buffering agent, a tonicity modifier, an antimicrobial agent, a surfactant, and / or salt. The excipient may vary and depends on the dosage form, mode of delivery, intended therapeutic application, etc. In some embodiments, the buffering agent is selected from disodium hydrogen phosphate dihydrate, di sodium hydrogen phosphate heptahydrate, sodium phosphate monobasic, potassium phosphate dibasic, sodium acetate, citric acid, sodium citrate, L-histidine, histidine hydrochloride, sodium succinate, sodium lactate, or combinations thereof. The tonicity modifier is selected from the group consisting of sodium chloride, glycerol, sucrose, mannitol, trehalose, propylene glycol, or combinations thereof. The antimicrobial preservative is selected from m-cresol, phenol, benzyl alcohol, or combinations thereof. The surfactant is selected from polysorbate 20, polysorbate 80, poloxamer 188, poloxamer 407, or combinations thereof.

[0105] In an embodiment, the composition may comprise 0.5 % w / w to 5% w / w of the peptides as disclosed herein.

[0106] In an embodiment, the composition comprises 0.05% w / w to 5% w / w of tonicity modifier with respect to the total weight of the composition, wherein the tonicity modifier comprises 0.05% w / w to 0.9% or 0.3% w / w to 0.9% w / w of ionic tonicity modifier, and / or 0.05% w / w to 0.9% or 0.3% w / w to 2.5% w / w of nonionic tonicity modifier.

[0107] In an embodiment, the buffering agent is in a concentration range of 0.01 % w / w % w / w to 2% w / w or 0.01 % w / w to 1% w / w, in respect of the total composition.

[0108] In an embodiment, the antimicrobial preservative is in a concentration range of 0.15% w / w to 0.35% w / w, in respect of the total composition.

[0109] In an embodiment, the surfactant is in a concentration range of 0.0001% w / w to 0.2 % w / w, in respect of the total composition.

[0110] Further examples of excipients include, but is not limited to, phosphate buffer saline (PBS), sodium or potassium salts, sugars, cyclodextrins, nanoparticles, and / or polymers (eg: PEG). Various other excipients are known to a person skilled in the art and may be used in various embodiments herein.

[0111] The composition may further be formulated in various dosage forms such as parenteral including subcutaneous, intravenous, intraperitoneal, or intramuscular; oral dosage forms including tablets, capsules, powders, or suspensions; transdermal; sprays, etc.Methods

[0112] The agonist peptides, according to embodiment herein, may be used for therapeutic applications. Accordingly, embodiments herein provide a method for modulating receptors including glucagon-like peptide- 1 receptor (GLP-1R), or modulating gastric inhibitory polypeptide receptor GIPR, and glucagon receptor GCGR. In an embodiment, the method for modulating / stimulating receptors including glucagon-like peptide-1 receptor (GLP-1R), gastric inhibitory polypeptide receptor GIPR, and glucagon receptor GCGR comprises providing an effective amount of the agonist peptide as disclosed herein.

[0113] Further embodiment herein provides a method for treating a metabolic disorder. Embodiments herein further include a method for treatment and / or management of diabetes. Embodiments herein further include a method fortreatment and / or management of blood glucose levels, and reduce adiposity. Embodiments herein further include a method for treatment and / or management of comorbidities of diabetes including cardiovascular disease, kidney disease, retinopathy, renal diseases, non-alcoholic fatty liver, neuropathy, and mental health issues.

[0114] In an embodiment, the method for treatment and / or management of obesity in a subject, comprising administering an effective amount of the agonist peptide as disclosed herein. In an embodiment, the method for treatment and / or management of Type 2 Diabetes in a subject, comprising administering an effective amount of the agonist peptide as disclosed herein. The agonist peptide as disclosed herein may be administered in combination with a therapeutic agent. Accordingly, in an embodiment, the method comprises administering a therapeutic agent selected from anti-diabetic agents, sodium-Glucose Transport Protein (SGLT) inhibitors, amylin analogues, dipeptidyl peptidase IV (DPP -4) inhibitors, thiazolidinediones (TZD’s), anti-obesity drugs, bile acid sequestrants, leptin analogues, or combination thereof. Non-limiting examples of anti-diabetic agent included metformin; SGLT inhibitors includes empagliflozin, dapagliflozin, and canagliflozin; amylin analogues include cagrilintide, and pramlintide; DPP-4 inhibitors include sitagliptin, and saxagliptin; thiazolidinediones (TZD’s) include Pioglitazone. Further, non-limiting examples of anti-obesity drugs include; phentermine-topiramate, and naltrexone-bupropion; bile acid sequestrants include Colesevelam; and Leptin analogues include metreleptin.

[0115] Embodiments herein may also be used to management of Type 2 Diabetes and / or obesity including management of symptoms and / or co-morbidities, thereof.

[0116] The term “effective amount” or “therapeutically effective amount”, used interchangeably herein, is an amount that is capable of exhibiting the desired effect in a subject. The desired effect may be stimulatory or modulatory or agonist effect on at least one incretin hormone receptors including glucagon -like peptide- 1receptor (GLP-1R), gastric inhibitory polypeptide receptor GIPR, and glucagon receptor GCGR; or therapeutic effect. The effective amount may vary and depend on various factors including age of subject, severity of the diabetes / obesity, mode of delivery, etc.

[0117] The term “subject”, as used herein, refers to any animal classified as a mammal, e.g., human and non-human mammals. Examples of non-human animals include non-human primates, dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, mice, rats, hamsters, guinea pigs, and etc. The terms “patient” or “subject” are used herein interchangeably. In an embodiment, the subject is human. In an embodiment, the subject is a patient having or suspected of a metabolic disorder selected from having diabetes including Type-2 Diabetes, comorbidities of diabetes (including cardiovascular disease, kidney disease, retinopathy, renal diseases, non-alcoholic fatty liver, neuropathy, and mental health issues); and obesity; or symptoms thereof.

[0118] The agonist peptide, according to embodiments herein, may be prepared by synthesizing the amino acid chain by methods generally known in the field. Exemplary methods of peptide synthesis include, but is not limited to, solid phase synthesis, vapor-phase synthesis, and liquid-phase synthesis. The amino acid chain is amidated to replace the C-terminal carboxyl (-COOH) group with an amide (-CONH2). Exemplary methods that my be used for amidation of the amino acid chain include Rink Amide Resin-Based Approach; Pre-Functionalized Resins; and On-Resin Amidation via Carbodiimide Coupling. The selection of amidtaion method may vary and depend on Peptide sequence complexity, Desired purity and yield, and Synthetic feasibility and reagent availability.

[0119] In an example, the agonist peptide assembly may be performed using Fmoc-SPPS on Rink Amide Resin. Standard deprotection, coupling cycles, and capping may be performed until full sequence elongation is achieved. Further, cleavage may be carried out using trifluoroacetic acid (TFA) to remove the peptide from the resin while leaving the C-terminal amidation intact. The amidated peptide may then be purified using HPLC, followed by lyophilization

[0120] In another example, a pre-functionalized resin based on the desired peptide properties maybe selected. Fmoc-based SPPS was performed, ensuring standard deprotection, capping, and coupling steps. Upon peptide completion, TFA cleavage may be used to release the peptide with a C-terminal amide (-CONH2). The amidated peptide may then be purified using HPLC, followed by lyophilization.

[0121] In yet another embodiment, the agonist peptide may be assembled using Wang Resin or another acid-labile resin. The C-terminal carboxyl (-COOH) may be activated, before cleavage, using carbodiimide coupling agents, such as: HBTU / HOBt(O-Benzotriazole-N, N, N', N'-tetramethyluronium hexafluorophosphate), DIC / DMAP (Diisopropylcarbodiimide / 4- Dimethylaminopyridine). The amide donor (e.g., NH3 in MeOH or DMF) may then be introduced to convert -COOH to -CONH2. Upon peptide completion, TFA cleavage may be used to release the peptide with a C-terminal amide (-CONH2). The amidated peptide may then be purified using HPLC, followed by lyophilization

[0122] The amidated amino acid chain may then be acylated by lipidation of the lysine residue. The s-amino group (-NH2) in lysine provides a site for selective acylation without modifying the peptide backbone. In an example, regents such as fatty acid chlorides or NHS esters (e.g., palmitoyl chloride, stearic acid-NHS), diisopropylcarbodiimide (DIC) or l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) / N-Hydroxysuccinimide (NHS) activation, or Base catalyst DIPEA (N, N-Diisopropylethylamine) and TEA (Triethylamine); and spacers and linker as described herein may be used in acylation of the amino acid chain.

[0123] In an embodiment, there is provided a method for preparation of the agonist peptide, said method comprising: (a) synthesizing the peptide by solidphase peptide synthesis and optionally including at least one non-natural amino acid; (b) optionally incorporating at least one modified amino acid residue; and cleaving and recovering the peptide to obtain the peptide of the present disclosure.

[0124] Although the subject matter has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the subject matter, will become apparent to persons skilled in the art upon reference to the description of the subject matter. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present subject matter as defined.EXAMPLES

[0125] The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, the exemplary methods, devices, and materials are described herein. It is to be understood that this disclosure is not limited to particular methods, and experimental conditions described, as such methods and conditions may apply.Example 1: Peptide synthesisPeptide construction:

[0126] The peptide sequences of the present disclosure were generated by solid-phase peptide synthesis using a Fmoc / tBu strategy on a PurePep™ Chorus or Prelude X peptide synthesizer (Gyros Protein Technologies). The synthesis was started from Tentagel Rink Amide resin to accommodate amidation at the C-terminus. During each standard coupling cycle, 4.8 equivalents of amino acid were activated using 2-cyano-2 (hydroxyimino)acetate (OxymaPure®) and diisopropylcarbodiimide (DIC) and the reaction mixture was agitated at 80 °C for 5 min. In the case of unnatural amino acids, an extended coupling time of 15 min was used. Capping was performed using acetic anhydride (0.5 M in DMF) to avoidthe formation of impurities due to amino acid deletions. Fmoc-deprotection was conducted using piperidine (20% v / v in DMF). To allow for site-specific incorporation of the fatty acid moiety at a later stage in the synthetic process, Fmoc-Lys(ivDde)-OH (CAS 204777-78-6) was incorporated at the required K residues of the backbone sequence.

[0127] Orthogonal ivDde-deprotection of the appropriate lysine residue was conducted by agitation of the resin-bound peptide in a solution of hydrazine in DMF (5% v / v). Stepwise assembly of the side chain was then performed at this position by solid phase peptide synthesis on the PurePep™ Chorus or Prelude X synthesizer using the standard OxymaPure® / DIC extended coupling chemistry described above.

[0128] Cleavage: The peptides were suspended in cleave cocktail (TFA-H2O-TIS-EDT; 90.5:5.0:2.5:2.0) and stirred at room temperature for 4 h. The peptides were precipitated into ice-cold Et2O and centrifuged. The pellet was then washed with Et2O to give the crude peptide as a white solid.

[0129] Purification: The crude peptides were purified to >98% purity by reverse-phase HPLC using a Luna C18 column (Phenomenex) and a water / acetonitrile gradient (containing 0.1% v / v TFA). Fractions containing the product that met purity were pooled and lyophilised. Peptide purity was examined by analytical reverse-phase HPLC (Luna C18 column; 2-90% B over 34 min; Buffer A: Water + 0.1% TFA; Buffer B: MeCN + 0.1% TFA; 214 nm) and peptide identity was confirmed by ESI-MS. Figure 1 depicts a schematic representation of the amino acid structures of the peptides ND-MC-49 (SEQ ID NO. 10 / SEQ ID NO.15), and ND-MC-50 (SEQ ID NO. 11 / SEQ ID NO. 16), in accordance with the embodiments herein.Example 2: Surface Plasmon binding studies

[0130] Binding kinetics of test peptides (SEQ ID NOs. 19 to 22 corresponding to ND-MC-ZB-50b, ND-MC-ZB-50c, ND-MC-ZB-50d, and ND-MC-50e, respectively) to human GLP-1R, GIPR, and GCGR were determined by Surface Plasmon Resonance (SPR) using a Biacore T200 instrument (Cytiva). Each receptor was covalently immobilized onto a CM5 sensor chip via standard amine coupling chemistry (EDC / NHS activation) in HBS-EP+ running buffer. A reference flow cell treated with EDC / NHS but without receptor was used for background subtraction. Test peptides and the reference compound LY were serially diluted in HBS-EP+ and injected over the receptor-immobilized flow cells at multiple concentrations at a flow rate of 30 µl / min during an association phase (~60 s) followed by a dissociation phase (~60 s). All sensorgrams are plotted as baseline-subtracted binding response (Resonance Units, RU) versus time (seconds). Multiconcentration sensorgrams were globally fitted to a 1: 1 Langmuir binding model to derive the association rate constant (ka, 1 / Ms), dissociation rate constant (kd, 1 / s), and equilibrium dissociation constant (KD, M).

[0131] Observations: The binding kinetics studies depicted in Figures 2-22 characterize the similar or better binding affinity for the peptides under evaluation with respect to the positive controls against all three receptor classes included GLP1R, GIPR and GCGR. These observations could be inferenced based on the association and dissociation profiles of these peptides relative to the positive control.Example 3: In vitro studies

[0132] GLP-1R, GIPR, and GCGR activation was assessed in-vitro for (SEQ ID NOs. 19 to 22 corresponding to ND-MC-ZB-50b, ND-MC-ZB-50c, ND-MC-ZB-50d, and ND-MC-50e, respectively) by performing cAMP assay carried out on GLP-1R, GIPR, and GCGR positive CHO cell lines. Receptor activation efficacy of the test peptides against the receptive receptors was assessed in vitro using the cAMP-Glo™ Max Assay (Promega, Cat. No. V1681) in Chinese Hamster Ovary (CHO) cells stably expressing human GLP-1R, GIPR, and GCGR (generated by in-house stable transduction). Cells were seeded at a density of 5,000 cells per well in white, opaque 96-well plates and allowed to adhere overnight. Prior to the assay, test peptides and Retatrutide (positive control) and Tirzepatide (positivecontrol) were serially diluted in assay buffer to achieve a final concentration range of 2×10−16M to 3.2×10−5M. Cells were treated with the respective peptide concentrations and incubated for 1 hour at 37°C. Following incubation, cAMP accumulation was measured according to the manufacturer's protocol. Luminescence was detected using a PerkinElmer VICTOR Nivo multiplate reader. Concentration-response data were analysed and EC50values were determined by nonlinear regression using a three-parameter logistic curve fit in GraphPad Prism. Data represent three independent biological replicates, each performed in triplicate technical wells. Results are expressed as relative luminescence units (RLU) plotted against the log of peptide concentration (M).

[0133] Observations: Figures 23 to 28 depicts results of cAMP based in-vitro assay for peptide induced receptor activation for GLP-1R, GIPR, and GCGR. Plots shown depict the activation of each receptor in presence of peptides represented by the SEQ ID NO. 19 - SEQ ID NO. 22 along with the positive control peptides Retatrutide and Tirzepatide. All peptides demonstrated similar or better potency for activating all the three receptor classes as compared to each of the controls which was characterized through the cAMP based functional assay Advantages of the present disclosure

[0134] The present disclosure provides agonist peptides against incretin hormone receptors, including glucagon-like peptide-1 receptor (GLP-1R), gastric inhibitory polypeptide receptor GIPR, and glucagon receptor GCGR. These peptides demonstrate good serum half-life, stability, and binding kinetics. The peptides have been designed with specific modifications that enable stabilized alpha-helix structures and contribute to the overall stability of the peptides. The peptides are also effective in vivo in stabilizing glucose levels, enhancing insulin sensitivity and ameliorating the adverse effects metabolic disorders including type-2 diabetes, obesity, and related co-morbidities. Also disclosed are methods for use and preparation of the peptide disclosed herein.

Claims

I / We Claim1. An agonist peptide comprising a peptide having at least 90% sequence identity to an amino acid sequence as set forth in:X1X2X3GTFTSDX10SX12X13LDX16X17AQX20X21FX23X24X25X26X27X28X29X30X31SX33X34X35PPPS(SEQ IDNO. 1),whereinXi is selected from Histidine (H) or Tyrosine (Y),X2is selected from Glycine (G), Serine (S), or a non-natural amino acid,X3 and X21 are, independently, selected from selected from Alanine (A), Glutamine (Q), or Glutamic acid (E),X10 is selected from Lysine (K), Tyrosine (Y) or acylated lysine (Km), Xuis selected from Lysine (K), Glutamic acid (E), or Isoleucine (I), X13is selected from Tyrosine (Y) or a non-natural amino acid, X16, X17, and X28are, independently, selected from selected from Lysine (K), Glutamic acid (E), Arginine (R), or Isoleucine (I), X20 is selected from lysine, an acylated lysine or a non-natural amino acid,X23-is selected from Isoleucine (I), Valine (V), or Leucine (L), X24is selected from Asparagine (N), Glutamic acid (E), or Valine (V), X25 is selected from Tyrosine (Y), Tryptophan (W), or Phenylalanine (F),X26 and X27 are, independently, selected from selected from Leucine (L), or Isoleucine (I), andX29, X30, X31, X33, X34 and X35 are, independently, selected from Glycine (G), Proline (P), Alanine (A), or non-natural amino acids; ora pharmaceutically acceptable salt thereof.

2. The agonist peptide as claimed in claim 1, wherein the peptide has an amino acid sequence selected from the group consisting of:(i) X1X2QGTFTSDYSX12X13LDX16X17AQX20EFLVFLLKGGPSSGA PPPS(SEQ ID NO. 2),whereinXi is selected from Histidine (H) or Tyrosine (Y),X2is selected from Glycine (G), Serine (S), or a non-natural amino acid,Xuis selected from Lysine (K), or Glutamic acid (E),X13is selected from Tyrosine (Y) or a non-natural amino acid, preferably Aib,Xi6 is selected from selected from Glutamic acid (E), or Arginine (R),X17 is selected from selected from Isoleucine (I), or Glutamic acid (E), andX20is selected from lysine, or an acylated lysine;(ii) X1X2EGTFTSDYSIX13LDEIAQX20EFVNWLIKGGPSSGAPPPS (SEQ ID NO. 3),whereinXi is selected from Histidine (H) or Tyrosine (Y),X2 is a non-natural amino acid,X13is selected from Tyrosine (Y) or a non-natural amino acid, preferably Aib,X20is selected from lysine, or an acylated lysine;(iii) X1X2QGTFTSDYSIX13LDKX17AQX20AFIEYLLEGGX31SSGX35P PPS(SEQ ID NO. 4),whereinXi is selected from Histidine (H) or Tyrosine (Y),X2is selected from Glycine (G) or Serine (S),X13 is a non-natural amino acid, preferably a-methylated amino acid, more preferably Alpha-MethylLeucine (αMeL),X17 is selected from lysine, or an acylated lysine,X2ois a non-natural amino acid, preferably Aib,X31 and X35 are, independently, selected from Proline (P) or non- natural amino acids;(iv) YX2QGTFTSDX10SX12X13LDKKAQ Aib AFIEYLLEGG X31SSG X35PPPS(SEQ ID NO. 23); and(v) YX2QGTFTSDX10SX12X13LDKKAQ Aib AFIEYLLEGG X31SSG X35PPPSKm (SEQ ID NO. 24)whereinX2is selected from Glycine (G), Serine (S), or a non-natural amino acid,X10 is selected from Lysine (K), Tyrosine (Y) or acylated lysine (Km),X12is selected from Lysine (K), Glutamic acid (E), or Isoleucine (I),X13is selected from Tyrosine (Y) or a non-natural amino acid, andX31 and X35 are, independently, selected from Glycine (G), Proline (P), Alanine (A), or non-natural amino acids.

3. The agonist peptide as claimed in claim 1 or 2, wherein the non-natural amino acids are selected from a group consisting of Alphaaminobutyric acid (Aib), Alpha-MethylLeucine (αMeL), HomoSerine (hSer), Norvaline (nVal), NorLeucine (nLeu), Diaminopimelic acid (DAP), Methionine sulfoxide (MetO), Selenocysteine (Sec), Methylalanine, alpha-4-pentenyl alanine, Bis-Pentenyl glycine, S- octenyl alanine, and R-octenyl alanine, preferably (S)-N-Fmoc-a-(4- pentenyl)alanine.

4. The agonist peptide as claimed in claim 1, wherein the peptide comprises a stabilized alpha-helix, and comprises non-natural amino acids linked by a peptide staple, preferably hydrocarbon staple, positioned to link the non-natural amino acids at positions i, i+4, preferably the non-natural amino acids at positions 30 and 34; 31 and 35; or 29 and 33; or a pharmaceutically acceptable salt thereof in the peptide.

5. The agonist peptide as claimed in claim 4, wherein the peptide staple is positioned to link the non-natural amino acids at positions 31 and 35, wherein the non-natural amino acids at positions X31 and X35 are selected from alpha-4-pentenyl alanine, Bis-Pentenyl glycine, S- octenyl alanine, and R-octenyl alanine, preferably (S)-N-Fmoc-a-(4- pentenyl)alanine.

6. The agonist peptide as claimed in claim 1, wherein acylated lysine comprises a fatty acid conjugated to the lysine residue via at least one linker and spacer, wherein the fatty acid is selected from a Cs- C22 fatty acid or diacid.

7. The agonist peptide as claimed in claim 1, wherein acylated lysine is lysine (K) attached to a diacid of Formula I by at least one yGlu linker and a spacer of Formula IICO2H-(CH2)a-CO- Formula I-(amino-(PEG / AEEA)b-CH2CO2H)c- Formula II wherein ‘a’ is in the range of 8 to 22, preferably 12 to 20, ‘b’ is in the range of 1 to 10, and ‘c’ is in the range of 1 to 10.

8. The peptide as claimed in claim 7, wherein the spacer is a compound of Formula II and is selected from(i) -(amino-(PEG)b-CH2CO2H)c-; or (ii) -(amino-(AEEA)b-CH2CO2H)c-,wherein ‘b’ is in the range of 1 to 10, and ‘c’ is in the range of 1 to 10.

9. The agonist peptide as claimed in claim 1, wherein the peptide has an amino acid sequence selected from the group consisting of SEQ ID NO. 5, SEQ ID NO. 6, SEQ ID NO. 7, and SEQ ID NO. 8:

10. The agonist peptide as claimed in claim 1, wherein the peptide has an amino acid sequence as set forth in YAibEGTFTSDYSIAibLDEIAQKmEFVNWLIKGGPSSGAPPPS (SEQ ID NO. 9).

11. The agonist peptide as claimed in claim 1, wherein the peptide has an amino acid sequence selected from the group consisting of:YSQGTFTSDYSI aMeLLDKKAQAibAFIEYLLEGGXsiSSGXssP PPS (SEQ ID NO. 10); andYGQGTFTSDYSI aMeLLDKKAQAibAFIEYLLEGGXsiSSGXssP PPS (SEQ ID NO. 11),wherein X31 and X35 are, independently, non-natural amino acids selected from alpha-4-pentenyl alanine, Bis-Pentenyl glycine, S- octenyl alanine, (S)-N-Fmoc-a-(4-pentenyl)alanine, and R-octenyl alanine, preferably (S)-N-Fmoc-a-(4-pentenyl)alanine.

12. The agonist peptide as claimed in claim 1, wherein the amino acid residue at the C-terminal end of the peptide is amidated.

13. The agonist peptide as claimed in claim 1 or claim 12, wherein the peptide is having an amino acid sequence selected from the group consisting of: SEQ ID NO. 5; SEQ ID NO. 6; SEQ ID NO. 7; SEQ ID NO. 8; SEQ ID NO. 9; SEQ ID NO.10; SEQ ID NO. 11; SEQ ID NO.12; SEQ ID NO. 13; SEQ ID NO. 14; SEQ ID NO. 15; SEQ ID NO.16, SEQ ID NO.17, SEQ ID NO. 18, SEQ ID NO. 19, SEQ ID NO.20, SEQ ID NO. 21, and SEQ ID NO. 22.

14. The agonist peptide as claimed in claim 1, wherein the agonist peptide exhibits agonist activity on glucagon-like peptide-1 receptor (GLP1R), gastric inhibitory polypeptide receptor GIPR, and / or glucagon receptor GCGR.

15. A composition comprising the at least one agonist peptide as claimed in claim 1, and at least one pharmaceutically acceptable excipient.

16. A method for modulating the activity of an incretin receptor and / or glucagon receptor, comprising providing an effective amount of the agonist peptide as claimed in claim 1 or the composition as claimed in claim 15.

17. A method for treatment and / or management of obesity in a subject, comprising providing an effective amount of the agonist peptide as claimed in claim 1 to said subject.

18. The method as claimed in claim 17, further comprising administering a therapeutic agent selected from anti-obesity drugs, bile acid sequestrants, leptin analogues, or combination thereof, to said subject.

19. A method for treatment and / or management of metabolic disorder in a subject, comprising providing an effective amount of the agonist peptide as claimed in claim 1 to said subject.

20. The method as claimed in claim 19, further comprising administering a therapeutic agent selected from anti-diabetic agents, sodium- Glucose Transport Protein (SGLT) inhibitors, amylin analogues, dipeptidyl peptidase IV (DPP -4) inhibitors, thiazolidinediones (TZD’s), or combination thereof, to said subject.

21. A method for preparation of the agonist peptide as claimed in claim 1, said method comprising:(a) synthesizing the peptide by solid-phase peptide synthesis and optionally including at least one non-natural amino acid;(b) optionally incorporating at least one modified amino acid residue; and (c) cleaving and recovering the peptide to obtain the peptide as claimed in claim 1.

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