Multi-action peptides

Abstract

The present disclosure relates to, inter alia, compositions and methods, including peptides or a derivatives thereof that find use, inter alia, in the treatment of diabetes, obesity, or metabolic syndrome.

Description

[0001] MULTI-ACTION PEPTIDES

[0002] TECHNICAL FIELD

[0003] The present disclosure relates to, inter alia, compositions and methods, including peptides, fusion protein comprising the peptides, and nucleic acids encoding the peptides or fusion proteins that find use, inter alia, in the treatment management of hyperglycemia, diabetes, including type II diabetes, obesity, metabolic syndrome and the reduction of cardiovascular risk.

[0004] PRIORITY

[0005] This application claims the benefit of, and priority to, U.S. Provisional Application No. 63 / 579,243, filed August 28, 2023, U.S. Provisional Application No. 63 / 606,414, filed December 5, 2023, and U.S. Provisional Application No. 63 / 656,436, filed June 5, 2024, the contents of each of which are hereby incorporated by reference in their entirety.

[0006] SEQUENCE LISTING

[0007] The instant application contains a sequence listing, which has been submitted in XML format via Patent Center. The contents of the XML copy named “SHK-095PC_116981 -5095_Sequence_Listing”, which was created on August 23, 2024, and is 61 ,868 bytes in size, are incorporated herein by reference in their entirety.

[0008] BACKGROUND

[0009] The worldwide prevalence of diabetes mellitus and obesity has been on the rise for past decades possibly because of stressful and sedentary lifestyles and unhealthy eating habits. Diabetes mellitus, obesity, diabesity, which is a term used to describe the combined harmful health outcomes of obesity and diabetes mellitus, are major health hazards affecting people worldwide. Ng et al., Diabesity: the combined burden of obesity and diabetes on heart disease and the role of imaging Nature Reviews Cardiology 2021 ; 18: 291 - 304. Based on an estimate from the World Health Organization (WHO), the people with diabetes rose from 108 million in 1980 to 422 million in 2014. According to the Center for Disease Control (CDC), diabetes affects about 37.3 million people in the US, which is 11.3% of the US population, and this number includes about 8.5 million people that have undiagnosed diabetes. Similarly, obesity has nearly tripled worldwide since 1975, with more than 1.9 billion overweight, and over 650 million obese adults worldwide as of 2016. likewise, US obesity prevalence increased from about 30.5% in year 2000 to about 41.9% in 2017 according to the CDC. Currently, over 20% children and over 40% adults suffer from obesity. Obesity is estimated to cost health services US $990 billion, which is 13% healthcare expenditure, per year globally. For example, the aggregate medical cost due to obesity among adults in the United States was $260.6 billion in 2016. Cawley et al. Direct medical costs of obesity in the United States and the most populous states, J Manag Care Spec Pharm 2021 ; 27(3): 354-366.

[0010] Diabetes is linked to a number of health problems, including microvascular complications, such as retinopathy, neuropathy, nephropathy, blindness in working-age adults, end-stage renal disease, peripheral artery disease (PAD), cardiovascular complications, and cardiovascular disease (CVD). Similarly, obesity itself increases risk for many serious diseases, including hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, metabolic syndrome, fatty liver disease, stroke, gallstones, cholecystitis, osteoarthritis, kidney disease, sleep apnea and breathing problems, clinical depression, anxiety, and many types of cancers.

[0011] Therefore, there remains a need for more effective and accessible methods of treating diabetes, obesity, diabesity and related diseases.

[0012] SUMMARY

[0013] In various aspects, the present disclosure provides compositions and methods that are useful, inter alia, in the treatment or prevention of hyperglycemia, diabetes, including type II diabetes, obesity, metabolic syndrome and the reduction of cardiovascular risk.

[0014] Accordingly, in aspects, the present disclosure provides a peptide capable of modulating at least two of GLP- 1 receptor (GLP-1 R), GIP receptor (GIPR), glucagon receptor (GCGR) and GLP-2 receptor (GLP-2R), or a polynucleotide encoding the peptide. In embodiments, the dual- or triple-action peptide comprises an amino acid sequence selected from the amino acid sequence of SEQ ID NOs: 60 to 69.

[0015] Accordingly, in aspects, the present disclosure provides a peptide or a derivative thereof, wherein the peptide comprises a general formula (I):

[0016] N-L1-[Aaa]1-[Aaa]2-[Aaa]3-Gly-Thr-Phe-Thr-Ser-Asp-[Aaa]4-Ser-[Aaa]5-[Aaa]6-[Aaa]7-[Aaa]8- [Aaa]9-[Aaa]10-[Aaa]11-[Aaa]12-[Aaa]13-[Aaa]14-Phe-[Aaa]15-[Aaa]16-[Aaa]17-Leu-[Aaa]18- [Aaa]19-[Aaa]20-Gly-Pro-[Aaa]21-[Aaa]22-[Aaa]23-[Aaa]24-Pro-Pro-Pro-[Aaa]25-L2-C

[0017] (I) wherein N is the N-terminus; L1 and / or L2 are independently present or absent; and L1 and / or L2, if present, are each independently selected from a carrier protein, a tag, and a polymer, optionally wherein the L1 and / or L2 further comprise a linker that adjoins the carrier protein, tag, or polymer with the peptide; [Aaa] 1 is His; [Aaa]2 is Ser or Gly; [Aaa]3 is His or Pro; [Aaa]4 is Phe or lie; [Aaa]5 is Leu or Vai; [Aaa]6 is Ala; [Aaa]7 is Leu or lie; [Aaa]8 is Asp or Glu; [Aaa]9 is Lys or Glu; [Aaa]10 is Gin; [Aaa]11 is Arg; [Aaa]12 is Gin; [Aaa]13 is Ala or Gin; [Aaa]14 is Glu; [Aaa]15 is lie or Leu; [Aaa]16 is Asp or Glu; [Aaa]17 is Trp; [Aaa]18 is Arg or Gly; [Aaa] 19 is Ala; [Aaa]20 is Gly or Ala; [Aaa]21 is Pro or Ser; [Aaa]22 is Ser or Thr; [Aaa]23 is Gly or Ala; [Aaa]24 is Arg or Lys; [Aaa]25 is Arg or Lys; and C is the C-terminus.

[0018] In aspects, the present disclosure provides a peptide or a derivative thereof, wherein the peptide comprises formula (II):

[0019] N-L1-[Aaa]1-[Aaa]2-[Aaa]3-Gly-Thr-Phe-Thr-Ser-Asp-[Aaa]4-Ser-[Aaa]5-[Aaa]6-[Aaa]7-[Aaa]8- [Aaa]9-[Aaa]10-[Aaa]11-[Aaa]12-[Aaa]13-[Aaa]14-Phe-[Aaa]15-[Aaa]16-[Aaa]17-Leu-[Aaa]18- [Aaa]19-[Aaa]20-Gly-Pro-[Aaa]21-[Aaa]22-[Aaa]23-[Aaa]24-Pro-Pro-Pro-[Aaa]25-L2-C

[0020] (II) wherein: N is the N-terminus; L1 and / or L2 are independently present or absent; and L1 and / or L2, if present, are each independently selected from a carrier protein, a tag, and a polymer; [Aaa]1 is a positively charged amino acid residue selected from His, Lys, and Arg; [Aaa]2 is a polar and neutral of charge hydrophilic amino acid selected from Ser, Asn, Gin, Thr, and Pro, or a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]3 is a positively charged amino acid residue selected from His, Lys, and Arg, or a polar and neutral of charge hydrophilic amino acid selected from Pro Ser, Asn, Gin, and Thr; [Aaa]4 is a, hydrophobic, aromatic amino acid selected from Phe, Trp, and Tyr, or a hydrophobic, aliphatic amino acid selected from lie, Gly, Ala, Leu, Met, and Vai; [Aaa]5 is a hydrophobic, aliphatic amino acid selected from Leu, Vai, lie, Gly, Ala, and Met; [Aaa]6 is a hydrophobic, aliphatic amino acid selected from Ala, Gly, Vai, lie, Leu, and Met; [Aaa]7 is a hydrophobic, aliphatic amino acid selected from Leu, lie, Vai, Gly, Ala, and Met; [Aaa]8 is a polar and negatively charged hydrophilic amino acid selected from Asp and Glu; [Aaa]9 is a polar and positively charged hydrophilic amino acid selected from Lys, His, and Arg, or a polar and negatively charged hydrophilic amino acid selected from Glu, and Asp; [Aaa]10 is a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa] 11 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; [Aaa]12 is a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa]13 is a hydrophobic, aliphatic amino acid selected from Ala, Vai, Gly, Leu, lie, and Met, or a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa]14 is a polar and negatively charged hydrophilic amino acid selected from Glu, and Asp; [Aaa]15 is a hydrophobic, aliphatic amino acid selected from lie, Leu, Vai, Ala, Gly, and Met; [Aaa]16 is a polar and negatively charged hydrophilic amino acid selected from Asp, and Glu; [Aaa]17 is hydrophobic, aromatic amino acid selected from Trp, Phe, and Tyr; [Aaa] 18 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His, or a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa] 19 is a hydrophobic, aliphatic amino acid selected from Ala, Gly, Vai, Leu, lie, and Met; [Aaa]20 is a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]21 is a polar and neutral of charge hydrophilic amino acid selected from Pro, Ser, Gin, Asn, and Thr; [Aaa]22 is a polar and neutral of charge hydrophilic amino acid selected from Ser, Thr, Gin, Asn, and Pro; [Aaa]23 a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]24 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; [Aaa]25 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; and C is the C-terminus.

[0021] In embodiments, [Aaa]1 is His. In embodiments, [Aaa]2 is Ser or Gly. In embodiments, [Aaa]3 is His or Pro.

[0022] In embodiments, [Aaa]4 is Phe or lie. In embodiments, [Aaa]5 is Leu or Vai. In embodiments, [Aaa]6 is Ala.

[0023] In embodiments, [Aaa]7 is Leu or lie. In embodiments, [Aaa]8 is Asp or Glu. In embodiments, [Aaa]9 is Lys or Glu. In embodiments, [Aaa]10 is Gin. In embodiments, [Aaa]11 is Arg. In embodiments, [Aaa]12 is Gin. In embodiments, [Aaa]13 is Ala or Gin. In embodiments, [Aaa]14 is Glu. In embodiments, [Aaa]15 is lie or Leu. In embodiments, [Aaa]16 is Asp or Glu. In embodiments, [Aaa]17 is Trp. In embodiments, [Aaa] 18 is Arg or Gly. In embodiments, [Aaa]19 is Ala. In embodiments, [Aaa]20 is Gly or Ala. In embodiments, [Aaa]21 is Pro or Ser. In embodiments, [Aaa]22 is Ser or Thr. In embodiments, [Aaa]23 is Gly or Ala. In embodiments, [Aaa]24 is Arg or Lys. In embodiments, and / or [Aaa]25 is Arg or Lys.

[0024] In embodiments, [Aaa]1 is His; [Aaa]2 is Ser or Gly; [Aaa]3 is His or Pro; [Aaa]4 is Phe or lie; [Aaa]5 is Leu or Vai; [Aaa]6 is Ala; [Aaa]7 is Leu or lie; [Aaa]8 is Asp or Glu; [Aaa]9 is Lys or Glu; [Aaa]10 is Gin; [Aaa]11 is Arg; [Aaa]12 is Gin; [Aaa]13 is Ala or Gin; [Aaa]14 is Glu; [Aaa]15 is lie or Leu; [Aaa]16 is Asp or Glu; [Aaa] 17 is Trp; [Aaa]18 is Arg or Gly; [Aaa]19 is Ala; [Aaa]20 is Gly or Ala; [Aaa]21 is Pro or Ser; [Aaa]22 is Ser or Thr; [Aaa]23 is Gly or Ala; [Aaa]24 is Arg or Lys; and / or [Aaa]25 is Arg or Lys.

[0025] In embodiments, the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60 to 69. In embodiments, the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60 to 69, or a variant thereof having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations with respect to an amino acid sequence selected from SEQ ID NOs: 60 to 69. In embodiments, the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60, SEQ ID NO: 64, SEO ID NO: 65, SEO ID NO: 68 and SEQ ID NO: 69, or a variant thereof having 1 or 2 amino acid mutations with respect to an amino acid sequence selected from SEQ ID NOs: 60, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 68 and SEQ ID NO: 69. In embodiments, the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 68 and SEQ ID NO: 69.

[0026] In embodiments, the peptide or the derivative thereof comprises a carrier protein selected from Fc domain, albumin, transferrin, or elastin-like protein, Keyhole Limpet Hemocyanin (KLH), ovalbulin, or a variant thereof. In embodiments, the carrier protein comprises an Fc domain selected from an IgG Fc domain, an IgA Fc domain, an IgM Fc domain, an IgE Fc domain, and an IgD Fc domain, or a variant thereof. In embodiments, the carrier protein comprises the IgG Fc domain selected from an lgG1 Fc domain, an lgG2 Fc domain, an lgG3 Fc domain, and an lgG4 Fc domain, or a variant thereof. In embodiments, the carrier protein comprises the IgG Fc domain is selected from a human lgG1 Fc domain, and a human lgG4 Fc domain, or a variant thereof. In embodiments, the human lgG1 Fc domain comprises a hinge-CH2-CH3-Fc domain derived from human lgG1 or a derivative thereof. In embodiments, the human I gG4 Fc domain comprises a hinge-CH2- CH3-Fc domain derived from human lgG4 or a derivative thereof.

[0027] In embodiments, the peptide or the derivative thereof further comprises a linker that adjoins the carrier protein with the peptide or the derivative thereof. In embodiments, the peptide linker is rigid. In embodiments, the peptide linker is flexible.

[0028] In embodiments, the peptide or the derivative thereof further comprises a glycosyl moiety. In embodiments, the glycosyl moiety is an N-linked glycosyl moiety. In embodiments, the glycosyl moiety is an O-linked glycosyl moiety. In embodiments, the peptide or the derivative thereof comprises one or more N-linked glycosylation consensus sites and / or O-linked glycosylation consensus sites.

[0029] In embodiments, the peptide or the derivative thereof is biosynthesized as a single polypeptide chain. In embodiments, the peptide or the derivative thereof is biosynthesized from a single open reading frame. In embodiments, the peptide or the derivative thereof is prepared using an expression system. In embodiments, the expression system is selected from bacterial, yeast, invertebrate, vertebrate, and plant expression system.

[0030] In embodiments, the peptide or the derivative thereof further comprises a non-natural amino acid selected from an amino isobutyric acid (Aib), a D-amino acid, and those comprising a modification selected from N- methylation (Nm), Ca-methylation (Cm), MJ(CH2NH) reduced amide bonds (Rd), and a peptoids (Pp)). In embodiments, the peptide or the derivative thereof comprises a polymer. In embodiments, the polymer is selected from poly(alkylene oxide) (e.g., polyethylene glycol (PEG)), poly(N-vinylpyrrolidone), poly(vinyl alcohol), poly(glycerol), poly(zwitterions), poly(carbonates), polyoxazoline, poly(acryloylmorpholine), poly(oxazolines), poly(sacharrides), and a combination thereof. In embodiments, the polymer is polyethylene glycol (PEG).

[0031] In embodiments, one or more amino acids present in the peptide or the derivative thereof is PEGylated. In embodiments, the one or more PEGylated amino acids are located inside the carrier protein. In embodiments, the PEGylation is conducted using a succinimidyl ester, an aldehyde, a maleimide, and / or a p-nitrophenyl carbonate ester reagent. In embodiments, one or more Lys residues, one or more Ser residues, one or more Tyr residues, one or more His residues, one or more Cys residues, the N-terminus and / or the C-terminus are PEGylated. In embodiments, at least about 1 , or at least about 3, or at least about 5, or at least about 8, or at least about 10, or more amino acid residues, the N-terminus and / or the C-terminus are PEGylated. In embodiments, the one or more PEGylated amino acids comprise a Lys. In embodiments, the PEGylation is conducted via amine conjugation. In embodiments, the one or more PEGylated amino acids comprise a Gin. In embodiments, the PEGylation is conducted via transglutaminase (TGase) mediated enzymatic conjugation. In embodiments, the one or more PEGylated amino acids comprise a Cys. In embodiments, the PEGylation is conducted via thiol conjugation.

[0032] In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on glucagon-like peptide- 1 receptor (GLP-1 R), glucagon-like peptide-2 receptor (GLP- 2R), gastric inhibitory peptide receptor (GIPR), and / or glucagon receptor (GCGR).

[0033] In embodiments, the peptide or the derivative thereof of any of the embodiments disclosed herein is dual active. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R and GCGR. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R and GIPR. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP- 1 R and GLP-2R. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-2R and GIPR. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-2R and GCGR. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GIPR and GCGR. In embodiments, the peptide or the derivative thereof of any of the embodiments disclosed herein is triple active. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R, GIPR and GCGR. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R, GLP-2R and GCGR. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R, GLP-2R and GIPR. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-2R, GIPR and GCGR. In an illustrative embodiment, the peptide or the derivative thereof has an agonistic activity on GLP-1 R, an agonistic activity on GIPR, and an antagonistic activity on GCGR. In another illustrative embodiment, the peptide or the derivative thereof has an agonistic activity on GLP-1 R, an antagonistic activity on GIPR, and an agonistic activity on GCGR.

[0034] In embodiments, the peptide or the derivative thereof of any of the embodiments disclosed herein is quadruple active. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R, GLP-2R, GIPR and GCGR. In an illustrative embodiment, the peptide or the derivative thereof has an agonistic activity on GLP-1 R, an agonistic activity on GLP-2R, an agonistic activity on GIPR, and an antagonistic activity on GCGR. In another illustrative embodiment, the peptide or the derivative thereof has an agonistic activity on GLP-1 R, an agonistic activity on GLP-2R, an antagonistic activity on GIPR, and an agonistic activity on GCGR.

[0035] In embodiments, the peptide or the derivative thereof exhibits an EC50 value for GLP-1 R in the range of 100 pM to 1000 nM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof exhibits an EC50 value for GLP-1 R in the range of 2 nM to 100 nM, as determined by a cell-based assay.

[0036] In embodiments, the peptide or the derivative thereof exhibits an EC50 value for GIPR in the range of 100 pM to 1000 nM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof exhibits an EC50 value for GIPR in the range of 100 pM to 2 nM, as determined by a cell-based assay.

[0037] In embodiments, the peptide or the derivative thereof exhibits an EC50 value for GCGR in the range of 100 pM to 1000 nM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof exhibits an EC50 value for GCGR in the range of 2 nM to 100 nM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof exhibits an I C50 value for GLP-1 R in the range of 10 pM to 10 pM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof exhibits an I C50 value for GIPR in the range of 10 pM to 10 pM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof exhibits an IC50 value for GCGR in the range of 10 pM to 10 pM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof exhibits an EC50 value for GLP-2R in the range of 10 pM to 10 pM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof exhibits an IC50 value for GLP-2R in the range of 10 pM to 10 pM, as determined by a cell-based assay.

[0038] In aspects, the present disclosure provides a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 60, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 60. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 60.

[0039] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 61 , or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 61. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 61 .

[0040] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 62, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 62. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 62.

[0041] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 63, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 63. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 63.

[0042] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 64, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 64. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 64.

[0043] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 65, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 65. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 65.

[0044] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 66, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 66. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 66.

[0045] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 67, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 67. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 67.

[0046] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 68, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 68. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 68.

[0047] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 69, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 69. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 69.

[0048] In embodiments, the hinge CH2-CH3-Fc domain is derived from lgG1. In embodiments, the lgG1 is human lgG1. In embodiments, the hinge-CH2-CH3 Fc domain is derived from lgG4. In embodiments, the lgG4 is human lgG4. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that is at least about 95%, or at least about 97%, or at least about 97%, or at least about 98% or at least 99% identical to the amino acid sequence SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4. In embodiments, the hinge CH2-CH3-Fc domain is fused to the peptide or a derivative thereof via a linker. In embodiments, the linker has an amino acid sequence selected from SEQ ID NOs: 5 to 53.

[0049] In aspects, the present disclosure provides an isolated polynucleotide encoding the peptide or the derivative thereof of any of the embodiments disclosed herein or the fusion proteins of any of the embodiments disclosed herein. In embodiments, the isolated polynucleotide is DNA. In embodiments, the nucleic acid is RNA.

[0050] In embodiments, the isolated polynucleotide is an mRNA. In embodiments, the mRNA a modified mRNA (mmRNA). In embodiments, the mmRNA comprises at least one nucleoside modification selected from pseudouridine, N1-methylpseudouridine, 5-methylcytosine, 5-methoxyuridine, pyridin-4-one ribonucleoside, 5-aza-uridine, 2-thio- 5-aza-uridine, 2-thiouridine, 4-thio-pseudouridine, 2-thio-pseudouridine, 5- hydroxyuridine, 3-methyluridine, 5-carboxymethyl-uridine, 1-carboxymethyl-pseudouridine, 5-propynyl- uridine, 1-propynyl-pseudouridine, 5-taurinomethyluridine, 1-taurinomethyl-pseudouridine, 5-taurinomethyl- 2-thio-uridine, 1-taurinomethyl-4-thio-uridine, 5-methyl-uridine, 1-methyl-pseudouridine, 4-thio-1 -methylpseudouridine, 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1 -deazapseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2- methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, 5- aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine, 5-formylcytidine, N4-methylcytidine, 5- hydroxymethylcytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio- cytidine, 2-thio-5-methyl-cytidine, 4-thio-pseudoisocytidine, 4-thio-1-methyl-pseudoisocytidine, 4-thio-1- methyl-1-deaza-pseudoisocytidine, 1 -methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5- methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl- cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy-1-methyl-pseudoisocytidine, 2-aminopurine, 2, 6- diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-aminopurine, 7-deaza-8-aza-2- aminopurine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1 -methyladenosine, N6- methyladenosine, N6-isopentenyladenosine, N6-(cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis- hydroxyisopentenyl) adenosine, N6-glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosine, 2- methylthio-N6-threonyl carbamoyladenosine, N6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio- adenine, and 2-methoxy-adenine, inosine, 1-methyl-inosine, wyosine, wybutosine, 7-deaza-guanosine, 7- deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7- methyl-guanosine, 6-thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1-methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosine, 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6- thio-guanosine, N2-methyl-6-thio-guanosine, and N2,N2-dimethyl-6-thio-guanosine, and combinations thereof. In embodiments, the mmRNA further comprises a 5'-cap and / or a poly A tail.

[0051] In aspects, the present disclosure provides an expression vector comprising the isolated polynucleotide of any of the embodiments disclosed herein. In aspects, the present disclosure provides an expression vector of any of the embodiments disclosed herein. In embodiments, the expression vector is a mammalian expression vector.

[0052] In aspects, the present disclosure provides a host cell comprising the isolated polynucleotide of the embodiments disclosed herein. In aspects, the present disclosure provides a host cell comprising the expression vector of the embodiments disclosed herein. In aspects, the present disclosure provides a pharmaceutical composition comprising the peptide or the derivative thereof of any of the embodiments disclosed herein. In aspects, the present disclosure provides a pharmaceutical composition comprising the fusion proteins of any of the embodiments disclosed herein. In aspects, the present disclosure provides a pharmaceutical composition comprising the isolated polynucleotide of any of the embodiments disclosed herein. In aspects, the present disclosure provides a pharmaceutical composition comprising the expression vector of any of the embodiments disclosed herein. In aspects, the present disclosure provides a pharmaceutical composition comprising the host cell of any of the embodiments disclosed herein.

[0053] In aspects, the present disclosure provides a method of treating or preventing hyperglycemia, diabetes, obesity or metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a cardiometabolic disease, or liver fibrosis or for reducing blood glucose, or for reducing fed and fasting blood glucose, or for reducing cardiovascular risk, or for decreasing body weight, decreasing food intake, decreasing blood glucose, decreasing liver adiposity, decreasing liver weight, decreasing subcutaneous white adipose tissue (sWAT), or for increasing glucose tolerance in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the fusion proteins of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, or the expression vector of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein.

[0054] Any aspect or embodiment disclosed herein can be combined with any other aspect or embodiment as disclosed herein.

[0055] BRIEF DESCRIPTION OF THE FIGURES

[0056] FIG. 1A shows an alignment of sequences of the illustrative, non-limiting peptides disclosed herein with glucagon (GCG), glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP). The regions showing identity are shown in a bold-underlined font. FIG. 1B shows an alignment of sequences of the illustrative, non-limiting hybrid peptide SL-044. The regions derived from source peptide is shown in a bold or underlined font.

[0057] FIG. 2A to FIG. 2C show the characterization of GLP-1 R / GIPR / GCGR agonist activity of te SL_TriAg_V1 , SL_TriAg_V2_Pro3 peptides in comparison with a GIPR / GLP-1 R / GCGR co-agonist peptide (Comparator 1) and a dual GIPR / GLP-1 R co-agonist (Comparator 2). FIG. 2A demonstrates the activation of GLP-1 R receptor as measured a cell-based reporter assay. FIG. 2B demonstrates the activation of GIP receptor (GIPR) as measured a cell-based reporter assay. FIG. 20 demonstrates the activation of Glucagon Receptor (GCGR) as measured a cell-based reporter assay.

[0058] FIG. 3 shows a summary of activation of glucagon-like peptide 1 (GLP-1) receptor, glucagon (GCG) receptor, glucose-dependent insulinotropic polypeptide (GIP) receptor by illustrative, non-limiting peptides disclosed herein.

[0059] DETAILED DESCRIPTION

[0060] Disclosed herein peptides and derivatives thereof having agonistic or antagonistic activity on two or three of glucagon-like peptide-1 receptor (GLP-1 R), gastric inhibitory peptide receptor (GIPR), and glucagon receptor (GCGR) that are useful, inter alia, for treating or preventing disease, such as therapies for diseases / disorders such as hyperglycemia, diabetes, obesity or metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or liver fibrosis or for reducing blood glucose, or for reducing fed and fasting blood glucose, or for reducing cardiovascular risk, or for decreasing body weight, decreasing food intake, decreasing blood glucose, decreasing liver adiposity, decreasing liver weight, decreasing subcutaneous white adipose tissue (sWAT), or for increasing glucose tolerance. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on at least one or at least two or all three of GLP-1 R, GIPR, and GCGR. In embodiments, the peptide or the derivative thereof exhibits an EC50 value for GLP-1 R in the range of 100 pM to 1000 nM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof exhibits an EC50 value for GLP-1 R in the range of 2 nM to 100 nM, an EC50 value for GIPR in the range of 100 pM to 2 nM, and / or an EC50 value for GCGR in the range of 100 pM to 1000 nM, as determined by a cell-based assay.

[0061] GLP-1, GLP-2, GIP, and Glucagon

[0062] In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), gastric inhibitory peptide (GIP), and glucagon (GCG). GLP-1, GLP-2, GIP, and / or glucagon play major roles in the obesity-diabetes-metabolic syndrome axis of metabolism, such as control of glucose, glycogenolysis, gluconeogenesis, appetite, food intake, satiety, insulin secretion, etc., that are at the base of the diabetesobesity axis. Receptors Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestine. GLP-1 is normally produced after meals and stimulates insulin secretion and inhibits glucagon secretion. It is also involved in the regulation of p-cell growth and survival, gastric emptying, and appetite. In the body, GLP-1 is degraded by dipeptidyl peptidase IV and has a short half-life of around 2 minutes. Reduced GLP-1 secretion is associated with type 2 diabetes and the development of obesity.

[0063] GLP-1, GLP-2 and glucagon are produced by the alpha cells of the pancreas and in the intestinal L cells in the distal ileum and colon in form of a precursor called preglucagon that is cleaved in different organs into glicentin, glicentin-related pancreatic polypeptide (GRPP), oxyntomodulin, glucagon (marked in a boldface- italicized font), glucagon-like peptide 1 (GLP-1, indicated in a boldface-underlined font), and glucagon-like peptide 2 (GLP-2, indicated in a italicized-underlined font). Preglucagon has the following sequence:

[0064] MKSlYFVAGLFVMLVQGSWQRSLQDTEEKSRSFSASQADPLSDPDQMNEDKRHSQGTFTSDySKYLDSR RAQDFVQWL / W / VTKRNRNNIAKRHDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGRRDFPEEVAI

[0065] \ / EE\.GRRHADGSFSDEMNTILDNLAARDFINWLIQTKITDRK (SEQ ID NO: 54)

[0066] In embodiments, the GLP-1 has the following sequence:

[0067] HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 55).

[0068] GLP-1 agonists and antagonists are disclosed in US Patent Nos. 5,188,666, 5,120,712, 5,523,549, 5,512,549, 5,977,071 , 6,191,102; 6,956,026; 6,506,724; 6,703,359; 6,858,576; 6,872,700; 6,902,744; 7,157,555; 7,223,725; 7,220,721 ; 9,161,953; PCT International Publication Nos: WO 1998 / 008871 ; WO 1998 / 05351; WO 1999 / 07404; WO 1999 / 25727; WO 1999 / 25728; WO 1999 / 40788; WO 2000 / 034331; WO 2000 / 41546; WO 2000 / 41548; WO 2000 / 069911; WO 2000 / 73331; WO 2001 / 004156; WO 2001 / 51078; WO 2003 / 018516; WO 2003 / 099314; U.S. Publication No. 2003 / 0036504; and U.S. Publication No. 2006 / 0094652, the entire contents of which are hereby incorporated by reference in their entirety.

[0069] Glucose-dependent insulinotropic polypeptide (GIP) is a biologically active 42-amino acid-long gastrointestinal peptide hormone, having a short half-life (2-5 min) in circulation, which is synthesized and secreted into the blood stream by intestinal endocrine K cells within minutes of ingesting a meal. GIP binds to a specific glucose-dependent insulinotropic polypeptide receptor (GIPR), which is a class B G-protein-coupled receptor (GPCR) expressed in the endocrine pancreas, gastrointestinal tract, brain, immune and cardiovascular systems, testis, pituitary, lung, kidney, thyroid, several regions of the central nervous system and adipose tissue. GIP is believed to induce insulin secretion, which is stimulated primarily by hyperosmolarity of glucose in the duodenum. The amount of insulin secreted is greater when glucose is administered orally than intravenously. GIP is also believed to reduce food intake upon signaling via the hypothalamic GIPR. Adriaenssens, et al., Glucose-Dependent Insulinotropic Polypeptide Receptor-Expressing Cells in the Hypothalamus Regulate Food Intake, Cell Metabolism 2019; 30(5): 987-996. GIP is known to inhibit apoptosis of the pancreatic beta cells and to promote their proliferation. It also stimulates glucagon secretion and fat accumulation. Both GIP receptor (GIPR) agonism and antagonism are effective strategies for inhibiting weight gain. Miyawaki et al., Inhibition of gastric inhibitory polypeptide signaling prevents obesity, Nat. Med., 2002; 8: 738-742; McClean et al., GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet, Am. J. Physiol. Endocrinol. Metab., 2007; 293: E1746-E1755. Boylan et al., Gastric inhibitory polypeptide immunoneutralization attenuates development of obesity in mice, Am. J. Physiol. Endocrinol. Metab., 309: E1008-E1018; Fulurija ef al., Vaccination against GIP for the treatment of obesity, PLoS One 2008; 3: e3163. Accordingly, in embodiments, the GIPR modulator is a GIPR agonist. In embodiments, the GIPR modulator is a GIPR antagonist.

[0070] GIP, which is encoded by the GIP gene, is derived from a 153-amino acid proprotein having the following sequence (GIP is shown in a boldface-underlined font):

[0071] MVATKTFALLLLSLFLAVGLGEKKEGHFSALPSLPVGSHAKVSSPQPRGPRYAEGTFISDYSIAMDKIHQQD FVNWLLAQKGKKNDWKHNITQREARALELASQANRKEEEAVEPQSSPAKNPSDEDLLRDLLIQELLACLL DQTNLCRLRSR (SEQ ID NO: 56)

[0072] In embodiments, the GIP has the following sequence:

[0073] YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ (SEQ ID NO: 57)

[0074] GIPR modulators (without limitations, e.g., GIP analogs, GIP agonists, and GIP antagonists) are disclosed in US Patent Nos 6,921 ,748; 8,497,240; 9,453,062; 10,253,078 and US Patent Application Publication Nos. 2003 / 0232761 ; 2008 / 0312157; 2011 / 0136737; 2014 / 0162945; 2015 / 0329611; 2017 / 0240609; 2017 / 0240609, the entire contents of which are hereby incorporated by reference in their entirety.

[0075] Glucagon is a peptide hormone, produced by alpha cells of the pancreas when the amount of glucose in the bloodstream is too low. Glucagon plays a critical role in maintaining glucose homeostasis as a counterregulatory hormone for insulin. Specifically, glucagon promotes hepatic glucose output by increasing glycogenolysis and gluconeogenesis in response to reduced blood levels of glucose. However, diabetic subjects have abnormal secretion of not only insulin but also glucagon compared with healthy subjects, leading to abnormalities in glucose homeostasis. Hyperglucagonemia and altered insulin-to-glucagon ratios play important roles in initiating and maintaining pathological hyperglycemic states.

[0076] Glucagon is produced by the alpha cells of the pancreas and in the intestinal L cells in the distal ileum and colon in form of a precursor called preglucagon that is cleaved in different organs by subtilisin-like proprotein convertases into glicentin, glicentin-related pancreatic polypeptide (GRPP), oxyntomodulin, glucagon (marked in a boldface-italicized font), glucagon-like peptide 1 (GLP-1 , indicated in a boldface-underlined font), and glucagon-like peptide 2 (GLP-2). Preglucagon has the following sequence:

[0077] MKSlYFVAGLFVMLVQGSWQRSLQDTEEKSRSFSASQADPLSDPDQMNEDKRHSQGTFTSDYSKyLDS / ? RAQDFYQWL / NTKRNRNNIAKRHDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGRRDFPEEVAI VEELGRRHADGSFSDEMNTILDNLAARDFINWLIQTKITDRK (SEQ ID NO: 54)

[0078] In embodiments, the glucagon has the following sequence:

[0079] HSQGTFTSDYSKYLDSRRAQDFVQWLMNT (SEQ ID NO: 58).

[0080] GLP-2 receptor agonists and antagonists are disclosed in PCT International Publication Nos: WO 2007 / 056362, WO 2008 / 086086, WO 2008 / 152403, WO 2009 / 155257, WO 2010 / 070253, WO 2010 / 070251 , WO 2010 / 070252, WO 2010 / 070255, WO 2011 / 006497, WO 2011 / 094337, WO 2011 / 117417, WO 2011 / 117416, WO 2011 / 160633, WO 2011 / 160630, WO 2012 / 130866, WO 2013 / 041678, WO 2013 / 092703, and WO 2014 / 016300 the entire contents of which are hereby incorporated by reference in their entirety.

[0081] GLP-2 is produced, along with GLP-1 and glucagon by the alpha cells of the pancreas and in the intestinal L cells in the distal ileum and colon in form of a precursor called preglucagon that is cleaved in different organs into glicentin, glicentin-related pancreatic polypeptide (GRPP), oxyntomodulin, glucagon (marked in a boldface-italicized font), glucagon-like peptide 1 (GLP-1 , indicated in a boldface-underlined font), and glucagon-like peptide 2 (GLP-2, indicated in a italicized-underlined font). Preglucagon has the following sequence:

[0082] MKSlYFVAGLFVMLVQGSWQRSLQDTEEKSRSFSASQADPLSDPDQMNEDKRHSQGTFTSDYSKyLDS / ? RAQDFI / QI / I / L / W / VTKRNRNNIAKRHDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGRRDFPEEVAI \ / EE\.GRRHADGSFSDEMNTILDNLAARDFINWLIQTKITDRK (SEQ ID NO: 54)

[0083] GLP-2 regulates gastric motility, gastric acid secretion, intestinal hexose transport, and increases the barrier function of the gut epithelium. GLP-2 is also known to enhance nutrient absorption and gut adaptation in rodents or humans with short bowel syndrome. GLP-2 acts via the GLP-2 receptor, a G protein-coupled receptor expressed in gut endocrine cells of the stomach, small bowel, and colon.

[0084] In embodiments, the GLP-2 has the following sequence:

[0085] HADGSFSDEMNTILDNLAARDFINWLIQTKITD (SEQ ID NO: 59).

[0086] GLP-2 receptor agonists and antagonists are disclosed in US Patent Nos. 6,051 ,557; 6,297,214; 6,943,151 ; 7,056,886; 7,745,403; 8,278,273; 8,263,552; 10,092,648 and U.S. Publication Nos. 2023 / 0295260, 2023 / 0057847; 2023 / 0057847 the entire contents of which are hereby incorporated by reference in their entirety.

[0087] Peptides having Actions on GLP-1R, GLP-2R, GIPR, and / or Glucagon Receptor (GCGR)

[0088] In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises a general formula (I):

[0089] N-L1 -[Aaa]1-[Aaa]2-[Aaa]3-Gly-Thr-Phe-Thr-Ser-Asp-[Aaa]4-Ser-[Aaa]5-[Aaa]6-[Aaa]7-[Aaa]8- [Aaa]9-[Aaa]10-[Aaa]11-[Aaa]12-[Aaa]13-[Aaa]14-Phe-[Aaa]15-[Aaa]16-[Aaa]17-Leu-[Aaa]18- [Aaa]19-[Aaa]20-Gly-Pro-[Aaa]21-[Aaa]22-[Aaa]23-[Aaa]24-Pro-Pro-Pro-[Aaa]25-L2-C

[0090] (I) wherein N is the N-terminus; L1 and / or L2 are independently present or absent; and L1 and / or L2, if present, are each independently selected from a carrier protein, a tag, and a polymer, optionally wherein the L1 and / or L2 further comprise a linker that adjoins the carrier protein, tag, or polymer with the peptide; [Aaa] 1 is His; [Aaa]2 is Ser or Gly; [Aaa]3 is His or Pro; [Aaa]4 is Phe or lie; [Aaa]5 is Leu or Vai; [Aaa]6 is Ala; [Aaa]7 is Leu or lie; [Aaa]8 is Asp or Glu; [Aaa]9 is Lys or Glu; [Aaa]10 is Gin; [Aaa]11 is Arg; [Aaa]12 is Gin; [Aaa]13 is Ala or Gin; [Aaa]14 is Glu; [Aaa]15 is lie or Leu; [Aaa]16 is Asp or Glu; [Aaa]17 is Trp; [Aaa]18 is Arg or Gly; [Aaa] 19 is Ala; [Aaa]20 is Gly or Ala; [Aaa]21 is Pro or Ser; [Aaa]22 is Ser or Thr; [Aaa]23 is Gly or Ala; [Aaa]24 is Arg or Lys; [Aaa]25 is Arg or Lys; and C is the C-terminus. In embodiments, the peptide or the derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR.

[0091] In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises formula (II): N-L1 -[Aaa]1-[Aaa]2-[Aaa]3-Gly-Thr-Phe-Thr-Ser-Asp-[Aaa]4-Ser-[Aaa]5-[Aaa]6-[Aaa]7-[Aaa]8- [Aaa]9-[Aaa]10-[Aaa]11-[Aaa]12-[Aaa]13-[Aaa]14-Phe-[Aaa]15-[Aaa]16-[Aaa]17-Leu-[Aaa]18- [Aaa]19-[Aaa]20-Gly-Pro-[Aaa]21-[Aaa]22-[Aaa]23-[Aaa]24-Pro-Pro-Pro-[Aaa]25-L2-C

[0092] (II) wherein: N is the N-terminus; L1 and / or L2 are independently present or absent; and L1 and / or L2, if present, are each independently selected from a carrier protein, a tag, and a polymer; [Aaa]1 is a positively charged amino acid residue selected from His, Lys, and Arg; [Aaa]2 is a polar and neutral of charge hydrophilic amino acid selected from Ser, Asn, Gin, Thr, and Pro, or a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]3 is a positively charged amino acid residue selected from His, Lys, and Arg, or a polar and neutral of charge hydrophilic amino acid selected from Pro Ser, Asn, Gin, and Thr; [Aaa]4 is a, hydrophobic, aromatic amino acid selected from Phe, Trp, and Tyr, or a hydrophobic, aliphatic amino acid selected from lie, Gly, Ala, Leu, Met, and Vai; [Aaa]5 is a hydrophobic, aliphatic amino acid selected from Leu, Vai, lie, Gly, Ala, and Met; [Aaa]6 is a hydrophobic, aliphatic amino acid selected from Ala, Gly, Vai, lie, Leu, and Met; [Aaa]7 is a hydrophobic, aliphatic amino acid selected from Leu, lie, Vai, Gly, Ala, and Met; [Aaa]8 is a polar and negatively charged hydrophilic amino acid selected from Asp and Glu; [Aaa]9 is a polar and positively charged hydrophilic amino acid selected from Lys, His, and Arg, or a polar and negatively charged hydrophilic amino acid selected from Glu, and Asp; [Aaa]10 is a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa] 11 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; [Aaa]12 is a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa]13 is a hydrophobic, aliphatic amino acid selected from Ala, Vai, Gly, Leu, lie, and Met, or a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa]14 is a polar and negatively charged hydrophilic amino acid selected from Glu, and Asp; [Aaa]15 is a hydrophobic, aliphatic amino acid selected from lie, Leu, Vai, Ala, Gly, and Met; [Aaa]16 is a polar and negatively charged hydrophilic amino acid selected from Asp, and Glu; [Aaa]17 is hydrophobic, aromatic amino acid selected from Trp, Phe, and Tyr; [Aaa]18 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His, or a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa] 19 is a hydrophobic, aliphatic amino acid selected from Ala, Gly, Vai, Leu, lie, and Met; [Aaa]20 is a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]21 is a polar and neutral of charge hydrophilic amino acid selected from Pro, Ser, Gin, Asn, and Thr; [Aaa]22 is a polar and neutral of charge hydrophilic amino acid selected from Ser, Thr, Gin, Asn, and Pro; [Aaa]23 a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]24 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; [Aaa]25 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; and C is the C-terminus. In embodiments, the peptide or the derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP- 2R, GIPR, and GCGR.

[0093] In embodiments, [Aaa]1 is His. In embodiments, [Aaa]2 is Ser or Gly. In embodiments, [Aaa]3 is His or Pro. In embodiments, [Aaa]4 is Phe or lie. In embodiments, [Aaa]5 is Leu or Vai. In embodiments, [Aaa]6 is Ala. In embodiments, [Aaa]7 is Leu or lie. In embodiments, [Aaa]8 is Asp or Glu. In embodiments, [Aaa]9 is Lys or Glu. In embodiments, [Aaa]10 is Gin. In embodiments, [Aaa]11 is Arg. In embodiments, [Aaa]12 is Gin. In embodiments, [Aaa]13 is Ala or Gin. In embodiments, [Aaa]14 is Glu. In embodiments, [Aaa]15 is lie or Leu. In embodiments, [Aaa]16 is Asp or Glu. In embodiments, [Aaa]17 is Trp. In embodiments, [Aaa] 18 is Arg or Gly. In embodiments, [Aaa]19 is Ala. In embodiments, [Aaa]20 is Gly or Ala. In embodiments, [Aaa]21 is Pro or Ser. In embodiments, [Aaa]22 is Ser or Thr. In embodiments, [Aaa]23 is Gly or Ala. In embodiments, [Aaa]24 is Arg or Lys. In embodiments, and / or [Aaa]25 is Arg or Lys.

[0094] In embodiments, the peptide or the derivative thereof comprises any 2 of, or any 3 of, or any 4 of, or any 5 of, or any 6 of, or any 7 of, or any 8 of, or any 9 of, or any 10 of, or any 11 of, or any 12 of, or any 13 of, or any 14 of, or any 15 of, or any 16 of, or any 17 of, or any 18 of, or any 19 of, or any 20 of, or any 21 of, or any 22 of, or any 23 of, or any 24 of, or all 25 of the following:

[0095] (1) [Aaa]1 is His;

[0096] (2) [Aaa]2 is Ser or Gly;

[0097] (3) [Aaa]3 is His or Pro;

[0098] (4) [Aaa]4 is Phe or lie;

[0099] (5) [Aaa]5 is Leu or Vai;

[0100] (6) [Aaa]6 is Ala;

[0101] (7) [Aaa]7 is Leu or lie;

[0102] (8) [Aaa]8 is Asp or Glu;

[0103] (9) [Aaa]9 is Lys or Glu;

[0104] (10) [Aaa]10 is Gin; (11) [Aaa]11 is Arg;

[0105] (12) [Aaa]12 is Gin;

[0106] (13) [Aaa]13 is Ala or Gin;

[0107] (14) [Aaa]14 is Glu;

[0108] (15) [Aaa]15 is lie or Leu;

[0109] (16) [Aaa]16 is Asp or Glu;

[0110] (17) [Aaa]17 is Trp;

[0111] (18) [Aaa]18 is Arg or Gly;

[0112] (19) [Aaa]19 is Ala;

[0113] (20) [Aaa]20 is Gly or Ala;

[0114] (21) [Aaa]21 is Pro or Ser;

[0115] (22) [Aaa]22 is Ser or Thr;

[0116] (23) [Aaa]23 is Gly or Ala; and

[0117] (24) [Aaa]24 is Arg or Lys; and / or

[0118] (25) [Aaa]25 is Arg or Lys.

[0119] In embodiments, [Aaa] 1 is His, [Aaa]2 is Ser or Gly; [Aaa]3 is His or Pro; [Aaa]4 is Phe or lie; [Aaa]5 is Leu or Vai; [Aaa]6 is Ala; [Aaa]7 is Leu or lie; [Aaa]8 is Asp or Glu; [Aaa]9 is Lys or Glu; [Aaa]10 is Gin; [Aaa]11 is Arg; [Aaa]12 is Gin; [Aaa]13 is Ala or Gin; [Aaa]14 is Glu; [Aaa]15 is lie or Leu; [Aaa]16 is Asp or Glu; [Aaa] 17 is Trp; [Aaa]18 is Arg or Gly; [Aaa]19 is Ala; [Aaa]20 is Gly or Ala; [Aaa]21 is Pro or Ser; [Aaa]22 is Ser or Thr; [Aaa]23 is Gly or Ala; [Aaa]24 is Arg or Lys; and [Aaa]25 is Arg or Lys.

[0120] In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R. In embodiments, the peptide or the derivative thereof has an antagonistic activity on GLP-1 R. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-2R. In embodiments, the peptide or the derivative thereof has an antagonistic activity on GLP-2R. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GIPR. In embodiments, the peptide or the derivative thereof has an antagonistic activity on GIPR. In embodiments, the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GCGR. In embodiments, the peptide or the derivative thereof has an antagonistic activity on GCGR.

[0121] In embodiments, the peptide or the derivative thereof has an agonistic activity and an antagonistic activity on GLP-1R, GLP-2R, GIPR, and / or Glucagon Receptor (GCGR).

[0122] In embodiments, the peptide or the derivative thereof of any of the embodiments disclosed herein is dual active. In embodiments, the peptide or the derivative thereof an agonistic activity or an antagonistic activity on GLP-1R, and an agonistic activity or an antagonistic activity on GLP-2R. In embodiments, the peptide or the derivative thereof an agonistic activity or an antagonistic activity on GLP-1 R, and an agonistic activity or an antagonistic activity on GIPR. In embodiments, the peptide or the derivative thereof an agonistic activity or an antagonistic activity on GLP-1 R, and an agonistic activity or an antagonistic activity on GCGR. In embodiments, the peptide or the derivative thereof an agonistic activity or an antagonistic activity on GLP- 2R, and an agonistic activity or an antagonistic activity on GIPR. In embodiments, the peptide or the derivative thereof an agonistic activity or an antagonistic activity on GLP-2R, and an agonistic activity or an antagonistic activity on GCGR. In embodiments, the peptide or the derivative thereof an agonistic activity or an antagonistic activity on GIPR, and an agonistic activity or an antagonistic activity on GCGR.

[0123] In embodiments, the peptide or the derivative thereof of any of the embodiments disclosed herein is triple active. In embodiments, the peptide or the derivative thereof an agonistic activity or an antagonistic activity on GLP-1 R, an agonistic activity or an antagonistic activity on GLP-2R, and an agonistic activity or an antagonistic activity on GIPR. In embodiments, the peptide or the derivative thereof an agonistic activity or an antagonistic activity on GLP-1 R, an agonistic activity or an antagonistic activity on GLP-2R, and an agonistic activity or an antagonistic activity on GCGR. In embodiments, the peptide or the derivative thereof an agonistic activity or an antagonistic activity on GLP-1 R, an agonistic activity or an antagonistic activity on GIPR, and an agonistic activity or an antagonistic activity on GCGR. In embodiments, the peptide or the derivative thereof an agonistic activity or an antagonistic activity on GLP-2R, an agonistic activity or an antagonistic activity on GIPR, and an agonistic activity or an antagonistic activity on GCGR.

[0124] In embodiments, the peptide or the derivative thereof of any of the embodiments disclosed herein is triple active. In embodiments, the peptide or the derivative thereof an agonistic activity or an antagonistic activity on GLP-1 R, an agonistic activity or an antagonistic activity on GLP-2R, an agonistic activity or an antagonistic activity on GIPR, and an agonistic activity or an antagonistic activity on GCGR. In embodiments, the peptide or the derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V1 , comprises the following sequence:

[0125] HSHGTFTSDFSLALDKQRQAEFIDWLRAGGPPSGRPPPR (SEQ ID NO: 60).

[0126] In embodiments, the SL_TriAg_V1 or a derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V1 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 60. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 60.

[0127] In embodiments, the peptide or the derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V2, comprises the following sequence:

[0128] HGHGTFTSDISVAIEEQRQQEFLEWLGAAGPSTAKPPPK (SEQ ID NO: 61).

[0129] In embodiments, the SL_TriAg_V2 or a derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V2 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 61. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to an amino acid sequence of SEQ ID NO: 61.

[0130] In embodiments, the peptide or the derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V3, comprises the following sequence:

[0131] HSHGTFTSDVSRIKDKQRQKEFADWLRAQGPPSGRPPPR (SEQ ID NO: 62). In embodiments, the SL_TriAg_V3 or a derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V3 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 62. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to an amino acid sequence of SEQ ID NO: 62.

[0132] In embodiments, the peptide or the derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V4, comprises the following sequence:

[0133] HGHGTFTSDSSHGREEQRQREFGEWLGAGGPSTAKPPPK (SEQ ID NO: 63).

[0134] In embodiments, the SL_TriAg_V4 or a derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V4 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 63. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 63.

[0135] In embodiments, the peptide or the derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V1_Pro3, comprises the following sequence:

[0136] HSPGTFTSDFSLALDKQRQAEFIDWLRAGGPPSGRPPPR (SEQ ID NO: 64).

[0137] In embodiments, the SL_Tri Ag_V1 _Pro3 or a derivative thereof has dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V1_Pro3 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 64. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 64.

[0138] In embodiments, the peptide or the derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V2_Pro3, comprises the following sequence:

[0139] HGPGTFTSDISVAIEEQRQQEFLEWLGAAGPSTAKPPPK (SEQ ID NO: 65).

[0140] In embodiments, the SL_TriAg_V2_Pro3 or a derivative thereof has dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V2_Pro3 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 65. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 65.

[0141] In embodiments, the peptide or the derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V3_Pro3, comprises the following sequence:

[0142] HSPGTFTSDVSRIKDKQRQKEFADWLRAQGPPSGRPPPR (SEQ ID NO: 66).

[0143] In embodiments, the SL_TriAg_V3_Pro3 or a derivative thereof has dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V3_Pro3 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 66. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 66. In embodiments, the peptide or the derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V4_Pro3, comprises the following sequence:

[0144] HGPGTFTSDSSHGREEQRQREFGEWLGAGGPSTAKPPPK (SEQ ID NO: 67)

[0145] In embodiments, the SL_TriAg_V4_Pro3 or a derivative thereof has dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V4_Pro3 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 67. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 67.

[0146] In embodiments, the peptide or the derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, which is also referred to herein as SL-045, comprises the following sequence:

[0147] HSHGTFTSDFSLALDKQRQAEFIDWLKAAGPPSAKPPPK (SEQ ID NO: 68)

[0148] In embodiments, the SL-045 or a derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP- 2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR is a variant of SL-045 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 68. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP- 2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 68.

[0149] In embodiments, the peptide or the derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, which is also referred to herein as SL-044, comprises the following sequence:

[0150] HSHGTFTSDFSLALDKQRQAEFIDWLGAAGPSTAKPPPK (SEQ ID NO: 69) In embodiments, the SL-044 or a derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP- 2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1R, GLP-2R, GIPR, and GCGR is a variant of SL-044 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 69. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP- 2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 69.

[0151] In embodiments, the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60 to 69. In embodiments, the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60 to 69, or a variant thereof having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations with respect to an amino acid sequence selected from SEQ ID NOs: 60 to 69. In embodiments, the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 68 and SEQ ID NO: 69, or a variant thereof having 1 or 2 amino acid mutations with respect to an amino acid sequence selected from SEQ ID NOs: 60, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 68 and SEQ ID NO: 69. In embodiments, the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 68 and SEQ ID NO: 69.

[0152] In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60 to 69. In embodiments, the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60 to 69, or a variant thereof having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations with respect to an amino acid sequence selected from SEQ ID NOs: 60 to 69.

[0153] In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0154] HSHGTFTSDFSLALDKQRQAEFIDWLRAGGPPSGRPPPR (SEQ ID NO: 60). In embodiments, the peptide or the derivative thereof is a variant of SEQ ID NO: 60 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 60. In embodiments, the peptide the peptide or the derivative thereof has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 60.

[0155] In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0156] HGHGTFTSDISVAIEEQRQQEFLEWLGAAGPSTAKPPPK (SEQ ID NO: 61).

[0157] In embodiments, the peptide or the derivative thereof is a variant of SEQ ID NO: 61 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 61. In embodiments, the peptide the peptide or the derivative thereof has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 61 .

[0158] In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0159] HSHGTFTSDVSRIKDKQRQKEFADWLRAQGPPSGRPPPR (SEQ ID NO: 62).

[0160] In embodiments, the peptide or the derivative thereof is a variant of SEQ ID NO: 62 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 62. In embodiments, the peptide the peptide or the derivative thereof has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 62. In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0161] HGHGTFTSDSSHGREEQRQREFGEWLGAGGPSTAKPPPK (SEQ ID NO: 63).

[0162] In embodiments, the peptide or the derivative thereof is a variant of SEQ ID NO: 63 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 63. In embodiments, the peptide the peptide or the derivative thereof has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 63.

[0163] In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0164] HSPGTFTSDFSLALDKQRQAEFIDWLRAGGPPSGRPPPR (SEQ ID NO: 64).

[0165] In embodiments, the peptide or the derivative thereof is a variant of SEQ ID NO: 64 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 64. In embodiments, the peptide the peptide or the derivative thereof has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 64.

[0166] In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0167] HGPGTFTSDISVAIEEQRQQEFLEWLGAAGPSTAKPPPK (SEQ ID NO: 65).

[0168] In embodiments, the peptide or the derivative thereof is a variant of SEQ ID NO: 65 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 65. In embodiments, the peptide the peptide or the derivative thereof has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 65.

[0169] In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0170] HSPGTFTSDVSRIKDKQRQKEFADWLRAQGPPSGRPPPR (SEQ ID NO: 66).

[0171] In embodiments, the peptide or the derivative thereof is a variant of SEQ ID NO: 66 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 66. In embodiments, the peptide the peptide or the derivative thereof has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 66.

[0172] In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0173] HGPGTFTSDSSHGREEQRQREFGEWLGAGGPSTAKPPPK (SEQ ID NO: 67)

[0174] In embodiments, the peptide or the derivative thereof is a variant of SEQ ID NO: 67 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 67. In embodiments, the peptide the peptide or the derivative thereof has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 67.

[0175] In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof: HSHGTFTSDFSLALDKQRQAEFIDWLKAAGPPSAKPPPK (SEQ ID NO: 68)

[0176] In embodiments, the peptide or the derivative thereof is a variant of SEQ ID NO: 68 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 68. In embodiments, the peptide the peptide or the derivative thereof has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 68.

[0177] In aspects, the present disclosure provides a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0178] HSHGTFTSDFSLALDKQRQAEFIDWLGAAGPSTAKPPPK (SEQ ID NO: 69)

[0179] In embodiments, the peptide or the derivative thereof is a variant of SEQ ID NO: 69 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 69. In embodiments, the peptide the peptide or the derivative thereof has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 69.

[0180] In embodiments, the peptide or the derivative thereof comprises a carrier protein selected from Fc domain, albumin, transferrin, or elastin-like protein, Keyhole Limpet Hemocyanin (KLH), ovalbulin, or a variant thereof.

[0181] In embodiments, the peptide or the derivative thereof comprises a carrier protein selected from Fc domain, albumin, transferrin, or elastin-like protein, Keyhole Limpet Hemocyanin (KLH), ovalbulin, or a variant thereof. In embodiments, the carrier protein comprises an Fc domain selected from an IgG Fc domain, an IgA Fc domain, an IgM Fc domain, an IgE Fc domain, and an IgD Fc domain, or a variant thereof. In embodiments, the carrier protein comprises the IgG Fc domain selected from an lgG1 Fc domain, an lgG2 Fc domain, an lgG3 Fc domain, and an lgG4 Fc domain, or a variant thereof. In embodiments, the carrier protein comprises the IgG Fc domain is selected from a human lgG1 Fc domain, and a human lgG4 Fc domain, or a variant thereof. In embodiments, the human lgG1 Fc domain comprises a hinge-CH2-CH3-Fc domain derived from human lgG1 or a derivative thereof. In embodiments, the human I gG4 Fc domain comprises a hinge-CH2- CH3-Fc domain derived from human lgG4 or a derivative thereof.

[0182] Fusion Proteins Comprising Peptides having Actions on GLP-1R, GLP-2R, GIPR, and / or Glucagon Receptor (GCGR)

[0183] In aspects, the present disclosure provides a fusion protein comprising a carrier protein joined, optionally via a linker, to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP- 1 , GLP-2, GIP, and / or glucagon of any of the embodiments disclosed herein. In embodiments, the peptide comprises a general formula (I):

[0184] N-L1-[Aaa]1-[Aaa]2-[Aaa]3-Gly-Thr-Phe-Thr-Ser-Asp-[Aaa]4-Ser-[Aaa]5-[Aaa]6-[Aaa]7-[Aaa]8- [Aaa]9-[Aaa]10-[Aaa]11-[Aaa]12-[Aaa]13-[Aaa]14-Phe-[Aaa]15-[Aaa]16-[Aaa]17-Leu-[Aaa]18- [Aaa]19-[Aaa]20-Gly-Pro-[Aaa]21-[Aaa]22-[Aaa]23-[Aaa]24-Pro-Pro-Pro-[Aaa]25-L2-C

[0185] (I) wherein N is the N-terminus; one of L1 or L2 is present the carrier protein, and the other is a tag, and a polymer, optionally wherein the L1 and / or L2 further comprise a linker that adjoins the carrier protein, tag, or polymer with the peptide; [Aaa] 1 is His; [Aaa]2 is Ser or Gly; [Aaa]3 is His or Pro; [Aaa]4 is Phe or lie; [Aaa]5 is Leu or Vai; [Aaa]6 is Ala; [Aaa]7 is Leu or lie; [Aaa]8 is Asp or Glu; [Aaa]9 is Lys or Glu; [Aaa]10 is Gin; [Aaa] 11 is Arg; [Aaa]12 is Gin; [Aaa]13 is Ala or Gin; [Aaa] 14 is Glu; [Aaa]15 is lie or Leu; [Aaa]16 is Asp or Glu; [Aaa]17 is Trp; [Aaa] 18 is Arg or Gly; [Aaa]19 is Ala; [Aaa]20 is Gly or Ala; [Aaa]21 is Pro or Ser; [Aaa]22 is Ser or Thr; [Aaa]23 is Gly or Ala; [Aaa]24 is Arg or Lys; [Aaa]25 is Arg or Lys; and C is the C-terminus. In embodiments, the peptide or the derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP- 2R, GIPR, and GCGR. In embodiments, the carrier protein is selected from Fc domain, albumin, transferrin, or elastin-like protein, Keyhole Limpet Hemocyanin (KLH), ovalbulin, or a variant thereof. In embodiments, the carrier protein is a hinge CH2-CH3-Fc domain. In embodiments, the a hinge CH2-CH3-Fc domain is derived from I gG1 or lgG4 (e.g., human lgG1 or lgG4).

[0186] In aspects, the present disclosure provides a fusion protein comprising a carrier protein joined, optionally via a linker, to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP- 1 , GLP-2, GIP, and / or glucagon of any of the embodiments disclosed herein. In embodiments, the peptide comprises a general formula (II): N-L1 -[Aaa]1-[Aaa]2-[Aaa]3-Gly-Thr-Phe-Thr-Ser-Asp-[Aaa]4-Ser-[Aaa]5-[Aaa]6-[Aaa]7-[Aaa]8- [Aaa]9-[Aaa]10-[Aaa]11-[Aaa]12-[Aaa]13-[Aaa]14-Phe-[Aaa]15-[Aaa]16-[Aaa]17-Leu-[Aaa]18- [Aaa]19-[Aaa]20-Gly-Pro-[Aaa]21-[Aaa]22-[Aaa]23-[Aaa]24-Pro-Pro-Pro-[Aaa]25-L2-C

[0187] (II) wherein N is the N-terminus; one of L1 or L2 is present the carrier protein, and the other is a tag, and a polymer, optionally wherein the L1 and / or L2 further comprise a linker that adjoins the carrier protein, tag, or polymer with the peptide; [Aaa] 1 is a positively charged amino acid residue selected from His, Lys, and Arg; [Aaa]2 is a polar and neutral of charge hydrophilic amino acid selected from Ser, Asn, Gin, Thr, and Pro, or a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]3 is a positively charged amino acid residue selected from His, Lys, and Arg, or a polar and neutral of charge hydrophilic amino acid selected from Pro Ser, Asn, Gin, and Thr; [Aaa]4 is a, hydrophobic, aromatic amino acid selected from Phe, Trp, and Tyr, or a hydrophobic, aliphatic amino acid selected from lie, Gly, Ala, Leu, Met, and Vai; [Aaa]5 is a hydrophobic, aliphatic amino acid selected from Leu, Vai, lie, Gly, Ala, and Met; [Aaa]6 is a hydrophobic, aliphatic amino acid selected from Ala, Gly, Vai, lie, Leu, and Met; [Aaa]7 is a hydrophobic, aliphatic amino acid selected from Leu, lie, Vai, Gly, Ala, and Met; [Aaa]8 is a polar and negatively charged hydrophilic amino acid selected from Asp and Glu; [Aaa]9 is a polar and positively charged hydrophilic amino acid selected from Lys, His, and Arg, or a polar and negatively charged hydrophilic amino acid selected from Glu, and Asp; [Aaa] 10 is a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa]11 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; [Aaa]12 is a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa] 13 is a hydrophobic, aliphatic amino acid selected from Ala, Vai, Gly, Leu, lie, and Met, or a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa]14 is a polar and negatively charged hydrophilic amino acid selected from Glu, and Asp; [Aaa] 15 is a hydrophobic, aliphatic amino acid selected from lie, Leu, Vai, Ala, Gly, and Met; [Aaa]16 is a polar and negatively charged hydrophilic amino acid selected from Asp, and Glu; [Aaa] 17 is hydrophobic, aromatic amino acid selected from Trp, Phe, and Tyr; [Aaa]18 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His, or a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]19 is a hydrophobic, aliphatic amino acid selected from Ala, Gly, Vai, Leu, lie, and Met; [Aaa]20 is a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]21 is a polar and neutral of charge hydrophilic amino acid selected from Pro, Ser, Gin, Asn, and Thr; [Aaa]22 is a polar and neutral of charge hydrophilic amino acid selected from Ser, Thr, Gin, Asn, and Pro; [Aaa]23 a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]24 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; [Aaa]25 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; and C is the C-terminus. In embodiments, the peptide or the derivative thereof present in the fusion protein has dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR. In embodiments, the carrier protein is selected from Fc domain, albumin, transferrin, or elastin-like protein, Keyhole Limpet Hemocyanin (KLH), ovalbulin, or a variant thereof. In embodiments, the carrier protein is a hinge CH2-CH3-Fc domain. In embodiments, the a hinge CH2-CH3-Fc domain is derived from lgG1 or lgG4 (e.g., human I gG1 or I gG4)

[0188] In embodiments, [Aaa]1 is His. In embodiments, [Aaa]2 is Ser or Gly. In embodiments, [Aaa]3 is His or Pro. In embodiments, [Aaa]4 is Phe or lie. In embodiments, [Aaa]5 is Leu or Vai. In embodiments, [Aaa]6 is Ala. In embodiments, [Aaa]7 is Leu or lie. In embodiments, [Aaa]8 is Asp or Glu. In embodiments, [Aaa]9 is Lys or Glu. In embodiments, [Aaa]10 is Gin. In embodiments, [Aaa]11 is Arg. In embodiments, [Aaa]12 is Gin. In embodiments, [Aaa]13 is Ala or Gin. In embodiments, [Aaa]14 is Glu. In embodiments, [Aaa]15 is lie or Leu. In embodiments, [Aaa]16 is Asp or Glu. In embodiments, [Aaa]17 is Trp. In embodiments, [Aaa] 18 is Arg or Gly. In embodiments, [Aaa]19 is Ala. In embodiments, [Aaa]20 is Gly or Ala. In embodiments, [Aaa]21 is Pro or Ser. In embodiments, [Aaa]22 is Ser or Thr. In embodiments, [Aaa]23 is Gly or Ala. In embodiments, [Aaa]24 is Arg or Lys. In embodiments, and / or [Aaa]25 is Arg or Lys.

[0189] In embodiments, the peptide or the derivative thereof present in the fusion protein comprises any 2 of, or any 3 of, or any 4 of, or any 5 of, or any 6 of, or any 7 of, or any 8 of, or any 9 of, or any 10 of, or any 11 of, or any 12 of, or any 13 of, or any 14 of, or any 15 of, or any 16 of, or any 17 of, or any 18 of, or any 19 of, or any 20 of, or any 21 of, or any 22 of, or any 23 of, or any 24 of, or all 25 of the following:

[0190] (1) [Aaa]1 is His;

[0191] (2) [Aaa]2 is Ser or Gly;

[0192] (3) [Aaa]3 is His or Pro;

[0193] (4) [Aaa]4 is Phe or lie;

[0194] (5) [Aaa]5 is Leu or Vai;

[0195] (6) [Aaa]6 is Ala;

[0196] (7) [Aaa]7 is Leu or lie; (8) [Aaa]8 is Asp or Glu;

[0197] (9) [Aaa]9 is Lys or Glu;

[0198] (10) [Aaa]10 is Gin;

[0199] (11) [Aaa]11 is Arg;

[0200] (12) [Aaa]12 is Gin;

[0201] (13) [Aaa]13 is Ala or Gin;

[0202] (14) [Aaa]14 is Glu;

[0203] (15) [Aaa]15 is lie or Leu;

[0204] (16) [Aaa]16 is Asp or Glu;

[0205] (17) [Aaa]17 is Trp;

[0206] (18) [Aaa]18 is Arg or Gly;

[0207] (19) [Aaa]19 is Ala;

[0208] (20) [Aaa]20 is Gly or Ala;

[0209] (21) [Aaa]21 is Pro or Ser;

[0210] (22) [Aaa]22 is Ser or Thr;

[0211] (23) [Aaa]23 is Gly or Ala; and

[0212] (24) [Aaa]24 is Arg or Lys; and / or

[0213] (25) [Aaa]25 is Arg or Lys.

[0214] In embodiments, [Aaa] 1 is His, [Aaa]2 is Ser or Gly; [Aaa]3 is His or Pro; [Aaa]4 is Phe or lie; [Aaa]5 is Leu or Vai; [Aaa]6 is Ala; [Aaa]7 is Leu or lie; [Aaa]8 is Asp or Glu; [Aaa]9 is Lys or Glu; [Aaa]10 is Gin; [Aaa]11 is Arg; [Aaa]12 is Gin; [Aaa]13 is Ala or Gin; [Aaa]14 is Glu; [Aaa]15 is lie or Leu; [Aaa]16 is Asp or Glu; [Aaa] 17 is Trp; [Aaa]18 is Arg or Gly; [Aaa]19 is Ala; [Aaa]20 is Gly or Ala; [Aaa]21 is Pro or Ser; [Aaa]22 is Ser or Thr; [Aaa]23 is Gly or Ala; [Aaa]24 is Arg or Lys; and [Aaa]25 is Arg or Lys.

[0215] In embodiments, the peptide or the derivative thereof present in the fusion protein has independently an agonistic activity or an antagonistic activity on GLP-1 R. In embodiments, the peptide or the derivative thereof present in the fusion protein has an antagonistic activity on GLP-1 R. In embodiments, the peptide or the derivative thereof present in the fusion protein has independently an agonistic activity or an antagonistic activity on GLP-2R. In embodiments, the peptide or the derivative thereof present in the fusion protein has an antagonistic activity on GLP-2R. In embodiments, the peptide or the derivative thereof present in the fusion protein has independently an agonistic activity or an antagonistic activity on GIPR. In embodiments, the peptide or the derivative thereof present in the fusion protein has an antagonistic activity on GIPR. In embodiments, the peptide or the derivative thereof present in the fusion protein has independently an agonistic activity or an antagonistic activity on GCGR. In embodiments, the peptide or the derivative thereof present in the fusion protein has an antagonistic activity on GCGR.

[0216] In embodiments, the peptide or the derivative thereof present in the fusion protein has an agonistic activity and an antagonistic activity on GLP-1 R, GLP-2R, GIPR, and / or Glucagon Receptor (GCGR).

[0217] In embodiments, the peptide or the derivative thereof present in the fusion protein of any of the embodiments disclosed herein is dual active. In embodiments, the peptide or the derivative thereof present in the fusion protein an agonistic activity or an antagonistic activity on GLP-1R, and an agonistic activity or an antagonistic activity on GLP-2R. In embodiments, the peptide or the derivative thereof present in the fusion protein an agonistic activity or an antagonistic activity on GLP-1 R, and an agonistic activity or an antagonistic activity on GIPR. In embodiments, the peptide or the derivative thereof present in the fusion protein an agonistic activity or an antagonistic activity on GLP-1 R, and an agonistic activity or an antagonistic activity on GCGR. In embodiments, the peptide or the derivative thereof present in the fusion protein an agonistic activity or an antagonistic activity on GLP-2R, and an agonistic activity or an antagonistic activity on GIPR. In embodiments, the peptide or the derivative thereof present in the fusion protein an agonistic activity or an antagonistic activity on GLP-2R, and an agonistic activity or an antagonistic activity on GCGR. In embodiments, the peptide or the derivative thereof present in the fusion protein an agonistic activity or an antagonistic activity on GIPR, and an agonistic activity or an antagonistic activity on GCGR.

[0218] In embodiments, the peptide or the derivative thereof present in the fusion protein of any of the embodiments disclosed herein is triple active. In embodiments, the peptide or the derivative thereof present in the fusion protein an agonistic activity or an antagonistic activity on GLP-1 R, an agonistic activity or an antagonistic activity on GLP-2R, and an agonistic activity or an antagonistic activity on GIPR. In embodiments, the peptide or the derivative thereof present in the fusion protein an agonistic activity or an antagonistic activity on GLP- 1 R, an agonistic activity or an antagonistic activity on GLP-2R, and an agonistic activity or an antagonistic activity on GCGR. In embodiments, the peptide or the derivative thereof present in the fusion protein an agonistic activity or an antagonistic activity on GLP-1 R, an agonistic activity or an antagonistic activity on GIPR, and an agonistic activity or an antagonistic activity on GCGR. In embodiments, the peptide or the derivative thereof present in the fusion protein an agonistic activity or an antagonistic activity on GLP-2R, an agonistic activity or an antagonistic activity on GIPR, and an agonistic activity or an antagonistic activity on GCGR.

[0219] In embodiments, the peptide or the derivative thereof present in the fusion protein of any of the embodiments disclosed herein is triple active. In embodiments, the peptide or the derivative thereof present in the fusion protein an agonistic activity or an antagonistic activity on GLP-1 R, an agonistic activity or an antagonistic activity on GLP-2R, an agonistic activity or an antagonistic activity on GIPR, and an agonistic activity or an antagonistic activity on GCGR.

[0220] In embodiments, the fusion protein comprises a carrier protein selected from an Fc domain, albumin, transferrin, or elastin-like protein, Keyhole Limpet Hemocyanin (KLH), ovalbulin, or a variant thereof. In embodiments, the fusion protein comprises a hinge CH2-CH3-Fc domain. In embodiments, the fusion protein comprises an Fc domain of an antibody (e.g., of IgG, IgA, IgD, and IgE, inclusive of subclasses (e.g., lgG1 , lgG2, lgG3, and I gG4, and I gA1 and lgA2)). In embodiments, the fusion protein comprises a hinge-CH2-CH3 Fc domain derived from lgG4, optionally human I gG4. In embodiments, the fusion protein comprises a hinge- CH2-CH3 Fc domain derived from lgG1 , optionally human lgG1.

[0221] In embodiments, the fusion protein comprises a hinge-CH2-CH3 Fc domain derived from lgG4. In embodiments, the fusion protein comprises a hinge-CH2-CH3 Fc domain derived from a human lgG4. In embodiments, the hinge-CH2-CH3 Fc domain has an amino acid sequence that has at least about 95%, or at least about 97%, or at least about 97%, or at least about 98% sequence identity with the amino acid sequence of any one of SEQ ID NO: 1 to SEQ ID NO: 4. In embodiments, the hinge-CH2-CH3 Fc domain has an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2. In embodiments, the hinge-CH2-CH3 Fc domain has an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 4.

[0222] In embodiments, the hinge-CH2-CH3 Fc domain is derived from a human lgG1 antibody. In embodiments, the Fc domain exhibits increased affinity for and enhanced binding to the neonatal Fc receptor (FcRn). In embodiments, the Fc domain includes one or more mutations that increases the affinity and enhances binding to FcRn. Without wishing to be bound by theory, it is believed that increased affinity and enhanced binding to FcRn increases the in vivo half-life of the present fusion proteins. In embodiments, the Fc domain contains one or more amino acid substitutions at amino acid residue 250, 252, 254, 256, 308, 309, 311, 416, 428, 433 or 434 (in accordance with Kabat numbering, as in as in Kabat, et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991) expressly incorporated herein by reference), or equivalents thereof. In embodiments, the amino acid substitution at amino acid residue 250 is a substitution with glutamine. In embodiments, the amino acid substitution at amino acid residue 252 is a substitution with tyrosine, phenylalanine, tryptophan or threonine. In embodiments, the amino acid substitution at amino acid residue 254 is a substitution with threonine. In embodiments, the amino acid substitution at amino acid residue 256 is a substitution with serine, arginine, glutamine, glutamic acid, aspartic acid, or threonine. In embodiments, the amino acid substitution at amino acid residue 308 is a substitution with threonine. In embodiments, the amino acid substitution at amino acid residue 309 is a substitution with proline. In embodiments, the amino acid substitution at amino acid residue 311 is a substitution with serine. In embodiments, the amino acid substitution at amino acid residue 385 is a substitution with arginine, aspartic acid, serine, threonine, histidine, lysine, alanine or glycine. In embodiments, the amino acid substitution at amino acid residue 386 is a substitution with threonine, proline, aspartic acid, serine, lysine, arginine, isoleucine, or methionine. In embodiments, the amino acid substitution at amino acid residue 387 is a substitution with arginine, proline, histidine, serine, threonine, or alanine. In embodiments, the amino acid substitution at amino acid residue 389 is a substitution with proline, serine or asparagine. In embodiments, the amino acid substitution at amino acid residue 416 is a substitution with serine. In embodiments, the amino acid substitution at amino acid residue 428 is a substitution with leucine. In embodiments, the amino acid substitution at amino acid residue 433 is a substitution with arginine, serine, isoleucine, proline, or glutamine. In embodiments, the amino acid substitution at amino acid residue 434 is a substitution with histidine, phenylalanine, or tyrosine.

[0223] In embodiments, the Fc domain (e.g., comprising an IgG constant region) comprises one or more mutations such as substitutions at amino acid residue 252, 254, 256, 433, 434, or 436 (in accordance with Kabat numbering, as in as in Kabat, ef al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991) expressly incorporated herein by reference). In embodiments, the Fc domain of the present fusion proteins comprise an IgG constant region includes a triple M252Y / S254T / T256E mutation or YTE mutation. In embodiments, the IgG constant region includes a triple H433K / N434F / Y436H mutation or KFH mutation. In embodiments, the IgG constant region includes an YTE and KFH mutation in combination. In embodiments, the IgG constant region that contains one or more mutations at amino acid residues 250, 253, 307, 310, 380, 428, 433, 434, and 435 (in accordance with Kabat numbering, as in as in Kabat, et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991) expressly incorporated herein by reference). Illustrative mutations include T250Q, M428L, T307A, E380A, I253A, H310A, M428L, H433K, N434A, N434F, N434S, and H435A. In embodiments, the IgG constant region comprises a M428L / N434S mutation or LS mutation. In embodiments, the IgG constant region comprises a T250Q / M428L mutation or QL mutation. In embodiments, the IgG constant region comprises an N434A mutation. In embodiments, the IgG constant region comprises a T307A / E380A / N434A mutation or AAA mutation. In embodiments, the IgG constant region comprises an I253A / H310A / H435A mutation or y mutation. In embodiments, the IgG constant region comprises a H433K / N434F mutation. In embodiments, the IgG constant region comprises a M252Y / S254T / T256E and a H433K / N434F mutation in combination. In embodiments, the IgG constant region comprises mutations that decrease Fc effector function (e.g., L234A and L235A mutations (LALA) with or without G236R and / or P329G mutations).

[0224] Additional exemplary mutations in the IgG constant region are described, for example, in Robbie, et al., Antimicrobial Agents and Chemotherapy (2013), 57(12):6147-6153, Dall’Acqua et al., JBC (2006), 281 (33):23514-24, Dall’Acqua et al., Journal of Immunology (2002), 169:5171-80, Ko et al. Nature (2014) 514:642-645, Grevys etal. Journal of Immunology. (2015), 194(11):5497-508, and U.S. Patent No. 7,083,784, the entire contents of which are hereby incorporated by reference.

[0225] In embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO: 1 (see Table 1), or at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. In embodiments, mutations are made to SEQ ID NO: 1 to increase stability and / or half-life. For instance, in embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO: 2 (see Table 1), or at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. An illustrative Fc stabilizing mutant is S228P. Illustrative Fc half-life extending mutants are T250Q, M428L, V308T, L309P, and Q311 S and the Fc domains may comprise 1 , or 2, or 3, or 4, or 5 of these mutants. In embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO: 3 (see Table 1), or at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto. In embodiments, the Fc domain comprises the amino acid sequence of SEQ ID NO: 4 (see Table 1), or at least about 90%, or at least about 93%, or at least about 95%, or at least about 97%, or at least about 98%, or at least about 99% identity thereto.

[0226] In embodiments, the fusion protein binds to FcRn with high affinity. In embodiments, the fusion protein may bind to FcRn with a KD of about 1 nM to about 80 nM. For example, the fusion protein may bind to FcRn with a KD of about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 15 nM, about 20 nM, about 25 nM, about 30 nM, about 35 nM, about 40 nM, about 45 nM, about 50 nM, about 55 nM, about 60 nM, about 65 nM, about 70 nM, about 71 nM, about 72 nM, about 73 nM, about 74 nM, about 75 nM, about 76 nM, about 77 nM, about 78 nM, about 79 nM, or about 80 nM. In embodiments, the fusion protein may bind to FcRn with a KD of about 9 nM. In embodiments, the fusion protein does not substantially bind to other Fc receptors ( / .e., other than FcRn) with effector function.

[0227] In embodiments, the Fc domain comprises a hinge region of an antibody (e.g., of IgG, IgA, IgD, and IgE, inclusive of subclasses (e.g., lgG1 , lgG2, lgG3, and lgG4, and lgA1 , and lgA2)). The hinge region, found in IgG, IgA, IgD, and IgE class antibodies, acts as a flexible spacer, allowing the Fab portion to move freely in space. In contrast to the constant regions, the hinge domains are structurally diverse, varying in both sequence and length among immunoglobulin classes and subclasses. For example, the length and flexibility of the hinge region varies among the IgG subclasses. The hinge region of lgG1 encompasses amino acids 216-231 and, because it is freely flexible, the Fab fragments can rotate about their axes of symmetry and move within a sphere centered at the first of two inter-heavy chain disulfide bridges. I gG2 has a shorter hinge than lgG1 , with 12 amino acid residues and four disulfide bridges. The hinge region of lgG2 lacks a glycine residue, is relatively short, and contains a rigid poly-proline double helix, stabilized by extra inter-heavy chain disulfide bridges. These properties restrict the flexibility of the I gG2 molecule. lgG3 differs from the other subclasses by its unique extended hinge region (about four times as long as the I gG 1 hinge), containing 62 amino acids (including 21 prolines and 11 cysteines), forming an inflexible poly-proline double helix. In lgG3, the Fab fragments are relatively far away from the Fc fragment, giving the molecule a greater flexibility. The elongated hinge in I gG3 is also responsible for its higher molecular weight compared to the other subclasses. The hinge region of I gG4 is shorter than that of lgG1 and its flexibility is intermediate between that of lgG1 and lgG2. The flexibility of the hinge regions reportedly decreases in the order lgG3>lgG1>lgG4>lgG2. In embodiments, the linker may be derived from human lgG4 and contain one or more mutations to enhance dimerization (including S228P) or FcRn binding. According to crystallographic studies, the immunoglobulin hinge region can be further subdivided functionally into three regions: the upper hinge region, the core region, and the lower hinge region. See Shin et al., 1992 Immunological Reviews 130:87. The upper hinge region includes amino acids from the carboxyl end of CHI to the first residue in the hinge that restricts motion, generally the first cysteine residue that forms an interchain disulfide bond between the two heavy chains. The length of the upper hinge region correlates with the segmental flexibility of the antibody. The core hinge region contains the inter-heavy chain disulfide bridges, and the lower hinge region joins the amino terminal end of the CH2 domain and includes residues in CH2. Id. The core hinge region of wild-type human lgG1 contains the sequence CPPC (SEQ ID NO: 24) which, when dimerized by disulfide bond formation, results in a cyclic octapeptide believed to act as a pivot, thus conferring flexibility. In embodiments, the present linker comprises, one, or two, or three of the upper hinge regions, the core region, and the lower hinge region of any antibody (e.g., of IgG, IgA, I g D, and IgE, inclusive of subclasses (e.g., lgG1 , lgG2, lgG3, and lgG4, and lgA1 and lgA2)). The hinge region may also contain one or more glycosylation sites, which include a number of structurally distinct types of sites for carbohydrate attachment. For example, lgA1 contains five glycosylation sites within a 17-amino-acid segment of the hinge region, conferring resistance of the hinge region polypeptide to intestinal proteases, considered an advantageous property for a secretory immunoglobulin. In embodiments, the linker of the present disclosure comprises one or more glycosylation sites.

[0228] In embodiments, the fusion protein disclosed herein comprise a linker. In embodiments, the linker is a polypeptide selected from a flexible amino acid sequence or an IgG hinge region. In embodiments, the linker is derived from naturally occurring multi-domain proteins or is an empirical linker as described, for example, in Chichili et al., (2013), Protein Sci. 22(2):153-167, Chen et al., (2013), Adv Drug Deliv Rev. 65(10):1357- 1369, the entire contents of which are hereby incorporated by reference. In embodiments, the linker may be designed using linker designing databases and computer programs such as those described in Chen et al., (2013), Adv Drug Deliv Rev. 65(10): 1357-1369 and Crasto et. al., (2000), Protein Eng. 13(5):309-312, the entire contents of which are hereby incorporated by reference.

[0229] In embodiments, the linker is a synthetic linker such as PEG.

[0230] In embodiments, the linker is flexible.

[0231] In embodiments, the linker is rigid. In embodiments, the linker is substantially comprised of glycine and serine residues (e.g., about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or about 97%, or about 98%, or about 99%, or about 100% glycines and serines).

[0232] In embodiments, the , the linker comprises an amino acid sequence selected from the amino acid sequence of SEQ ID NOs: 5-53 (or a variant thereof).

[0233] In embodiments, the present fusion proteins may comprise variants of the linkers disclosed in Table 1, below. For instance, a linker may have at least about 60%, or at least about 61%, or at least about 62%, or at least about 63%, or at least about 64%, or at least about 65%, or at least about 66%, or at least about 67%, or at least about 68%, or at least about 69%, or at least about 70%, or at least about 71 %, or at least about 72%, or at least about 73%, or at least about 74%, or at least about 75%, or at least about 76%, or at least about 77%, or at least about 78%, or at least about 79%, or at least about 80%, or at least about 81 %, or at least about 82%, or at least about 83%, or at least about 84%, or at least about 85%, or at least about 86%, or at least about 87%, or at least about 88%, or at least about 89%, or at least about 90%, or at least about 91 %, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% sequence identity with the amino acid sequence of any one of SEQ ID NOs: 5-53.

[0234] Without wishing to be bound by theory, including at least a part of an Fc domain in the fusion protein, helps avoid formation of insoluble and, likely, non-functional protein concatamers and / or aggregates. This is in part due to the presence of cysteines in the Fc domain which are capable of forming disulfide bonds between fusion proteins.

[0235] In embodiments, the first and / or second linkers are independently selected from the amino acid sequences of SEQ ID NOs: 5-53 and are provided in Table 1 below:

[0236] Table 1 : Illustrative linkers (Fc domains and linkers)

[0237] In embodiments, the linker substantially comprises glycine and serine residues (e.g., about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or about 97%, or about 98%, or about 99%, or about 100% glycines and serines). For example, in embodiments, the linker is (Gly4Ser)n, where n is from about 1 to about 8, e.g., 1 , 2, 3, 4, 5, 6, 7, or 8 (SEQ ID NO: 26 to SEQ ID NO: 33, respectively). In embodiments, the linker sequence is GGSGGSGGGGSGGGGS (SEQ ID NO: 34). Additional illustrative linkers include, but are not limited to, linkers having the sequence LE, (EAAAK)n (n=1 - 3) (SEQ ID NO: 37 to SEQ ID NO: 39), A(EAAAK)nA (n = 2-5) (SEQ ID NO: 40 to SEQ ID NO: 43), A(EAAAK)4ALEA(EAAAK)4A (SEQ ID NO: 44), PAPAP (SEQ ID NO: 45), KESGSVSSEQLAQFRSLD (SEQ ID NO: 46), GSAGSAAGSGEF (SEQ ID NO: 47), and (XP)n, with X designating any amino acid, e.g., Ala, Lys, or Glu. In embodiments, a linker has the sequence (Gly)n where n is any number from 1 to 100, for example: (Gly)s (SEQ ID NO: 35) and (Gly)e (SEQ ID NO: 36). In embodiments, the linker has the amino acid sequence GGS (SEQ ID NO: 4), or GS or LE.

[0238] In embodiments, the linker is one or more of GGGSE (SEQ ID NO: 48), GSESG (SEQ ID NO: 49), GSEGS (SEQ ID NO: 50), GEGGSGEGSSGEGSSSEGGGSEGGGSEGGGSEGGS (SEQ ID NO: 51), and a linker of randomly placed G, S, and E every 4 amino acid intervals. In embodiments, the linker has the amino acid sequence EPKSCDKTHTCP (SEQ ID NO: 52). In embodiments, the linker has the amino acid sequence EPKSVDKTHTCP (SEQ ID NO: 53).

[0239] In embodiments, the fusion protein comprises a hinge-CH2-CH3 Fc domain (e.g., comprising an amino acid sequence having at least 95% sequence identity with one of SEQ ID NOs: 1-4), joined to the peptide or a derivative thereof of any of the embodiments disclosed herein via a linker having an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0240] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence selected from SEQ ID NOs: 60 to 69, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NOs: 60 to 69. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1, 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0241] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 60, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 60. In embodiments, the hinge CH2- CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1 , 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0242] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 61 , or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 61. In embodiments, the hinge CH2- CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1 , 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53. In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 62, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 62. In embodiments, the hinge CH2- CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1 , 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0243] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 63, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 63. In embodiments, the hinge CH2- CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1 , 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0244] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 64, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 64. In embodiments, the hinge CH2- CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1 , 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0245] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 65, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 65. In embodiments, the hinge CH2- CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1 , 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0246] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 66, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 66. In embodiments, the hinge CH2- CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1 , 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53. In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 67, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 67. In embodiments, the hinge CH2- CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1 , 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0247] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 68, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 68. In embodiments, the hinge CH2- CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1 , 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0248] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 69, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 69. In embodiments, the hinge CH2- CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1 , 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0249] In aspects, the present disclosure provides a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 60, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 60. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 60.

[0250] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 61 , or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 61. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 61 .

[0251] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 62, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 62. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 62.

[0252] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 63, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 63. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 63.

[0253] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 64, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 64. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 64.

[0254] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 65, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 65. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 65.

[0255] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 66, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 66. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 66.

[0256] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 67, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 67. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 67.

[0257] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 68, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 68. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 68.

[0258] In aspects, the present disclosure provides a fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP- 2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 69, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 69. In embodiments, the peptide comprises an amino acid sequence of SEQ ID NO: 69.

[0259] In embodiments, the hinge CH2-CH3-Fc domain is derived from IgG, IgM, IgA, IgD, or IgE. In embodiments, the IgG is selected from lgG1, lgG2, lgG3, and lgG4. In embodiments, the hinge CH2-CH3-Fc domain is derived from lgG1. In embodiments, the lgG1 is human lgG1. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that is at least about 95%, or at least about 97%, or at least about 97%, or at least about 98% or at least 99% identical to the amino acid sequence of SEQ ID NO: 4.

[0260] In embodiments, the hinge-CH2-CH3 Fc domain is derived from lgG4. In embodiments, the lgG4 is human lgG4. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that is at least about 95%, or at least about 97%, or at least about 97%, or at least about 98% or at least 99% identical to the amino acid sequence SEQ ID NO: 1 , SEQ ID NO: 2, or SEQ ID NO: 3. In embodiments, the hinge CH2- CH3-Fc domain is fused to the peptide or a derivative thereof via a linker. In embodiments, the linker has an amino acid sequence selected from SEQ ID NOs: 5 to 53.

[0261] In embodiments, the peptide or the derivative thereof or the fusion protein further comprises a glycosyl moiety. In embodiments, the glycosyl moiety is an N-linked glycosyl moiety. In embodiments, the glycosyl moiety is an O-linked glycosyl moiety. In embodiments, the peptide or the derivative thereof or the fusion protein comprises one or more N-linked glycosylation consensus sites and / or O-linked glycosylation consensus sites.

[0262] In embodiments, the peptide or the derivative thereof or the fusion protein is biosynthesized as a single polypeptide chain. In embodiments, the peptide or the derivative thereof or the fusion protein is biosynthesized from a single open reading frame. In embodiments, the peptide or the derivative thereof or the fusion protein is prepared using an expression system. In embodiments, the expression system is selected from bacterial, yeast, invertebrate, vertebrate, and plant expression system.

[0263] In embodiments, the peptide or the derivative thereof or the fusion protein or the fusion protein is chemically synthesized. In embodiments, the peptide or the derivative thereof or the fusion protein is produced by in vitro translation of a polynucleotide encoding the peptide or the derivative thereof or the fusion protein. In embodiments, the polynucleotide encoding the peptide or the derivative thereof or the fusion protein of any of the embodiments disclosed herein is used for in vitro translation.

[0264] In embodiments, the peptide or the derivative thereof or the fusion protein is then chemically modified. The chemical modifications include but are not limited to chemical modification of side chain of an amino acid, the N-terminus and / or the C-terminus. In embodiments, the chemical modification is carried out via conjugation of side chain of an amino acid, the N-terminus and / or the C-terminus to a chemical entity (without limitation, e.g., a polymer such as PEG). In embodiments, the chemical modification or the conjugation is performed directly on side chain of an amino acid, the N-terminus and / or the C-terminus. In embodiments, the chemical modification or the conjugation uses a suitable linker that adjoins the conjugated chemical entity with side chain of an amino acid, the N-terminus and / or the C-terminus.

[0265] In embodiments, the peptide or the derivative thereof or the fusion protein further comprises a non-natural amino acid selected from an amino isobutyric acid (Aib), a D-amino acid, and those comprising a modification selected from N-methylation (Nm), Ca-methylation (Cm), 4J(CH2NH) reduced amide bonds (Rd), and a peptoids (Pp)).

[0266] In embodiments, the peptide or the derivative thereof or the fusion protein comprises a polymer. In embodiments, the polymer is selected from poly(alkylene oxide) (e.g., polyethylene glycol (PEG)), polyvinylpyrrolidone), poly(vinyl alcohol), poly(glycerol), poly(zwitterions), poly(carbonates), polyoxazoline, poly(acryloylmorpholine), poly(oxazolines), poly(sacharrides), and a combination thereof. In embodiments, the polymer is polyethylene glycol (PEG). In embodiments, one or more amino acids present in the peptide or the derivative thereof or the fusion protein is PEGylated. In embodiments, the one or more PEGylated amino acids are located inside the carrier protein. In embodiments, the PEGylation is conducted using a succinimidyl ester, an aldehyde, a maleimide, and / or a p-nitrophenyl carbonate ester reagent. In embodiments, one or more Lys residues, one or more Ser residues, one or more Tyr residues, one or more His residues, one or more Cys residues, the N-terminus and / or the C-terminus are PEGylated. In embodiments, at least about 1 , or at least about 3, or at least about 5, or at least about 8, or at least about 10, or more amino acid residues, the N-terminus and / or the C-terminus are PEGylated. In embodiments, the one or more PEGylated amino acids comprise a Lys. In embodiments, the PEGylation is conducted via amine conjugation. In embodiments, the one or more PEGylated amino acids comprise a Gin. In embodiments, the PEGylation is conducted via transglutaminase (TGase) mediated enzymatic conjugation. In embodiments, the one or more PEGylated amino acids comprise a Cys. In embodiments, the PEGylation is conducted via thiol conjugation.

[0267] In embodiments, the peptide or the derivative thereof or the fusion protein has independently an agonistic activity or an antagonistic activity on glucagon-like peptide- 1 receptor (GLP-1 R), glucagon-like peptide-2 receptor (GLP-2R), gastric inhibitory peptide receptor (GIPR), and / or glucagon receptor (GCGR).

[0268] In embodiments, the peptide or the derivative thereof or the fusion protein of any of the embodiments disclosed herein is dual active. In embodiments, the peptide or the derivative thereof or the fusion protein has independently an agonistic activity or an antagonistic activity on GLP-1 R and GCGR. In embodiments, the peptide or the derivative thereof or the fusion protein has independently an agonistic activity or an antagonistic activity on GLP-1 R and GIPR. In embodiments, the peptide or the derivative thereof or the fusion protein has independently an agonistic activity or an antagonistic activity on GLP-2R and GIPR. In embodiments, the peptide or the derivative thereof or the fusion protein has independently an agonistic activity or an antagonistic activity on GLP-2R and GCGR. In embodiments, the peptide or the derivative thereof or the fusion protein has independently an agonistic activity or an antagonistic activity on GLP-1 R and GLP-2R. In embodiments, the peptide or the derivative thereof or the fusion protein has independently an agonistic activity or an antagonistic activity on GIPR and GCGR.

[0269] In embodiments, the peptide or the derivative thereof or the fusion protein of any of the embodiments disclosed herein is triple active. In embodiments, the peptide or the derivative thereof or the fusion protein has independently an agonistic activity or an antagonistic activity on GLP-1 R, GIPR and GCGR. In embodiments, the peptide or the derivative thereof or the fusion protein has independently an agonistic activity or an antagonistic activity on GLP-1 R, GLP-2R and GCGR. In embodiments, the peptide or the derivative thereof or the fusion protein has independently an agonistic activity or an antagonistic activity on GLP-1R, GLP-2R and GIPR. In embodiments, the peptide or the derivative thereof or the fusion protein has independently an agonistic activity or an antagonistic activity on GLP-2R, GIPR and GCGR.

[0270] In embodiments, the peptide or the derivative thereof or the fusion protein of any of the embodiments disclosed herein is quadruple active. In embodiments, the peptide or the derivative thereof or the fusion protein has independently an agonistic activity or an antagonistic activity on GLP-1 R, GLP-2R, GIPR and GCGR.

[0271] In embodiments, the peptide or the derivative thereof or the fusion protein exhibits an ECso value for GLP- 1 R in the range of 100 pM to 1000 nM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof or the fusion protein exhibits an EC50 value for GLP-1 R in the range of 2 nM to 100 nM, as determined by a cell-based assay.

[0272] In embodiments, the peptide or the derivative thereof or the fusion protein exhibits an EC50 value for GIPR in the range of 100 pM to 1000 nM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof or the fusion protein exhibits an EC50 value for GIPR in the range of 100 pM to 2 nM, as determined by a cell-based assay.

[0273] In embodiments, the peptide or the derivative thereof or the fusion protein exhibits an EC50 value for GCGR in the range of 100 pM to 1000 nM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof or the fusion protein exhibits an EC50 value for GCGR in the range of 2 nM to 100 nM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof or the fusion protein exhibits an IC50 value for GLP-1 R in the range of 10 pM to 10 pM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof or the fusion protein exhibits an IC50 value for GIPR in the range of 10 pM to 10 pM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof or the fusion protein exhibits an I C50 value for GCGR in the range of 10 pM to 10 pM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof or the fusion protein exhibits an EC50 value for GLP-2R in the range of 10 pM to 10 pM, as determined by a cell-based assay. In embodiments, the peptide or the derivative thereof or the fusion protein exhibits an I C50 value for GLP-2R in the range of 10 pM to 10 pM, as determined by a cell-based assay. Isolated Polynucleotide Encoding the Peptide, or the fusion protein, or the Derivative thereof

[0274] In aspects, the present disclosure provides an isolated polynucleotide encoding the peptide or the derivative thereof of any of the embodiments disclosed herein.

[0275] In aspects, the present disclosure provides an isolated polynucleotide encoding a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises a general formula (I):

[0276] N-L1 -[Aaa]1-[Aaa]2-[Aaa]3-Gly-Thr-Phe-Thr-Ser-Asp-[Aaa]4-Ser-[Aaa]5-[Aaa]6-[Aaa]7-[Aaa]8- [Aaa]9-[Aaa]10-[Aaa]11-[Aaa]12-[Aaa]13-[Aaa]14-Phe-[Aaa]15-[Aaa]16-[Aaa]17-Leu-[Aaa]18- [Aaa]19-[Aaa]20-Gly-Pro-[Aaa]21-[Aaa]22-[Aaa]23-[Aaa]24-Pro-Pro-Pro-[Aaa]25-L2-C

[0277] (I) wherein N is the N-terminus; L1 and / or L2 are independently present or absent; and L1 and / or L2, if present, are each independently selected from a carrier protein, a tag, and a polymer, optionally wherein the L1 and / or L2 further comprise a linker that adjoins the carrier protein, tag, or polymer with the peptide; [Aaa] 1 is His; [Aaa]2 is Ser or Gly; [Aaa]3 is His or Pro; [Aaa]4 is Phe or lie; [Aaa]5 is Leu or Vai; [Aaa]6 is Ala; [Aaa]7 is Leu or lie; [Aaa]8 is Asp or Glu; [Aaa]9 is Lys or Glu; [Aaa]10 is Gin; [Aaa]11 is Arg; [Aaa]12 is Gin; [Aaa]13 is Ala or Gin; [Aaa]14 is Glu; [Aaa]15 is lie or Leu; [Aaa]16 is Asp or Glu; [Aaa]17 is Trp; [Aaa]18 is Arg or Gly; [Aaa] 19 is Ala; [Aaa]20 is Gly or Ala; [Aaa]21 is Pro or Ser; [Aaa]22 is Ser or Thr; [Aaa]23 is Gly or Ala; [Aaa]24 is Arg or Lys; [Aaa]25 is Arg or Lys; and C is the C-terminus. In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof has dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR.

[0278] In aspects, the present disclosure provides an isolated polynucleotide encoding a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises formula (II):

[0279] N-L1 -[Aaa]1-[Aaa]2-[Aaa]3-Gly-Thr-Phe-Thr-Ser-Asp-[Aaa]4-Ser-[Aaa]5-[Aaa]6-[Aaa]7-[Aaa]8- [Aaa]9-[Aaa]10-[Aaa]11-[Aaa]12-[Aaa]13-[Aaa]14-Phe-[Aaa]15-[Aaa]16-[Aaa]17-Leu-[Aaa]18- [Aaa]19-[Aaa]20-Gly-Pro-[Aaa]21-[Aaa]22-[Aaa]23-[Aaa]24-Pro-Pro-Pro-[Aaa]25-L2-C

[0280] (II) wherein: N is the N-terminus; L1 and / or L2 are independently present or absent; and L1 and / or L2, if present, are each independently selected from a carrier protein, a tag, and a polymer; [Aaa] 1 is a positively charged amino acid residue selected from His, Lys, and Arg; [Aaa]2 is a polar and neutral of charge hydrophilic amino acid selected from Ser, Asn, Gin, Thr, and Pro, or a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]3 is a positively charged amino acid residue selected from His, Lys, and Arg, or a polar and neutral of charge hydrophilic amino acid selected from Pro Ser, Asn, Gin, and Thr; [Aaa]4 is a, hydrophobic, aromatic amino acid selected from Phe, Trp, and Tyr, or a hydrophobic, aliphatic amino acid selected from lie, Gly, Ala, Leu, Met, and Vai; [Aaa]5 is a hydrophobic, aliphatic amino acid selected from Leu, Vai, lie, Gly, Ala, and Met; [Aaa]6 is a hydrophobic, aliphatic amino acid selected from Ala, Gly, Vai, lie, Leu, and Met; [Aaa]7 is a hydrophobic, aliphatic amino acid selected from Leu, lie, Vai, Gly, Ala, and Met; [Aaa]8 is a polar and negatively charged hydrophilic amino acid selected from Asp and Glu; [Aaa]9 is a polar and positively charged hydrophilic amino acid selected from Lys, His, and Arg, or a polar and negatively charged hydrophilic amino acid selected from Glu, and Asp; [Aaa]10 is a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa] 11 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; [Aaa]12 is a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa]13 is a hydrophobic, aliphatic amino acid selected from Ala, Vai, Gly, Leu, lie, and Met, or a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa]14 is a polar and negatively charged hydrophilic amino acid selected from Glu, and Asp; [Aaa]15 is a hydrophobic, aliphatic amino acid selected from lie, Leu, Vai, Ala, Gly, and Met; [Aaa]16 is a polar and negatively charged hydrophilic amino acid selected from Asp, and Glu; [Aaa]17 is hydrophobic, aromatic amino acid selected from Trp, Phe, and Tyr; [Aaa] 18 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His, or a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa] 19 is a hydrophobic, aliphatic amino acid selected from Ala, Gly, Vai, Leu, lie, and Met; [Aaa]20 is a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]21 is a polar and neutral of charge hydrophilic amino acid selected from Pro, Ser, Gin, Asn, and Thr; [Aaa]22 is a polar and neutral of charge hydrophilic amino acid selected from Ser, Thr, Gin, Asn, and Pro; [Aaa]23 a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]24 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; [Aaa]25 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; and C is the C-terminus. In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR.

[0281] In embodiments, [Aaa]1 is His. In embodiments, [Aaa]2 is Ser or Gly. In embodiments, [Aaa]3 is His or Pro. In embodiments, [Aaa]4 is Phe or lie. In embodiments, [Aaa]5 is Leu or Vai. In embodiments, [Aaa]6 is Ala. In embodiments, [Aaa]7 is Leu or lie. In embodiments, [Aaa]8 is Asp or Glu. In embodiments, [Aaa]9 is Lys or Glu. In embodiments, [Aaa]10 is Gin. In embodiments, [Aaa]11 is Arg. In embodiments, [Aaa]12 is Gin. In embodiments, [Aaa]13 is Ala or Gin. In embodiments, [Aaa]14 is Glu. In embodiments, [Aaa]15 is lie or Leu. In embodiments, [Aaa]16 is Asp or Glu. In embodiments, [Aaa]17 is Trp. In embodiments, [Aaa] 18 is Arg or Gly. In embodiments, [Aaa]19 is Ala. In embodiments, [Aaa]20 is Gly or Ala. In embodiments, [Aaa]21 is Pro or Ser. In embodiments, [Aaa]22 is Ser or Thr. In embodiments, [Aaa]23 is Gly or Ala. In embodiments, [Aaa]24 is Arg or Lys. In embodiments, and / or [Aaa]25 is Arg or Lys.

[0282] In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof comprises any 2 of, or any 3 of, or any 4 of, or any 5 of, or any 6 of, or any 7 of, or any 8 of, or any 9 of, or any 10 of, or any 11 of, or any 12 of, or any 13 of, or any 14 of, or any 15 of, or any 16 of, or any 17 of, or any 18 of, or any 19 of, or any 20 of, or any 21 of, or any 22 of, or any 23 of, or any 24 of, or all 25 of the following:

[0283] (1) [Aaa]1 is His;

[0284] (2) [Aaa]2 is Ser or Gly;

[0285] (3) [Aaa]3 is His or Pro;

[0286] (4) [Aaa]4 is Phe or lie;

[0287] (5) [Aaa]5 is Leu or Vai;

[0288] (6) [Aaa]6 is Ala;

[0289] (7) [Aaa]7 is Leu or lie;

[0290] (8) [Aaa]8 is Asp or Glu;

[0291] (9) [Aaa]9 is Lys or Glu;

[0292] (10) [Aaa]10 is Gin;

[0293] (11) [Aaa]11 is Arg;

[0294] (12) [Aaa]12 is Gin;

[0295] (13) [Aaa]13 is Ala or Gin;

[0296] (14) [Aaa]14 is Glu;

[0297] (15) [Aaa] 15 is lie or Leu; (16) [Aaa]16 is Asp or Glu;

[0298] (17) [Aaa]17 is Trp;

[0299] (18) [Aaa]18 is Arg or Gly;

[0300] (19) [Aaa]19 is Ala;

[0301] (20) [Aaa]20 is Gly or Ala;

[0302] (21) [Aaa]21 is Pro or Ser;

[0303] (22) [Aaa]22 is Ser or Thr;

[0304] (23) [Aaa]23 is Gly or Ala; and

[0305] (24) [Aaa]24 is Arg or Lys; and / or

[0306] (25) [Aaa]25 is Arg or Lys.

[0307] In embodiments, [Aaa] 1 is His, [Aaa]2 is Ser or Gly; [Aaa]3 is His or Pro; [Aaa]4 is Phe or lie; [Aaa]5 is Leu or Vai; [Aaa]6 is Ala; [Aaa]7 is Leu or lie; [Aaa]8 is Asp or Glu; [Aaa]9 is Lys or Glu; [Aaa]10 is Gin; [Aaa]11 is Arg; [Aaa]12 is Gin; [Aaa]13 is Ala or Gin; [Aaa]14 is Glu; [Aaa]15 is lie or Leu; [Aaa]16 is Asp or Glu; [Aaa] 17 is Trp; [Aaa]18 is Arg or Gly; [Aaa]19 is Ala; [Aaa]20 is Gly or Ala; [Aaa]21 is Pro or Ser; [Aaa]22 is Ser or Thr; [Aaa]23 is Gly or Ala; [Aaa] 24 is Arg or Lys; and [Aaa]25 is Arg or Lys.

[0308] In embodiments, the isolated polynucleotide encodes a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V1 , comprises the following sequence:

[0309] HSHGTFTSDFSLALDKQRQAEFIDWLRAGGPPSGRPPPR (SEQ ID NO: 68).

[0310] In embodiments, the SL_TriAg_V1 or a derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V1 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 68. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 68. In embodiments, the isolated polynucleotide encodes a peptide or a derivative thereof having agonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V2, comprises the following sequence:

[0311] HGHGTFTSDISVAIEEQRQQEFLEWLGAAGPSTAKPPPK (SEQ ID NO: 61).

[0312] In embodiments, the SL_TriAg_V2 or a derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V2 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 61. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to an amino acid sequence of SEQ ID NO: 61.

[0313] In embodiments, the isolated polynucleotide encodes a peptide or a derivative thereof having agonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V3, comprises the following sequence:

[0314] HSHGTFTSDVSRIKDKQRQKEFADWLRAQGPPSGRPPPR (SEQ ID NO: 62).

[0315] In embodiments, the SL_TriAg_V3 or a derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V3 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 62. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to an amino acid sequence of SEQ ID NO: 62.

[0316] In embodiments, the isolated polynucleotide encodes a peptide or a derivative thereof having agonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V4, comprises the following sequence:

[0317] HGHGTFTSDSSHGREEQRQREFGEWLGAGGPSTAKPPPK (SEQ ID NO: 63). In embodiments, the SL_TriAg_V4 or a derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V4 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 63. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 63.

[0318] In embodiments, the isolated polynucleotide encodes a peptide or a derivative thereof having agonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V1_Pro3, comprises the following sequence:

[0319] HSPGTFTSDFSLALDKQRQAEFIDWLRAGGPPSGRPPPR (SEQ ID NO: 64).

[0320] In embodiments, the SL_Tri Ag_V1 _Pro3 or a derivative thereof has dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V1_Pro3 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 64. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 64.

[0321] In embodiments, the isolated polynucleotide encodes a peptide or a derivative thereof having agonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V2_Pro3, comprises the following sequence:

[0322] HGPGTFTSDISVAIEEQRQQEFLEWLGAAGPSTAKPPPK (SEQ ID NO: 65).

[0323] In embodiments, the SL_TriAg_V2_Pro3 or a derivative thereof has dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V2_Pro3 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 65. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 65.

[0324] In embodiments, the isolated polynucleotide encodes a peptide or a derivative thereof having agonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V3_Pro3, comprises the following sequence:

[0325] HSPGTFTSDVSRIKDKQRQKEFADWLRAQGPPSGRPPPR (SEQ ID NO: 66).

[0326] In embodiments, the SL_TriAg_V3_Pro3 or a derivative thereof has dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V3_Pro3 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 66. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 66.

[0327] In embodiments, the isolated polynucleotide encodes a peptide or a derivative thereof having agonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, which is also referred to herein as SL_TriAg_V4_Pro3, comprises the following sequence:

[0328] HGPGTFTSDSSHGREEQRQREFGEWLGAGGPSTAKPPPK (SEQ ID NO: 67)

[0329] In embodiments, the SL_TriAg_V4_Pro3 or a derivative thereof has dual, triple or quadruple actions on GLP- 1 R, GLP-2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR is a variant of SL_TriAg_V4_Pro3 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 67. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 67. In embodiments, the peptide or the derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, which is also referred to herein as SL-045, comprises the following sequence:

[0330] HSHGTFTSDFSLALDKQRQAEFIDWLKAAGPPSAKPPPK (SEQ ID NO: 68)

[0331] In embodiments, the SL-045 or a derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP- 2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR is a variant of SL-045 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 68. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP- 2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 68.

[0332] In embodiments, the peptide or the derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, which is also referred to herein as SL-044, comprises the following sequence:

[0333] HSHGTFTSDFSLALDKQRQAEFIDWLGAAGPSTAKPPPK (SEQ ID NO: 69)

[0334] In embodiments, the SL-044 or a derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP- 2R, GIPR, and GCGR. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR is a variant of SL-044 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 69. In embodiments, the peptide having dual, triple or quadruple actions on GLP-1 R, GLP- 2R, GIPR, and GCGR has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 69.

[0335] In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60 to 69. In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60 to 69, or a variant thereof having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations with respect to an amino acid sequence selected from SEQ ID NOs: 60 to 69. In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 68 and SEQ ID NO: 69, or a variant thereof having 1 or 2 amino acid mutations with respect to an amino acid sequence selected from SEQ ID NOs: 60, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 68 and SEQ ID NO: 69. In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 68 and SEQ ID NO: 69.

[0336] In aspects, the present disclosure provides an isolated polynucleotide encoding a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60 to 69. In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60 to 69, or a variant thereof having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations with respect to an amino acid sequence selected from SEQ ID NOs: 60 to 69.

[0337] In aspects, the present disclosure provides an isolated polynucleotide encoding a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0338] HSHGTFTSDFSLALDKQRQAEFIDWLRAGGPPSGRPPPR (SEQ ID NO: 68).

[0339] In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof is a variant of SEQ ID NO: 68 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 68. In embodiments, the isolated polynucleotide encodes the peptide the peptide or the derivative thereof that has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 68.

[0340] In aspects, the present disclosure provides an isolated polynucleotide encoding a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof: HGHGTFTSDISVAIEEQRQQEFLEWLGAAGPSTAKPPPK (SEQ ID NO: 61).

[0341] In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof is a variant of SEQ ID NO: 61 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 61 . In embodiments, the isolated polynucleotide encodes the peptide the peptide or the derivative thereof that has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 61.

[0342] In aspects, the present disclosure provides an isolated polynucleotide encoding a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0343] HSHGTFTSDVSRIKDKQRQKEFADWLRAQGPPSGRPPPR (SEQ ID NO: 62).

[0344] In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof is a variant of SEQ ID NO: 62 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 62. In embodiments, the isolated polynucleotide encodes the peptide the peptide or the derivative thereof that has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 62.

[0345] In aspects, the present disclosure provides an isolated polynucleotide encoding a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0346] HGHGTFTSDSSHGREEQRQREFGEWLGAGGPSTAKPPPK (SEQ ID NO: 63).

[0347] In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof is a variant of SEQ ID NO: 63 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 63. In embodiments, the isolated polynucleotide encodes the peptide the peptide or the derivative thereof that has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 63.

[0348] In aspects, the present disclosure provides an isolated polynucleotide encoding a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0349] HSPGTFTSDFSLALDKQRQAEFIDWLRAGGPPSGRPPPR (SEQ ID NO: 64).

[0350] In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof is a variant of SEQ ID NO: 64 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 64. In embodiments, the isolated polynucleotide encodes the peptide the peptide or the derivative thereof that has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 64.

[0351] In aspects, the present disclosure provides an isolated polynucleotide encoding a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0352] HGPGTFTSDISVAIEEQRQQEFLEWLGAAGPSTAKPPPK (SEQ ID NO: 65).

[0353] In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof is a variant of SEQ ID NO: 65 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 65. In embodiments, the isolated polynucleotide encodes the peptide the peptide or the derivative thereof that has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 65.

[0354] In aspects, the present disclosure provides an isolated polynucleotide encoding a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0355] HSPGTFTSDVSRIKDKQRQKEFADWLRAQGPPSGRPPPR (SEQ ID NO: 66). In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof is a variant of SEQ ID NO: 66 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 66. In embodiments, the isolated polynucleotide encodes the peptide the peptide or the derivative thereof that has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 66.

[0356] In aspects, the present disclosure provides an isolated polynucleotide encoding a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0357] HGPGTFTSDSSHGREEQRQREFGEWLGAGGPSTAKPPPK (SEQ ID NO: 67)

[0358] In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof is a variant of SEQ ID NO: 67 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 67. In embodiments, the isolated polynucleotide encodes the peptide the peptide or the derivative thereof that has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 67.

[0359] In aspects, the present disclosure provides an isolated polynucleotide encoding a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0360] HSHGTFTSDFSLALDKQRQAEFIDWLKAAGPPSAKPPPK (SEQ ID NO: 68)

[0361] In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof is a variant of SEQ ID NO: 68 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 68. In embodiments, the isolated polynucleotide encodes the peptide the peptide or the derivative thereof that has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 68. In aspects, the present disclosure provides an isolated polynucleotide encoding a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises the following sequence, or a variant thereof:

[0362] HSHGTFTSDFSLALDKQRQAEFIDWLGAAGPSTAKPPPK (SEQ ID NO: 69)

[0363] In embodiments, the isolated polynucleotide encodes the peptide or the derivative thereof is a variant of SEQ ID NO: 69 having one or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 69. In embodiments, the isolated polynucleotide encodes the peptide the peptide or the derivative thereof that has a dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR, and has an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NO: 69.

[0364] In aspects, the present disclosure provides an isolated polynucleotide encoding a fusion protein comprising a carrier protein joined, optionally via a linker, to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon of any of the embodiments disclosed herein. In embodiments, the peptide comprises a general formula (I):

[0365] N-L1-[Aaa]1-[Aaa]2-[Aaa]3-Gly-Thr-Phe-Thr-Ser-Asp-[Aaa]4-Ser-[Aaa]5-[Aaa]6-[Aaa]7-[Aaa]8- [Aaa]9-[Aaa]10-[Aaa]11-[Aaa]12-[Aaa]13-[Aaa]14-Phe-[Aaa]15-[Aaa]16-[Aaa]17-Leu-[Aaa]18- [Aaa]19-[Aaa]20-Gly-Pro-[Aaa]21-[Aaa]22-[Aaa]23-[Aaa]24-Pro-Pro-Pro-[Aaa]25-L2-C

[0366] (I) wherein N is the N-terminus; one of L1 or L2 is present the carrier protein, and the other is a tag, and a polymer, optionally wherein the L1 and / or L2 further comprise a linker that adjoins the carrier protein, tag, or polymer with the peptide; [Aaa] 1 is His; [Aaa]2 is Ser or Gly; [Aaa]3 is His or Pro; [Aaa]4 is Phe or lie; [Aaa]5 is Leu or Vai; [Aaa]6 is Ala; [Aaa]7 is Leu or lie; [Aaa]8 is Asp or Glu; [Aaa]9 is Lys or Glu; [Aaa]10 is Gin; [Aaa] 11 is Arg; [Aaa]12 is Gin; [Aaa]13 is Ala or Gin; [Aaa] 14 is Glu; [Aaa]15 is lie or Leu; [Aaa]16 is Asp or Glu; [Aaa]17 is Trp; [Aaa]18 is Arg or Gly; [Aaa]19 is Ala; [Aaa]20 is Gly or Ala; [Aaa]21 is Pro or Ser; [Aaa]22 is Ser or Thr; [Aaa]23 is Gly or Ala; [Aaa]24 is Arg or Lys; [Aaa]25 is Arg or Lys; and C is the C-terminus. In embodiments, the peptide or the derivative thereof has dual, triple or quadruple actions on GLP-1 R, GLP- 2R, GIPR, and GCGR. In embodiments, the carrier protein is selected from Fc domain, albumin, transferrin, or elastin-like protein, Keyhole Limpet Hemocyanin (KLH), ovalbulin, or a variant thereof. In embodiments, the carrier protein is a hinge CH2-CH3-Fc domain. In embodiments, the a hinge CH2-CH3-Fc domain is derived from I gG1 or lgG4 (e.g., human lgG1 or lgG4).

[0367] In aspects, the present disclosure provides an isolated polynucleotide encoding a fusion protein comprising a carrier protein joined, optionally via a linker, to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon of any of the embodiments disclosed herein. In embodiments, the peptide comprises a general formula (II):

[0368] N-L1-[Aaa]1-[Aaa]2-[Aaa]3-Gly-Thr-Phe-Thr-Ser-Asp-[Aaa]4-Ser-[Aaa]5-[Aaa]6-[Aaa]7-[Aaa]8- [Aaa]9-[Aaa]10-[Aaa]11-[Aaa]12-[Aaa]13-[Aaa]14-Phe-[Aaa]15-[Aaa]16-[Aaa]17-Leu-[Aaa]18- [Aaa]19-[Aaa]20-Gly-Pro-[Aaa]21-[Aaa]22-[Aaa]23-[Aaa]24-Pro-Pro-Pro-[Aaa]25-L2-C

[0369] (II) wherein N is the N-terminus; one of L1 or L2 is present the carrier protein, and the other is a tag, and a polymer, optionally wherein the L1 and / or L2 further comprise a linker that adjoins the carrier protein, tag, or polymer with the peptide; [Aaa] 1 is a positively charged amino acid residue selected from His, Lys, and Arg; [Aaa]2 is a polar and neutral of charge hydrophilic amino acid selected from Ser, Asn, Gin, Thr, and Pro, or a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]3 is a positively charged amino acid residue selected from His, Lys, and Arg, or a polar and neutral of charge hydrophilic amino acid selected from Pro Ser, Asn, Gin, and Thr; [Aaa]4 is a, hydrophobic, aromatic amino acid selected from Phe, Trp, and Tyr, or a hydrophobic, aliphatic amino acid selected from lie, Gly, Ala, Leu, Met, and Vai; [Aaa]5 is a hydrophobic, aliphatic amino acid selected from Leu, Vai, lie, Gly, Ala, and Met; [Aaa]6 is a hydrophobic, aliphatic amino acid selected from Ala, Gly, Vai, lie, Leu, and Met; [Aaa]7 is a hydrophobic, aliphatic amino acid selected from Leu, lie, Vai, Gly, Ala, and Met; [Aaa]8 is a polar and negatively charged hydrophilic amino acid selected from Asp and Glu; [Aaa]9 is a polar and positively charged hydrophilic amino acid selected from Lys, His, and Arg, or a polar and negatively charged hydrophilic amino acid selected from Glu, and Asp; [Aaa] 10 is a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa]11 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; [Aaa]12 is a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa] 13 is a hydrophobic, aliphatic amino acid selected from Ala, Vai, Gly, Leu, lie, and Met, or a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro; [Aaa]14 is a polar and negatively charged hydrophilic amino acid selected from Glu, and Asp; [Aaa] 15 is a hydrophobic, aliphatic amino acid selected from lie, Leu, Vai, Ala, Gly, and Met; [Aaa]16 is a polar and negatively charged hydrophilic amino acid selected from Asp, and Glu; [Aaa]17 is hydrophobic, aromatic amino acid selected from Trp, Phe, and Tyr; [Aaa]18 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His, or a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]19 is a hydrophobic, aliphatic amino acid selected from Ala, Gly, Vai, Leu, lie, and Met; [Aaa] 20 is a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]21 is a polar and neutral of charge hydrophilic amino acid selected from Pro, Ser, Gin, Asn, and Thr; [Aaa]22 is a polar and neutral of charge hydrophilic amino acid selected from Ser, Thr, Gin, Asn, and Pro; [Aaa]23 a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met; [Aaa]24 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; [Aaa]25 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; and C is the C-terminus. In embodiments, the peptide or the derivative thereof present in the fusion protein has dual, triple or quadruple actions on GLP-1 R, GLP-2R, GIPR, and GCGR. In embodiments, the carrier protein is selected from Fc domain, albumin, transferrin, or elastin-like protein, Keyhole Limpet Hemocyanin (KLH), ovalbulin, or a variant thereof. In embodiments, the carrier protein is a hinge CH2-CH3-Fc domain. In embodiments, the a hinge CH2-CH3-Fc domain is derived from lgG1 or lgG4 (e.g., human I gG1 or I gG4)

[0370] In embodiments, [Aaa]1 is His. In embodiments, [Aaa]2 is Ser or Gly. In embodiments, [Aaa]3 is His or Pro.

[0371] In embodiments, [Aaa]4 is Phe or lie. In embodiments, [Aaa]5 is Leu or Vai. In embodiments, [Aaa]6 is Ala.

[0372] In embodiments, [Aaa]7 is Leu or lie. In embodiments, [Aaa]8 is Asp or Glu. In embodiments, [Aaa]9 is Lys or Glu. In embodiments, [Aaa]10 is Gin. In embodiments, [Aaa]11 is Arg. In embodiments, [Aaa]12 is Gin. In embodiments, [Aaa]13 is Ala or Gin. In embodiments, [Aaa]14 is Glu. In embodiments, [Aaa]15 is lie or Leu. In embodiments, [Aaa]16 is Asp or Glu. In embodiments, [Aaa]17 is Trp. In embodiments, [Aaa] 18 is Arg or Gly. In embodiments, [Aaa]19 is Ala. In embodiments, [Aaa]20 is Gly or Ala. In embodiments, [Aaa]21 is Pro or Ser. In embodiments, [Aaa]22 is Ser or Thr. In embodiments, [Aaa]23 is Gly or Ala. In embodiments, [Aaa]24 is Arg or Lys. In embodiments, and / or [Aaa]25 is Arg or Lys.

[0373] In embodiments, the peptide or the derivative thereof present in the fusion protein comprises any 2 of, or any 3 of, or any 4 of, or any 5 of, or any 6 of, or any 7 of, or any 8 of, or any 9 of, or any 10 of, or any 11 of, or any 12 of, or any 13 of, or any 14 of, or any 15 of, or any 16 of, or any 17 of, or any 18 of, or any 19 of, or any 20 of, or any 21 of, or any 22 of, or any 23 of, or any 24 of, or all 25 of the following:

[0374] (1) [Aaa]1 is His;

[0375] (2) [Aaa]2 is Ser or Gly; (3) [Aaa]3 is His or Pro;

[0376] (4) [Aaa]4 is Phe or lie;

[0377] (5) [Aaa]5 is Leu or Vai;

[0378] (6) [Aaa]6 is Ala;

[0379] (7) [Aaa]7 is Leu or lie;

[0380] (8) [Aaa]8 is Asp or Glu;

[0381] (9) [Aaa]9 is Lys or Glu;

[0382] (10) [Aaa]10 is Gin;

[0383] (11) [Aaa]11 is Arg;

[0384] (12) [Aaa]12 is Gin;

[0385] (13) [Aaa]13 is Ala or Gin;

[0386] (14) [Aaa]14 is Glu;

[0387] (15) [Aaa]15 is lie or Leu;

[0388] (16) [Aaa]16 is Asp or Glu;

[0389] (17) [Aaa]17 is Trp;

[0390] (18) [Aaa]18 is Arg or Gly;

[0391] (19) [Aaa]19 is Ala;

[0392] (20) [Aaa]20 is Gly or Ala;

[0393] (21) [Aaa]21 is Pro or Ser;

[0394] (22) [Aaa]22 is Ser or Thr;

[0395] (23) [Aaa]23 is Gly or Ala; and

[0396] (24) [Aaa]24 is Arg or Lys; and / or

[0397] (25) [Aaa]25 is Arg or Lys.

[0398] In embodiments, [Aaa] 1 is His, [Aaa]2 is Ser or Gly; [Aaa]3 is His or Pro; [Aaa]4 is Phe or lie; [Aaa]5 is Leu or Vai; [Aaa]6 is Ala; [Aaa]7 is Leu or lie; [Aaa]8 is Asp or Glu; [Aaa]9 is Lys or Glu; [Aaa]10 is Gin; [Aaa]11 is Arg; [Aaa]12 is Gin; [Aaa]13 is Ala or Gin; [Aaa]14 is Glu; [Aaa]15 is lie or Leu; [Aaa]16 is Asp or Glu; [Aaa] 17 is Trp; [Aaa]18 is Arg or Gly; [Aaa]19 is Ala; [Aaa]20 is Gly or Ala; [Aaa]21 is Pro or Ser; [Aaa]22 is Ser or Thr; [Aaa]23 is Gly or Ala; [Aaa]24 is Arg or Lys; and [Aaa]25 is Arg or Lys.

[0399] In aspects, the present disclosure provides an isolated polynucleotide encoding a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence selected from SEQ ID NOs: 60 to 69, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NOs: 60 to 69. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1 , 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0400] In aspects, the present disclosure provides an isolated polynucleotide encoding a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 60, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 60. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1, 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53. In aspects, the present disclosure provides an isolated polynucleotide encoding a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 61 , or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO:

[0401] 61. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1, 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0402] In aspects, the present disclosure provides an isolated polynucleotide encoding a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 62, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO:

[0403] 62. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1, 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0404] In aspects, the present disclosure provides an isolated polynucleotide encoding a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 63, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO:

[0405] 63. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1, 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0406] In aspects, the present disclosure provides an isolated polynucleotide encoding a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 64, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO:

[0407] 64. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1, 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0408] In aspects, the present disclosure provides an isolated polynucleotide encoding a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 65, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO:

[0409] 65. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1, 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0410] In aspects, the present disclosure provides an isolated polynucleotide encoding a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 66, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO:

[0411] 66. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1, 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0412] In aspects, the present disclosure provides an isolated polynucleotide encoding a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 67, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO:

[0413] 67. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1, 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53. In aspects, the present disclosure provides an isolated polynucleotide encoding a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 68, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO:

[0414] 68. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1, 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0415] In aspects, the present disclosure provides an isolated polynucleotide encoding a fusion protein comprising a hinge CH2-CH3-Fc domain fused via a linker to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 69, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO:

[0416] 69. In embodiments, the hinge CH2-CH3-Fc domain comprises an amino acid sequence that at least 95% sequence identical to the amino acid sequence of one of SEQ ID NOs: 1-4. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53, or an amino acid sequence having about 1, 2, 3 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence of SEQ ID NOs: 5-53. In embodiments, the linker has an amino acid sequence selected from the amino acid sequences of SEQ ID NOs: 5-53.

[0417] In embodiments, the isolated polynucleotide is RNA, optionally, an mRNA. In embodiments, the isolated polynucleotide is codon optimized.

[0418] In embodiments, the isolated polynucleotide is mRNA or a modified mRNA (mmRNA). In embodiments, the polypeptide includes a polynucleotide modification including, but not limited to, a nucleoside modification. In embodiments, the isolated polynucleotide is an mmRNA. In embodiments, the mmRNA comprises one or more nucleoside modifications. In embodiments, the nucleoside modifications are selected from pyridin-4- one ribonucleoside, 5-aza-uridine, 2-thio-5-aza-uridine, 2-thiouridine, pseudouridine, 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxyuridine, 3-methyluridine, 5-carboxymethyl-uridine, 1 -carboxymethylpseudouridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyluridine, 1-taurinomethyl- pseudouridine, 5-taurinomethyl-2-thio-uridine, 1 -taurinomethyl-4-thio-uridine, 5-methyl-uridine, 1-methyl- pseudouridine, 4-thio-1-methyl-pseudouridine, 2-thio-1 -methyl-pseudouridine, 1 -methyl- 1 -deazapseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio- dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy- pseudouridine, 4-methoxy-2-thio-pseudouridine, 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4- acetylcytidine, 5-formylcytidine, N4-methylcytidine, 5-hydroxymethylcytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio- pseudoisocytidine, 4-thio-1-methyl-pseudoisocytidine, 4-thio-1-methyl-1-deaza-pseudoisocytidine, 1-methyl- 1 -deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl-zebularine, 5-aza-2-thio-zebularine, 2- thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl-cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy- 1 -methyl-pseudoisocytidine, 2-aminopurine, 2, 6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-aminopurine, 7-deaza-8-aza-2-aminopurine, 7-deaza-2, 6-diaminopurine, 7-deaza-8-aza-2,6- diaminopurine, 1 -methyladenosine, N6-methyladenosine, N6-isopentenyladenosine, N6-(cis- hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine, N6- glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosine, 2-methylthio-N6-threonyl carbamoyladenosine, N6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, and 2-methoxy- adenine, inosine, 1 -methyl-inosine, wyosine, wybutosine, 7-deaza-guanosine, 7-deaza-8-aza-guanosine, 6- thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyl-guanosine, 6-thio-7- methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1 -methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosine, 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2- methyl-6-thio-guanosine, and N2,N2-dimethyl-6-thio-guanosine, and combinations thereof.

[0419] In embodiments, the polypeptide the at least one chemically modified nucleoside is selected from pseudouridine ('+’), N1 -methylpseudouridine (m1l), 2-thiouridine (s2U), 4’ -thiouridine, 5-methylcytosine, 2- th io- 1 -methyl- 1 -deaza-pseudouridine, 2-thio- 1 -methyl-pseudouridine, 2-th io-5-aza-uridi ne, 2-thio- dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4- methoxy-pseudouridine, 4-thio-1 -methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5-methoxyuridine, 2’-O-methyl uridine, 1-methyl-pseudouridine (m14J), 5-methoxy-uridine (mo5U), 5-methyl-cytidine (m5C), .alpha.-thio-guanosine, .alpha.-thio-adenosine, 5-cyano uridine, 4’-thio uridine 7-deaza-adenine, 1-methyl-adenosine (m1A), 2-methyl-adenine (m2A), N6- methyl-adenosine (m6A), and 2,6-Diaminopurine, (I), 1-methylinosine (ml I), wyosine (imG), methylwyosine (mimG), 7-deaza-guanosine, 7-cyano-7-deaza-guanosine (preQO), 7-aminomethyl-7-deaza-guanosine (preQ1), 7-methyl-guanosine (m7G), 1-methyl-guanosine (m1G), 8-oxo-guanosine, 7-methyl-8-oxo- guanosine, and two or more combinations thereof.

[0420] In embodiments, the mmRNA does not cause a substantial induction of the innate immune response of a cell into which the mmRNA is introduced. In embodiments, the modification in the mmRNA enhance one or more of the efficiency of production of the peptide or the derivative thereof , intracellular retention of the mmRNA, and viability of contacted cells, and possess reduced immunogenicity.

[0421] In embodiments, the mmRNA has a length sufficient to include an open reading frame encoding the peptide or the derivative thereof of the present disclosure.

[0422] Modified mRNAs need not be uniformly modified along the entire length of the molecule. Different nucleotide modifications and / or backbone structures may exist at various positions in the nucleic acid. One of ordinary skill in the art will appreciate that the nucleotide analogs or other modification(s) may be located at any position(s) of a nucleic acid such that the function of the nucleic acid is not substantially decreased. A modification may also be a 5' or 3' terminal modification. The nucleic acids may contain at a minimum one and at maximum 100% modified nucleotides, or any intervening percentage, such as at least about 50% modified nucleotides, at least about 80% modified nucleotides, or at least about 90% modified nucleotides.

[0423] In embodiments, the mmRNAs may contain a modified pyrimidine such as uracil or cytosine. In embodiments, at least about 5%, at least about 10%, at least about 25%, at least about 50%, In embodiments, the modified uracil may be replaced by a compound having a single unique structure or can be replaced by a plurality of compounds having different structures disclosed above (e.g., same mmRNA may contain 2, 3, 4 or more types of uniquely modified uracil). In embodiments, at least about 5%, at least about 10%, at least about 25%, at least about 50%, at least about 80%, at least about 90% or 100% of the cytosine in the nucleic acid may be replaced with a modified cytosine. The modified cytosine can be replaced by a compound having a single unique structure or can be replaced by a plurality of compounds having different structures disclosed above (e.g., same mmRNA may contain 2, 3, 4 or more types of uniquely modified cytosine). In embodiments, the mmRNA comprises at least one chemically modified nucleoside. In embodiments, wherein the at least one chemically modified nucleoside is selected from pseudouridine (1), N1- methylpseudouridine (ml ), 2-thiouridine (s2U), 4’-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1 -deazapseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio- dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1- methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5- methoxyuridine, 2’-O-methyl uridine, 1-methyl-pseudouridine (ml ), 5-methoxy-uridine (mo5U), 5-methyl- cytidine (m5C), .alpha. -thio-guanosine, .alpha.-thio-adenosine, 5-cyano uridine, 4’-thio uridine 7-deaza- adenine, 1-methyl-adenosine (m1A), 2-methyl-adenine (m2A), N6-methyl-adenosine (m6A), and 2,6- Diaminopurine, (I), 1-methylinosine (ml I), wyosine (imG), methylwyosine (mimG), 7-deaza-guanosine, 7- cyano-7-deaza-guanosine (preQO), 7-aminomethyl-7-deaza-guanosine (preQ1), 7-methyl-guanosine (m7G),

[0424] 1-methyl-guanosine (m1G), 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, and two or more combinations thereof. In embodiments, the mmRNA comprises at least one chemically modified nucleoside, wherein the at least one chemically modified nucleoside is selected from pseudouridine, N1 -methylpseudouridine, 5- methylcytosine, 5-methoxyuridine, and a combination thereof. In embodiments, the mmRNA comprises at least one chemically modified nucleoside is N1 -methylpseudouridine. In embodiments, the mmRNA is fully modified with chemically-modified uridines. In embodiments, the mmRNA is a fully modified N1- methylpseudouridine mRNA. Additional chemical modifications are disclosed in US Patent Application Publication No. 20190111003, the entire contents of which are hereby incorporated by reference.

[0425] In embodiments, modified nucleosides include pyridin-4-one ribonucleoside, 5-aza-uridine, 2-thio-5-aza- uridine, 2-thiouridine, pseudouridine, 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxyuridine, 3- methyluridine, 5-carboxymethyl-uridine, 1 -carboxymethyl-pseudouridine, 5-propynyl-uridine, 1-propynyl- pseudouridine, 5-taurinomethyluridine, 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine, 1- taurinomethyl-4-thio-uridine, 5-methyl-uridine, 1-methyl-pseudouridine, 4-thio-1-methyl-pseudouridine, 2- thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxyuridine,

[0426] 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, and 4-methoxy-2-thio-pseudouridine. In embodiments, modified nucleosides include 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine, 5- formylcytidine, N4-methylcytidine, 5-hydroxymethylcytidine, 1 -methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio-pseudoisocytidine, 4-thio-1- methyl-pseudoisocytidine, 4-thio-1-methyl-1-deaza-pseudoisocytidine, 1 -methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy- cytidine, 2-methoxy-5-methyl-cytidine, 4-methoxy-pseudoisocytidine, and 4-methoxy-1-methyl- pseudoisocytidine.

[0427] In embodiments, modified nucleosides include 2-aminopurine, 2, 6-diaminopurine, 7-deaza-adenine, 7- deaza-8-aza-adenine, 7-deaza-2-aminopurine, 7-deaza-8-aza- 2-aminopurine, 7-deaza-2, 6-diaminopurine, 7-deaza-8-aza-2, 6-diaminopurine, 1 -methyladenosine, N6-methyladenosine, N6-isopentenyladenosine, N6- (cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine, N6- glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosine, 2-methylthio-N6-threonyl carbamoyladenosine, N6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, and 2-methoxy- adenine.

[0428] In embodiments, modified nucleosides include inosine, 1-methyl-inosine, wyosine, wybutosine, 7-deaza- guanosine, 7-deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza- guanosine, 7-methyl-guanosine, 6-thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1- methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosine, 8-oxo-guanosine, 7-methyl-8-oxo- guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, and N2,N2-dimethyl-6-thio-guanosine.

[0429] In embodiments, the nucleotide can be modified on the major groove face and can include replacing hydrogen on C-5 of uracil with a methyl group or a halo group.

[0430] In embodiments, a modified nucleoside is 5'-0-(1-Thiophosphate)-Adenosine, 5'-O-(1 -Thiophosphate)- Cytidine, 5'-O-(1-Thiophosphate)-Guanosine, 5'-O-(1-Thiophosphate)-Uridine or 5'-O-(1-Thiophosphate)- Pseudouridine.

[0431] Further examples of modified nucleotides and modified nucleotide combinations are disclosed in US Patent Nos. 8,710,200; 8,822,663; 8,999,380; 9,181,319; 9,254,311; 9,334,328; 9,464,124; 9,950,068; 10,626,400; 10,808,242; 11,020,477, and US Patent Application Publication Nos. 20220001026, 20210318817, 20210283262, 20200360481, 20200113844, 20200085758, 20170204152, 20190114089, 20190114090, 20180369374, 20180318385, 20190111003, and PCT International Application Publication Nos. WO / 2017112943, WO 2014 / 028429, WO 2017 / 201325 the entire contents of which are hereby incorporated by reference. The methods for synthesizing the modified mRNA are disclosed, e.g., in US Patent Application Publication Nos. 20170204152, the entire contents of which are hereby incorporated by reference. In embodiments, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% of the cytosine residues of the mmRNA are replaced by modified cytosine residues. In embodiments, at least 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% of the uracil residues of the mmRNA are replaced by modified uracil residues.

[0432] In embodiments, the mmRNA further comprises a 5' untranslated region (UTR) and / or a 3'UTR, wherein either or both may independently contain one or more different nucleoside modifications. In such embodiments, nucleoside modifications may also be present in the translatable region. In embodiments, the mmRNA further comprises a Kozak sequence. In embodiments, the mmRNA further comprises a internal ribosome entry site (IRES).

[0433] In embodiments, the mmRNA further comprises a 5'-cap and / or a poly A tail.

[0434] In embodiments, the 5'-cap contains a 5'-5'-triphosphate linkage between the 5'-most nucleotide and guanine nucleotide. In embodiments, the 5'-cap comprises a methylation of the ultimate and penultimate most 5'- nucleotides on the 2'-hydroxyl group. In embodiments, the 5'-cap facilitates binding the mRNA Cap Binding Protein (CBP), confers mRNA stability in the cell and / or confers translation competency.

[0435] In embodiments, the poly-A tail is greater than about 30 nucleotides, or greater than about 40 nucleotides in length. In embodiments, the poly-A tail at least about 40 nucleotides, or at least about 45 nucleotides, or at least about 55 nucleotides, or at least about 60 nucleotides, or at least about 80 nucleotides, or at least about 90 nucleotides, or at least about 100 nucleotides, or at least about 120 nucleotides, or at least about 140 nucleotides, or at least about 160 nucleotides, or at least about 180 nucleotides, or at least about 200 nucleotides, or at least about 250 nucleotides, or at least about 300 nucleotides, or at least about 350 nucleotides, or at least about 400 nucleotides, or at least about 450 nucleotides, or at least about 500 nucleotides, or at least about 600 nucleotides, or at least about 700 nucleotides, or at least about 800 nucleotides, or at least about 900 nucleotides, or at least about 1000 nucleotides in length.

[0436] In embodiments, the mmRNA comprises a 3’ untranslated region (UTR). In embodiments, the 3’ UTR comprises a nucleic acid sequence at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a sequence listed in Table 4 of US Patent Application Publication No. 20190114089, which is incorporated herein in its entirety. In embodiments, the 3’ UTR comprises at least one microRNA-122 (miR-122) binding site, wherein the miR-122 binding site is a miR-122-3p binding site or a miR-122-5-binding site. In embodiments, the mmRNA comprises a nucleic acid sequence comprising a miRNA binding site. In some embodiments, the miRNA binding site binds to miR-122. In a particular embodiment, the miRNA binding site binds to miR-122-3p or miR-122-5p. In embodiments, the mmRNA comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten miRNA binding sites.

[0437] In embodiments, the miRNA binding site is inserted within the 3’ UTR. In embodiments, the isolated polynucleotide is DNA. In embodiments, the further comprises a spacer sequence between the open reading frame and the miRNA binding site. In aspects, the spacer sequence comprises at least about 10 nucleotides, at least about 20 nucleotides, at least about 30 nucleotides, at least about 40 nucleotides, at least about 50 nucleotides, at least about 60 nucleotides, at least about 70 nucleotides, at least about 80 nucleotides, at least about 90 nucleotides, or at least about 100 nucleotides.

[0438] In embodiments, the mmRNA further comprises a 5’ UTR. In embodiments, the 5’ UTR comprises a nucleic acid sequence at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a sequence listed in Table 3 of US Patent Application Publication No. 20190114089, or a sequence disclosed in PCT International Application Publication Nos. WO 2017 / 201325 and WO 2014 / 164253, each of which is incorporated herein in its entirety. In embodiments, the 5’ UTR bears features, which play roles in translation initiation. In embodiments, the 5’ UTR harbors signatures like Kozak sequences which are commonly known to be involved in the process by which the ribosome initiates translation of many genes. In embodiments, the 5’ UTR forms secondary structures which are involved in elongation factor binding. In embodiments, the 5’ UTR of mRNA known to be upregulated in cancers, such as c-myc, may be used to enhance expression of a nucleic acid molecule, such as a polynucleotides, in cancer cells. In embodiments, the 5’ UTR of mRNA known to be upregulated in liver and / or spleen may be used to enhance expression of a nucleic acid molecule, such as a polynucleotides, in liver and / or spleen.

[0439] In embodiments, at least one of the regions of linked nucleosides of A comprises a sequence of linked nucleosides which functions as a 5’ UTR and at least one of the regions of linked nucleosides of C comprises a sequence of linked nucleosides which functions as a 3’ UTR. In embodiments, the 5’ UTR and the 3’ UTR are from the same or different species. In embodiments, the 5’ UTR and the 3’ UTR may be the native untranslated regions from different proteins from the same or different species. In embodiments, the 5’ UTR and the 3’ UTR may have synthetic sequences.

[0440] In embodiments, the mmRNA further comprises a 3’ polyadenylation (polyA tail).

[0441] In embodiments, the mmRNA further comprises a 5’ terminal cap. In embodiments, the 5’ terminal cap is a CapO, Cap1 , ARCA, inosine, N1-methyl-guanosine, 2’fluoro-guanosine, 7-deaza-guanosine, 8-oxo- guanosine, 2-amino-guanosine, LNA-guanosine, 2-azidoguanosine, Cap2, Cap4, 5’ methylG cap, or an analog thereof.

[0442] In embodiments, the isolated polynucleotide is in vitro transcribed (IVT). In embodiments, the isolated polynucleotide is chimeric. In embodiments, the isolated polynucleotide is circular.

[0443] In embodiments, the isolated polynucleotide is or comprises DNA. In embodiments, the isolated polynucleotide is or comprises a minicircle or a plasmid DNA. In embodiments, the plasmid DNA is devoid of any prokaryotic components. In embodiments, the isolated polynucleotide comprises a tissue-specific control element. In embodiments, the tissue-specific control element is a promoter or an enhancer. In embodiments, the plasmid DNA is an expression vector. In embodiments, the DNA is or comprises a minicircle. In embodiments, the minicircle is a circular molecule, which is optionally small. In embodiments, the minicircle utilizes a cellular transcription and translation machinery to produce an encoded gene product. In embodiments, the minicircle is devoid of any prokaryotic components. In embodiments, the minicircle only comprises substantially only sequences of mammalian origin (or those that have been optimized for mammalian cells). In embodiments, the minicircle lacks or has reduced amount of DNA sequence elements that are recognized by the innate immune system and / or toll-like receptors. In embodiments, the minicircle is produced by excising any bacterial components of from a parental plasmid, thereby making it smaller than a parental DNA sequence. In embodiments, the minicircle is of non-viral origin. In embodiments, the minicircle remains episomal. In embodiments, the minicircle does not replicate with a host cell. In embodiments, expression of the peptide or the derivative thereof in non-dividing cells harboring a minicircle lasts for at least 2 days, or at least 4 days, or at least 6 days, or at least 8 days, or at least 10 days, or at least 12 days, or at least 14 days, or at least 16 days, or at least 18 days, or at least 20 days, or at least 22 days, or at least 24 days, or longer in dividing cells. In embodiments, expression of the peptide or the derivative thereof in nondividing cells harboring a minicircle lasts for at least 4 days, or at least 6 days, or at least 8 days, or at least 10 days, or at least 1 week, or at least 2 weeks, or at least 3 weeks, or at least 4 weeks, or at least 5 weeks, or at least 6 weeks, or at least 1 month, or at least 2 months, or at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 8 months, or longer in dividing cells.

[0444] In embodiments, the mmRNAs of the present disclosure are produced by means available in the art, including but not limited to in vitro transcription (IVT) and synthetic methods. Enzymatic IVT, solid-phase, liquid-phase, combined synthetic methods, small region synthesis, and ligation methods may be utilized. In embodiments, mmRNAs are made using IVT enzymatic synthesis methods. Methods of making polynucleotides by IVT are known in the art and are described in International Application PCT International Patent Publication No. WO2013151666, the contents of which are incorporated herein by reference in their entirety. Accordingly, the present disclosure also includes polynucleotides, e.g., DNA, constructs and vectors that may be used to in vitro transcribe an mRNA described herein.

[0445] In embodiments, the isolated polynucleotide is DNA. In embodiments, the isolated polynucleotide comprises a liver-specific control element. In embodiments, the liver-specific control element is a liver-specific promoter selected from albumin promoter, thyroxine-binding globulin (TBG) promoter, hybrid liver-specific promoter (HLP), human a 1 -antitrypsin promoter, LP1 promoter, and hemopexin promoter. The gene therapy in accordance with the present disclosure can be performed using vector systems. In embodiments, the liverspecific promoter is an LP1 promoter. The LP1 promoter can be a human LP1 promoter, which can be constructed as described, e.g., in Nathwani et al. Blood vol. 107(7) (2006):2653-61 , which is incorporated herein by reference in its entirety.

[0446] In aspects, the present disclosure provides a vector comprising the isolated polynucleotide of any one of the embodiments disclosed herein. In embodiments, the peptide or the derivative thereof can be provided as an expression vector. In embodiments, the expression vector is a DNA expression vector or an RNA expression vector. In embodiments, the expression vector is a viral expression vector. In embodiments, the expression vector is a non-viral expression vector (without limitation, e.g., a plasmid).

[0447] In embodiments, the present non-viral vectors are linear or circular DNA molecules that comprise a polynucleotide encoding a polypeptide and is operably linked to control sequences, wherein the control sequences provide for expression of the isolated polynucleotide encoding the polypeptide. In embodiments, the non-viral vector comprises a promoter sequence, and transcriptional and translational stop signal sequences. In embodiments, the expression vector may include, among others, chromosomal and episomal vectors, e.g., vectors derived from bacterial plasmids, from transposons, from yeast episomes, from insertion elements, from yeast chromosomal elements, and vectors derived from combinations thereof. The present constructs may contain control regions that regulate as well as engender expression.

[0448] A vector generally comprises an isolated nucleic acid and which can be used to deliver the isolated nucleic acid to the interior of a cell. Numerous vectors are known in the art including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses. In embodiments, the expression vector is an autonomously replicating plasmid or a virus (e.g., AAV vectors). In embodiments, the expression vector is non-plasmid and non-viral compounds that facilitate transfer of nucleic acid into cells, such as, for example, polylysine compounds, liposomes, and the like. Examples of viral vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, and the like.

[0449] In embodiments, the isolated polynucleotide or cell therapy may employ expression vectors, which comprise the nucleic acid encoding the peptide or the derivative thereof operably linked to an expression control region that is functional in the host cell. The expression control region is capable of driving expression of the operably linked encoding nucleic acid such that the peptide or the derivative thereof is produced in a human cell transformed with the expression vector. Expression control regions are regulatory polynucleotides (sometimes referred to herein as elements), such as promoters and enhancers, that influence expression of an operably linked nucleic acid. An expression control region of an expression vector is capable of expressing operably linked encoding nucleic acid in a human cell. In an embodiment, the expression control region confers regulatable expression to an operably linked nucleic acid. A signal (sometimes referred to as a stimulus) can increase or decrease expression of a nucleic acid operably linked to such an expression control region. Such expression control regions that increase expression in response to a signal are often referred to as inducible. Such expression control regions that decrease expression in response to a signal are often referred to as repressible. In various embodiments, the peptide or the derivative thereof expression is inducible or repressible. Typically, the amount of increase or decrease conferred by such elements is proportional to the amount of signal present; the greater the amount of signal, the greater the increase or decrease in expression.

[0450] Expression systems functional in human cells are well known in the art and include viral systems. Generally, a promoter functional in a human cell is any DNA sequence capable of binding mammalian RNA polymerase and initiating the downstream (3') transcription of a coding sequence into mRNA. A promoter will have a transcription-initiating region, which is usually placed proximal to the 5' end of the coding sequence, and typically a TATA box located 25-30 base pairs upstream of the transcription initiation site. The TATA box is thought to direct RNA polymerase II to begin RNA synthesis at the correct site. A promoter will also typically contain an upstream promoter element (enhancer element), typically located within 100 to 200 base pairs upstream of the TATA box. An upstream promoter element determines the rate at which transcription is initiated and can act in either orientation. Of particular use as promoters are the promoters from mammalian viral genes, since the viral genes are often highly expressed and have a broad host range. Examples include the SV40 early promoter, mouse mammary tumor virus LTR promoter, adenovirus major late promoter, herpes simplex virus promoter, and the CMV promoter.

[0451] Where appropriate, gene delivery agents such as, e.g., integration sequences can also be employed. Numerous integration sequences are known in the art (see, e.g., Nunes-Duby et al., Nucleic Acids Res. 26:391-406, 1998; Sadwoski, J. Bacterio!., 165:341-357, 1986; Bestor, Cell, 122(3): 322-325, 2005; Plasterk et al., TIG 15:326-332, 1999; Kootstra et al., Ann. Rev. Pharm. Toxicol., 43:413-439, 2003). These include recombinases and transposases. Examples include Cre (Sternberg and Hamilton, J. Mol. Biol., 150:467-486, 1981), lambda (Nash, Nature, 247, 543-545, 1974), Flp (Broach, et al., Cell, 29:227-234, 1982), R (Matsuzaki, et al., J. Bacteriology, 172:610-618, 1990), cpC31 (see, e.g., Groth et al., J. Mol. Biol. 335:667- 678, 2004), sleeping beauty, transposases of the mariner family, and components for integrating viruses such as AAV, retroviruses, and antiviruses having components that provide for virus integration such as the LTR sequences of retroviruses or lentivirus and the ITR sequences of AAV (Kootstra et al., Ann. Rev. Pharm. Toxicol., 43:413-439, 2003). In addition, direct and targeted genetic integration strategies may be used to insert nucleic acid sequences including CRISPR / CAS9, zinc finger, TALEN, and meganuclease gene-editing technologies.

[0452] In aspects, the present disclosure provides a host cell comprising the vector of any of the embodiments disclosed herein. A host cell comprising the mmRNA of any of the embodiments disclosed herein.

[0453] Pharmaceutical Compositions

[0454] In aspects, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, the mmRNA of any of the embodiments disclosed herein, or the vector of any of the embodiments disclosed herein, or the host cell of any of the embodiments disclosed herein. In embodiments, the pharmaceutical composition comprises the mmRNA of any of the embodiments disclosed herein. In aspects, the present disclosure provides a pharmaceutical composition comprising the mmRNA of any of the embodiments disclosed herein, and a pharmaceutically acceptable carrier. In embodiments, the carrier is a lipidoid, a liposome, a lipoplex, a lipid nanoparticle, a polymeric nanoparticle, a peptide, a protein, a cell, a nanoparticle mimic, a nanotube, or a conjugate. In embodiments, the pharmaceutical composition is formulated as a lipid nanoparticle (LNPs), a lipoplex, or a liposome. In embodiments, the pharmaceutical composition is formulated as a lipid nanoparticle (LNPs). In embodiments, the lipid nanoparticles comprise lipids selected from an ionizable lipid e.g., an ionizable cationic lipid selected from DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, DLin-MC3-DMA, 98N12-5, and C12-200); a structural lipid (e.g., distearoylphosphatidylcholine (DSPC)); cholesterol, and a polyethyleneglycol (PEG)-lipid (e.g., a PEG- diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide (Cer), or a mixture thereof, or a PEG-dilauryloxypropyl (C12, a PEG-dimyristyloxypropyl (C14), a PEG- dipalmityloxypropyl (C16), or a PEG-distearyloxypropyl (C18)); 1 ,2-dioleoyl-3-trimethylammoniumpropane (DOTAP); dioleoylphosphatidylethanolamine (DOPE); and the mmRNA. In embodiments, the lipid nanoparticles comprise (a) a cationic lipid comprising from 50 mol % to 85 mol % of the total lipid present in the particle; (b) a non-cationic lipid comprising from 13 mol % to 49.5 mol % of the total lipid present in the particle; and (c) a conjugated lipid that inhibits aggregation of particles comprising from 0.5 mol % to 2 mol % of the total lipid present in the particle. In embodiments, the lipid nanoparticles comprise a lipid selected from SM-102, DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, DLin-MC3-DMA, 98N12-5, and C12-200; a cholesterol; and a PEG-lipid.

[0455] Suitable pharmaceutical compositions are disclosed in US Patent Nos. 8,710,200; 8,822,663; 8,999,380; 9,181 ,319; 9,254,311 ; 9,334,328; 9,464,124; 9,950,068; 10,626,400; 10,808,242; 11,020,477, US Patent Application Publication Nos. 20220001026, 20210318817, 20210283262, 20200360481, 20200113844, 20200085758, 20170204152, 20190114089, 20190114090, 20180369374, 20180318385, 20190111003, and PCT International Application Publication Nos. WO / 2017112943, WO 2014 / 028429, WO 2017 / 201325 the entire contents of which are hereby incorporated by reference.

[0456] In aspects, the present disclosure relates to a pharmaceutical composition comprising an isolated modified mRNA (mmRNA) encoding a heterologous fusion protein having an amino acid sequence that has at least about 95% sequence identity with an amino acid sequence selected from SEQ ID NOs: 620-93.

[0457] In embodiments, the carrier is mmRNA comprises a modification (e.g., an RNA element), wherein the modification provides a desired translational regulatory activity. Such modifications are described in PCT Application No. PCT International Application Publication No. WO2018213789, the entire contents of which are herein incorporated by reference.

[0458] In embodiments, the mmRNA further comprises a 3’ untranslated region (UTR). In embodiments, the 3’ UTR comprises at least one microRNA-122 (miR-122) binding site. In embodiments, the miR-122 binding site is a miR-122-3p binding site or a miR-122-5-binding site. In embodiments, the mmRNA further comprises a spacer sequence between the open reading frame and the miRNA binding site. In embodiments, the spacer sequence comprises at least about 10 nucleotides, at least about 20 nucleotides, at least about 30 nucleotides, at least about 40 nucleotides, at least about 50 nucleotides, at least about 60 nucleotides, at least about 70 nucleotides, at least about 80 nucleotides, at least about 90 nucleotides, or at least about 100 nucleotides.

[0459] In embodiments, the mmRNA further comprises a 5’ UTR. In embodiments, the 5’ UTR harbors a Kozak sequence and / or forms a secondary structure that stimulate elongation factor binding.

[0460] In embodiments, the mmRNA further comprises a 5’ terminal cap. In embodiments, the 5’ terminal cap is a CapO, Cap1 , ARCA, inosine, N1-methyl-guanosine, 2’fluoro-guanosine, 7-deaza-guanosine, 8-oxo- guanosine, 2-amino-guanosine, LNA-guanosine, 2-azidoguanosine, Cap2, Cap4, 5’ methylG cap, or an analog thereof.

[0461] In any of the embodiments disclosed herein, the mmRNA may comprise one or more modifications. In any of the embodiments disclosed herein, the mmRNA may comprise at least one modification. In embodiments, the modification is nucleoside modification. In embodiments, the modification is a base modification. In embodiments, the modification is a sugar-phosphate backbone modification.

[0462] In embodiments, the modifications are selected from pyridin-4-one ribonucleoside, 5-aza-uridine, 2-thio-5- aza-uridine, 2-thiouridine, pseudouridine, 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxyuridine, 3- methyluridine, 5-carboxymethyl-uridine, 1-carboxymethyl-pseudouridine, 5-propynyl-uridine, 1-propynyl- pseudouridine, 5-taurinomethyluridine, 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine, 1- taurinomethyl-4-thio-uridine, 5-methyl-uridine, 1-methyl-pseudouridine, 4-thio-1-methyl-pseudouridine, 2- thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine, 5-formylcytidine, N4-methylcytidine, 5- hydroxymethylcytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio- cytidine, 2-thio-5-methyl-cytidine, 4-thio-pseudoisocytidine, 4-thio-1-methyl-pseudoisocytidine, 4-thio-1- methyl-1-deaza-pseudoisocytidine, 1 -methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5- methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl- cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy-1-methyl-pseudoisocytidine, 2-aminopurine, 2, 6- diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-aminopurine, 7-deaza-8-aza-2- aminopurine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1 -methyladenosine, N6- methyladenosine, N6-isopentenyladenosine, N6-(cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis- hydroxyisopentenyl) adenosine, N6-glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosine, 2- methylthio-N6-threonyl carbamoyladenosine, N6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio- adenine, and 2-methoxy-adenine, inosine, 1-methyl-inosine, wyosine, wybutosine, 7-deaza-guanosine, 7- deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7- methyl-guanosine, 6-thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1-methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosine, 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6- thio-guanosine, N2-methyl-6-thio-guanosine, and N2,N2-dimethyl-6-thio-guanosine, and a combination of any two or more thereof. In embodiments, the modifications are selected from pseudouridine ( ), N1- methylpseudouridine (mI ), 2-thiouridine (s2U), 4’ -thiouridine, 5-methylcytosine, 2-thio-1-methyl-1 -deazapseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio- dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1- methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5- methoxyuridine, 2’-O-methyl uridine, 1-methyl-pseudouridine (mi l1), 5-methoxy-uridine (mo5U), 5-methyl- cytidine (m5C), .alpha. -thio-guanosine, .alpha.-thio-adenosine, 5-cyano uridine, 4’-thio uridine 7-deaza- adenine, 1-methyl-adenosine (m1A), 2-methyl-adenine (m2A), N6-methyl-adenosine (m6A), and 2,6- Diaminopurine, (I), 1-methylinosine (ml I), wyosine (imG), methylwyosine (mimG), 7-deaza-guanosine, 7- cyano-7-deaza-guanosine (preQO), 7-aminomethyl-7-deaza-guanosine (preQ1), 7-methyl-guanosine (m7G), 1-methyl-guanosine (m1 G), 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, and a combination of any two or more thereof. In embodiments, modification is selected from pseudouridine, N1 -methylpseudouridine, 5- methylcytosine, 5-methoxyuridine, and a combination thereof.

[0463] In embodiments, the mmRNA comprises at least one N1 -methylpseudouridine. In embodiments, the mmRNA is fully modified with chemically-modified uridines. In embodiments, the mmRNA is a fully modified with N1- methylpseudouridine. In embodiments, the modifications are selected from pyridin-4-one ribonucleoside, 5-aza-uridine, 2-thio-5- aza-uridine, 2-thiouridine, pseudouridine, 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxyuridine, 3- methyluridine, 5-carboxymethyl-uridine, 1 -carboxymethyl-pseudouridine, 5-propynyl-uridine, 1-propynyl- pseudouridine, 5-taurinomethyluridine, 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine, 1- taurinomethyl-4-thio-uridine, 5-methyl-uridine, 1-methyl-pseudouridine, 4-thio-1-methyl-pseudouridine, 2- thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, and 4-methoxy-2-thio-pseudouridine or a combination of any two or more thereof.

[0464] In embodiments, the modifications are selected from 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine, 5-formylcytidine, N4-methylcytidine, 5-hydroxymethylcytidine, 1-methyl- pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4- thio-pseudoisocytidine, 4-thio- 1 -methyl-pseudoisocytidine, 4-thio-1 -methyl- 1 -deaza-pseudoisocytidine, 1 - methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl-zebularine, 5-aza-2-thio- zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl-cytidine, 4-methoxy- pseudoisocytidine, and 4-methoxy-1 -methyl-pseudoisocytidine.

[0465] In embodiments, the modifications are selected from 2-aminopurine, 2, 6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza- 2-aminopurine, 7-deaza-8-aza-2-aminopurine, 7-deaza-2, 6-diaminopurine, 7-deaza-8-aza-2, 6-diaminopurine, 1 -methyladenosine, N6-methyladenosine, N6-isopentenyladenosine, N6- (cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine, N6- glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosine, 2-methylthio-N6-threonyl carbamoyladenosine, N6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, and 2-methoxy- adenine.

[0466] In embodiments, the modifications are selected from inosine, 1 -methyl-inosine, wyosine, wybutosine, 7- deaza-guanosine, 7-deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8- aza-guanosine, 7-methyl-guanosine, 6-thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1- methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosine, 8-oxo-guanosine, 7-methyl-8-oxo- guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, and N2,N2-dimethyl-6-thio-guanosine.

[0467] In embodiments, the modifications are present on the major groove face. In embodiments, a hydrogen on C- 5 of uracil is replaced with a methyl group or a halo group. In embodiments, the mmRNA further comprises one or more modifications selected from 5’-O-(1- Thiophosphate)-Adenosine, 5’-O-(1 -Thiophosphate)-Cytidine, 5’-O-(1-Thiophosphate)-Guanosine, 5’-O-(1- Thiophosphate)-Uridine and 5’-O-(1-Thiophosphate)-Pseudouridine.

[0468] In embodiments, the pharmaceutical composition is formulated as a lipid nanoparticle (LNP), a lipoplex, or a liposome. In embodiments, the pharmaceutical composition is formulated as a lipid nanoparticle (LNP). In embodiments, the mmRNAs described herein may be formulated in a cationic oil-in-water emulsion where the emulsion particle comprises an oil core and a cationic lipid that can interact with the mRNA anchoring the molecule to the emulsion particle. In embodiments, the mRNAs described herein may be formulated in a water-in-oil emulsion comprising a continuous hydrophobic phase in which the hydrophilic phase is dispersed. Exemplary emulsions can be made by the methods described in PCT International Application Publication Nos. WO 2012006380 and WO 201087791, each of which is herein incorporated by reference in its entirety.

[0469] In some embodiments, nucleic acids of the invention (e.g., mRNA) are formulated in a lipid nanoparticle (LNP). Lipid nanoparticles comprise typically comprise ionizable cationic lipid, non-cationic lipid, sterol and PEG lipid components along with the nucleic acid cargo of interest. The lipid nanoparticles of the invention can be generated using components, compositions, and methods as are disclosed, e.g., in PCT International Application Publication Nos. WO 2021231854, WO 2021050986, WO 2021055833, WO 2021213924, WO2021055849, WO 2021214204, WO 2021188969, WO 2021055835, WO 2020061284, WO 2020061295, WO 2017049245, WO 2017031232, WO 2017112865, WO 2017218704, WO 2017218704, WO 2017099823, WO 2017049074, WO 2017117528, WO 2017180917, WO 2017075531, WO 2017223135, WO 2016118724, WO 2015164674, WO 2015038892, WO 2014152211, and WO 2013090648, the entire contents of each which are herein incorporated by reference. PEG-lipids selected from an ionizable lipid (e.g., as known in the art, such as those described in U.S. Pat. No. 8,158,601 and PCT International Application Publication Nos. WO 2012099755 and WO 2015 / 130584, which are incorporated herein by reference in their entirety. The ionizable lipid may be selected from, but not limited to, an ionizable lipid described in International Publication Nos. WO 2013086354 and WO 2013116126; the contents of each of which are herein incorporated by reference in their entirety. In embodiments, the lipid may be a cleavable lipid such as those described in PCT International Publication No. WO 2012170889, herein incorporated by reference in its entirety. In embodiments, the lipid may be synthesized by methods known in the art and / or as described in International Publication Nos. WO 2013086354; the contents of each of which are herein incorporated by reference in their entirety. In embodiments, the LNP formulations described herein can additionally comprise a permeability enhancer molecule. Non-limiting permeability enhancer molecules are described in U.S. Publication No. US 20050222064, herein incorporated by reference in its entirety.

[0470] In embodiments, the carrier is a lipidoid, a liposome, a lipoplex, a lipid nanoparticle, a polymeric nanoparticle, a peptide, a protein, a cell, a nanoparticle mimic, a nanotube, or a conjugate. In embodiments, the pharmaceutical composition is formulated as a lipid nanoparticle (LNP), a lipoplex, or a liposome. In embodiments, the pharmaceutical composition is formulated as a lipid nanoparticle (LNP). In embodiments, the lipid nanoparticles comprise lipids selected from an ionizable lipid (e.g., an ionizable cationic lipid selected from DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, DLin-MC3-DMA, 98N12-5, and C12-200); a structural lipid (e.g., distearoylphosphatidylcholine (DSPC)); cholesterol, and a polyethyleneglycol (PEG)-lipid (e.g., a PEG- diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide (Cer), or a mixture thereof, or a PEG-dilauryloxypropyl (C12, a PEG-dimyristyloxypropyl (C14), a PEG- dipalmityloxypropyl (C16), or a PEG-distearyloxypropyl (C18)); 1 ,2-dioleoyl-3-trimethylammoniumpropane (DOTAP); dioleoylphosphatidylethanolamine (DOPE).

[0471] In embodiments, the pharmaceutical composition is formulated as a lipid nanoparticle (LNP). In embodiments, the LNP comprises a molar ratio of about 20-60% ionizable amino lipid, about 5-25% phospholipid, about 25-55% structural lipid, and about 0.5-1.5% PEG lipid. In embodiments, the LNP comprises a molar ratio of about 50% ionizable amino lipid, about 8-12% phospholipid, about 37-40% structural lipid, and about 1-2% PEG lipid. In embodiments, the lipid nanoparticles comprise lipids selected from an ionizable lipid (e.g., an ionizable cationic lipid selected from DLin-DMA, DLin-K-DMA, DLin-KC2- DMA, DLin-MC3-DMA, 98N12-5, and C12-200); a structural lipid (e.g.., distearoylphosphatidylcholine (DSPC)); cholesterol, and a polyethyleneglycol (PEG)-lipid (e.g.., a PEG-diacylglycerol (DAG), a PEG- dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide (Cer), or a mixture thereof, or a PEG- dilauryloxypropyl (C12, a PEG-dimyristyloxypropyl (C14), a PEG-dipalmityloxypropyl (C16), or a PEG- distearyloxypropyl (C18)); 1 ,2-dioleoyl-3-trimethylammoniumpropane (DOTAP); dioleoylphosphatidylethanolamine (DOPE).

[0472] In embodiments, the carrier is a lipidoid, a liposome, a lipoplex, a lipid nanoparticle, a polymeric nanoparticle, a peptide, a protein, a cell, a nanoparticle mimic, a nanotube, or a conjugate. In embodiments, the pharmaceutical composition is formulated as a lipid nanoparticle (LNP), a lipoplex, or a liposome. In embodiments, the pharmaceutical composition is formulated as a lipid nanoparticle (LNP). In embodiments, the lipid nanoparticles comprise lipids selected from an ionizable lipid (e.g., an ionizable cationic lipid selected from DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, DLin-MC3-DMA, 98N12-5, and C12- 200); a structural lipid (e.g., distearoylphosphatidylcholine (DSPC)); cholesterol, and a polyethyleneglycol (PEG)-lipid (e.g, a PEG-diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG- ceramide (Cer), or a mixture thereof, or a PEG-dilauryloxypropyl (C12, a PEG-dimyristyloxypropyl (C14), a PEG-dipalmityloxypropyl (C16), or a PEG-distearyloxypropyl (C18)); 1 ,2-dioleoyl-3- trimethylammoniumpropane (DOTAP); dioleoylphosphatidylethanolamine (DOPE); and the mmRNA.

[0473] In embodiments, the lipid nanoparticles comprise lipids selected from an ionizable lipid; a structural lipid; cholesterol, and a polyethyleneglycol (PEG)-lipid; 1 ,2-dioleoyl-3-trimethylammoniumpropane (DOTAP); dioleoylphosphatidylethanolamine (DOPE); and the mmRNA. In embodiments, the ionizable lipid is an ionizable cationic lipid selected from DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, DLin-MC3-DMA, 98N12-5, and C12-200. In embodiments, the polyethyleneglycol (PEG)-lipid is selected from a PEG-diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide (Cer), or a mixture thereof, or a PEG-dilauryloxypropyl (e.g, C12, a PEG-dimyristyloxypropyl (C14), a PEG-dipalmityloxypropyl (C16), or a PEG-distearyloxypropyl (C18)).

[0474] In embodiments, the lipid nanoparticles comprise (a) a cationic lipid comprising from 50 mol % to 85 mol % of the total lipid present in the particle; (b) a non-cationic lipid comprising from 13 mol % to 49.5 mol % of the total lipid present in the particle; and (c) a conjugated lipid that inhibits aggregation of particles comprising from 0.5 mol % to 2 mol % of the total lipid present in the particle. In embodiments, the lipid nanoparticles comprise a lipid selected from SM-102, DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, DLin-MC3-DMA, 98N12- 5, and C12-200; a cholesterol; and a PEG-lipid.

[0475] In any of the embodiments disclosed herein, the pharmaceutical composition is formulated for parenteral administration. In any of the embodiments disclosed herein, the pharmaceutical composition is formulated for topical administration

[0476] In aspects, the present disclosure provides a pharmaceutical composition comprising the mmRNA of any embodiment disclosed herein, or an LNP comprising an mmRNA of any embodiment disclosed herein. In embodiments, the pharmaceutical composition is formulated for parenteral administration.

[0477] In embodiments, the pharmaceutical composition comprises a modified mRNA (mmRNA) encoding a heterologous fusion protein having an amino acid sequence that has at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% sequence identity with the amino acid sequence selected from SEQ ID NOs: 620-93. In embodiments, the pharmaceutical composition is formulated as an LNP comprising an ionizable amino lipid, a phospholipid, a structural lipid and a PEG lipid.

[0478] In embodiments, the pharmaceutical composition is formulated for parenteral administration. In embodiments, the pharmaceutical composition is formulated for topical, dermal, intradermal, intramuscular, intraperitoneal, intraarticular, intravenous, subcutaneous, intraarterial or transdermal administration. In embodiments, the pharmaceutical composition is formulated for topical administration.

[0479] In aspects, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier, and the peptide or the derivative thereof of any one of the embodiments disclosed herein, the isolated polynucleotide of any one of the embodiments disclosed herein, the vector of the embodiments disclosed herein, or the host cell of any of the embodiments disclosed herein. In embodiments, the pharmaceutical composition comprises the nucleic acid, e.g., the mmRNA of any one of the embodiments disclosed herein.

[0480] In embodiments, the isolated polynucleotide is conjugated polynucleotide sequence that is introduced into cells by various transfection methods such as, e.g., methods that employ lipid particles. In embodiments, a composition, including a gene transfer construct, comprises a delivery particle. In embodiments, the delivery particle comprises a lipid-based particle (e.g., a lipid nanoparticle (LNP)), cationic lipid, or a biodegradable polymer). Lipid nanoparticle (LNP) delivery of gene transfer construct provides certain advantages, including transient, non-integrating expression to limit potential off-target events and immune responses, and efficient delivery with the capacity to transport large cargos. LNPs have been used for delivery of small interfering RNA (siRNA) and mRNA, and for in vitro and in vivo delivering CRISPR / Cas9 components to hepatocytes and the liver. For example, U.S. Pat. No. 10,195,291 describes the use of LNPs for delivery of RNA interference (RNAi) therapeutic agents.

[0481] In embodiments, the composition in accordance with embodiments of the present disclosure is in the form of a LNP. In embodiments, the LNP comprises one or more lipids selected from 1 ,2-dioleoyl-3- trimethylammonium propane (DOTAP); N,N-dioleyl-N,N-dimethylammonium chloride (DODAC); N-(2,3- dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA); N,N-distearyl-N,N-dimethylammonium bromide (DDAB), a cationic cholesterol derivative mixed with dimethylaminoethane-carbamoyl (DC-Chol), phosphatidylcholine (PC), triolein (glyceryl trioleate), and 1 ,2-distearoyl-sn-glycero-3-phosphoethanolamine- N-[carboxy(polyethylene glycol)-2000] (DSPE-PEG), 1 ,2-dimyristoyl-rac-glycero-3- methoxypolyethyleneglycol - 2000 (DMG-PEG 2K), and 1 ,2 distearol-sn-glycerol-3phosphocholine (DSPC).

[0482] In embodiments, the composition can have a lipid and a polymer in various ratios, wherein the lipid can be selected from, e.g., DOTAP, DC-Chol, PC, Triolein, DSPE-PEG, and wherein the polymer can be, e.g., PEI or Poly Lactic-co-Glycolic Acid (PLGA). Any other lipid and polymer can be used additionally or alternatively. In embodiments, the ratio of the lipid and the polymer is about 0.5:1 , or about 1 :1 , or about 1 :1.5, or about 1 :2, or about 1 :2.5, or about 1 :3, or about 3:1, or about 2.5:1 , or about 2:1 , or about 1.5:1 , or about 1 :1 , or about 1 :0.5.

[0483] In embodiments, the LNP comprises a cationic lipid, non-limiting examples of which include N,N-dioleyl-N,N- dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(l-(2,3- dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(l-(2,3-dioleyloxy)propyl)-N,N,N- trimethylammonium chloride (DOTMA), N,N-dimethyl-2,3-dioleyloxy)propylamine (DODMA), 1,2- Di Li noleyloxy-N, N-dimethylaminopropane (DLinDMA), 1 , 2-Dili nolenyloxy-N, N-dimethylami nopropane (DLenDMA), 1,2-Dilinoleylcarbamoyloxy-3-dimethylaminopropane (DLin-C-DAP), 1, 2-Dili noleyoxy-3- (dimethylamino)acetoxypropane (DLin-DAC), 1 ,2-Dilinoleyoxy-3-morpholinopropane (DLin-MA), 1 ,2- Dili noleoyl-3-dimethyl ami nopropane (DLinDAP), 1 , 2-Dili noleylthio-3-dimethylaminopropane (DLin-S-DMA), 1 -Linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), 1 ,2-Dilinoleyloxy-3- trimethylaminopropane chloride salt (DLin-TMA.CI), 1,2-Dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.CI), 1 ,2-Dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), or 3-(N,N-Dilinoleylamino)-1 ,2- propanediol (DLinAP), 3-(N,N-Dioleylamino)-1 ,2-propanedio (DOAP), 1 ,2-Dilinolenyloxy-N,N- dimethylaminopropane (DLinDMA), 2,2-Dilinoleyl-4-dimethylaminomethyl-[1 ,3]-dioxolane (DLin-K-DMA) or analogs thereof, (3aR,5s,6aS)-N,N-dimethyl-2,2-di((9Z,12Z)-octadeca-9,12-dienyl)tetrahydro-3aH- cyclopenta[d][1 ,3]dioxol-5-amine (ALN100), (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4- (dimethylamino)butanoate (MC3), 1 ,1'-(2-(4-(2-((2-(bis(2-‘)amino)ethyl)(2 hydroxydodecyl)amino)ethyl) piperazin-1 -yl)ethylazanediyl)didodecan-2-ol (Tech G1), 1 ,2-Dilinoleyloxo-3-(2-N,N-dimethylamino) ethoxypropane (DLin-EG-DMA), or a mixture thereof.

[0484] In embodiments, the LNP comprises one or more molecules selected from polyethylenimine (PEI) and poly(lactic-co-glycolic acid) (PLGA), and N-Acetylgalactosamine (GalNAc), which are suitable for hepatic delivery. In embodiments, the LNP comprises a hepatic-directed compound as described, e.g., in U.S. Pat. No. 5,985,826, which is incorporated by reference herein in its entirety. GalNAc is known to target Asialoglycoprotein Receptor (ASGPR) expressed on mammalian hepatic cells. See Hu et al. Protein Pept Lett. 2014;21 (10): 1025-30.

[0485] In some examples, the isolated polynucleotide can be formulated or complexed with PEI or a derivative thereof, such as polyethyleneimine-polyethyleneglycol-N-acetylgalactosamine (PEI-PEG-GAL) or polyethyleneimine-polyethyleneglycol-tri-N-acetylgalactosamine (PEI-PEG-triGAL) derivatives.

[0486] In embodiments, the lipid nanoparticles comprise lipids selected from an ionizable lipid (e.g., an ionizable cationic lipid selected from DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, DLin-MC3-DMA, 98N12-5, and C12- 200); a structural lipid (e.g., distearoylphosphatidylcholine (DSPC)); cholesterol, and a polyethyleneglycol (PEG)-lipid (e.g., a PEG-diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG- ceramide (Cer), or a mixture thereof, or a PEG-dilauryloxypropyl (C12, a PEG-dimyristyloxypropyl (C14), a PEG-dipalmityloxypropyl (C16), or a PEG-distearyloxypropyl (C18)); 1 ,2-dioleoyl-3- trimethylammoniumpropane (DOTAP); dioleoylphosphatidylethanolamine (DOPE); and the nucleic acid, e.g., the mmRNA.

[0487] In embodiments, the LNP comprises a molar ratio of about 20-60% ionizable amino lipid, about 5-25% phospholipid, about 25-55% structural lipid, and about 0.5-1.5% PEG lipid. In embodiments, the ionizable amino lipid comprises the following formula:

[0488] In embodiments, the lipid nanoparticles comprise lipids selected from an ionizable lipid; a structural lipid; cholesterol, and a polyethyleneglycol (PEG)-lipid; 1,2-dioleoyl-3-trimethylammoniumpropane (DOTAP); dioleoylphosphatidylethanolamine (DOPE); and the nucleic acid, e.g., the mmRNA. In embodiments, the ionizable lipid is an ionizable cationic lipid selected from DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, DLin- MC3-DMA, 98N12-5, and C12-200. In embodiments, the polyethyleneglycol (PEG)-lipid is selected from a PEG-diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide (Cer), or a mixture thereof, or a PEG-dilauryloxypropyl (e.g., C12, a PEG-dimyristyloxypropyl (C14), a PEG- dipalmityloxypropyl (C16), or a PEG-distearyloxypropyl (C18)). In embodiments, the LNP is a conjugated lipid, non-limiting examples of which include a polyethyleneglycol (PEG)-lipid including, without limitation, a PEG-diacylglycerol (DAG), a PEG-dialkyloxypropyl (DAA), a PEG- phospholipid, a PEG-ceramide (Cer), or a mixture thereof. The PEG-DAA conjugate may be, for example, a PEG-dilauryloxypropyl (C12, a PEG-dimyristyloxypropyl (C14), a PEG-dipalmityloxypropyl (C16), or a PEG- distearyloxypropyl (C18).

[0489] In embodiments, the LNP formulations may further contain a phosphate conjugate, which can increase in vivo circulation times and / or increase the targeted delivery of the nanoparticle. Phosphate conjugates can be made by the methods described in, e.g., PCT International Publication No. WO 2013033438 or U.S. Pub. No. US 20130196948. The LNP formulation can also contain a polymer conjugate (e.g., a water-soluble conjugate) as described in, e.g., U.S. Publication Nos. US 20130059360, US 20130196948, and US 20130072709, each of the references is herein incorporated by reference in its entirety.

[0490] In embodiments, the LNP formulations may comprise a carbohydrate carrier. As a non-limiting example, the carbohydrate carrier can include, but is not limited to, an anhydride-modified phytoglycogen or glycogen-type material, phytoglycogen octenyl succinate, phytoglycogen beta-dextrin, anhydride-modified phytoglycogen beta-dextrin (e.g., PCT International Publication No. WO 2012109121 , herein incorporated by reference in its entirety). In embodiments, the LNP formulations can be coated with a surfactant or polymer to improve the delivery of the particle. In some embodiments, the LNP can be coated with a hydrophilic coating such as, but not limited to, PEG coatings and / or coatings that have a neutral surface charge as described in U.S. Publication No. US 20130183244, herein incorporated by reference in its entirety. In embodiments, the LNP formulations can be engineered to alter the surface properties of particles so that the lipid nanoparticles can penetrate the mucosal barrier as described in U.S. Pat. No. 8,241 ,670 or PCT International Publication No. WO 2013110028, each of which is herein incorporated by reference in its entirety. In embodiments, the mucus penetrating LNP can be a hypotonic formulation comprising a mucosal penetration enhancing coating. The formulation can be hypotonic for the epithelium to which it is being delivered. Non-limiting examples of hypotonic formulations can be found in, e.g., PCT International Publication No. WO 2013110028, herein incorporated by reference in its entirety.

[0491] In embodiments, an mmRNA described herein is formulated as a solid lipid nanoparticle (SLN), which can be spherical with an average diameter between 10 to 1000 nm. SLN possess a solid lipid core matrix that can solubilize lipophilic molecules and can be stabilized with surfactants and / or emulsifiers. Exemplary SLN can be those as described in PCT International Publication No. WO 2013105101 , herein incorporated by reference in its entirety.

[0492] In embodiments, a nanoparticle is a particle having a diameter of less than about 1000 nm. In embodiments, nanoparticles of the present disclosure have a greatest dimension (e.g., diameter) of about 500 nm or less, or about 400 nm or less, or about 300 nm or less, or about 200 nm or less, or about 100 nm or less. In embodiments, nanoparticles of the present disclosure have a greatest dimension ranging between about 50 nm and about 150 nm, or between about 70 nm and about 130 nm, or between about 80 nm and about 120 nm, or between about 90 nm and about 110 nm. In embodiments, the nanoparticles of the present disclosure have a greatest dimension (e.g. , a diameter) of about 100 nm.

[0493] In embodiments, the peptide or the derivative thereof or the therapeutic nanoparticle comprising mRNA can be formulated for sustained release, which, as used herein, refers to a pharmaceutical composition or compound that conforms to a release rate over a specific period of time. In embodiments, the period of time may include, but is not limited to, hours, days, weeks, months and years. As a non-limiting example, the sustained release nanoparticle of the mRNAs described herein can be formulated as disclosed in PCT International Publication No. WO 2010075072 and U.S. Publication Nos. US 20100216804, US 20110217377, US 20120201859 and US 20130150295, each of which is herein incorporated by reference in their entirety.

[0494] In embodiments, the peptide or the derivative thereof or the isolated polynucleotide or mmRNA (and / or additional agents) are included various formulations. Any fusion protein, or the isolated polynucleotide or mmRNA (and / or additional agents) described herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. DNA or RNA constructs encoding the protein sequences may also be used. In embodiments, the composition is in the form of a capsule (see, e.g., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.

[0495] In embodiments, the present disclosure provides an expression vector, comprising a nucleic acid encoding the peptide or the derivative thereof described herein. In embodiments, the expression vector comprises DNA or RNA. In embodiments, the expression vector is a mammalian expression vector. Both prokaryotic and eukaryotic vectors can be used for expression of the peptide or the derivative thereof. Prokaryotic vectors include constructs based on E. coll sequences (see, e.g., Makrides, Microbiol Rev 1996, 60:512-538). Non-limiting examples of regulatory regions that can be used for expression in E. coli include lac, trp, Ipp, phoA, recA, tac, T3, T7 and APL. Non-limiting examples of prokaryotic expression vectors may include the Agt vector series such as Agt11 (Huynh et al., in “DNA Cloning Techniques, Vol. I: A Practical Approach,” 1984, (D. Glover, ed.), pp. 49-78, IRL Press, Oxford), and the pET vector series (Studier et al., Methods Enzymol 1990, 185:60-89). Prokaryotic host-vector systems cannot perform much of the post- translational processing of mammalian cells, however. Thus, eukaryotic host- vector systems may be particularly useful. Avariety of regulatory regions can be used for expression of the peptides or the derivatives thereof in mammalian host cells. For example, the SV40 early and late promoters, the cytomegalovirus (CMV) immediate early promoter, and the Rous sarcoma virus long terminal repeat (RSV-LTR) promoter can be used. Inducible promoters that may be useful in mammalian cells include, without limitation, promoters associated with the metallothionein II gene, mouse mammary tumor virus glucocorticoid responsive long terminal repeats (MMTV-LTR), the p-interferon gene, and the hsp70 gene (see, Williams et al., Cancer Res 1989, 49:2735-42; and Taylor et al., Mol Cell Biol 1990, 10:165-75). Heat shock promoters or stress promoters also may be advantageous for driving expression of the peptides or the derivatives thereof in recombinant host cells.

[0496] In embodiments, expression vectors of the disclosure comprise a nucleic acid encoding the peptides or the derivatives thereof (and / or additional agents), or a complement thereof, operably linked to an expression control region, or complement thereof, that is functional in a mammalian cell. The expression control region is capable of driving expression of the operably linked blocking and / or stimulating agent encoding nucleic acid such that the blocking and / or stimulating agent is produced in a human cell transformed with the expression vector.

[0497] Expression control regions are regulatory polynucleotides (sometimes referred to herein as elements), such as promoters and enhancers, that influence expression of an operably linked nucleic acid. An expression control region of an expression vector of the disclosure is capable of expressing operably linked encoding nucleic acid in a human cell. In embodiments, the cell is a tumor cell. In embodiments, the cell is a non-tumor cell. In embodiments, the expression control region confers regulatable expression to an operably linked nucleic acid. A signal (sometimes referred to as a stimulus) can increase or decrease expression of a nucleic acid operably linked to such an expression control region. Such expression control regions that increase expression in response to a signal are often referred to as inducible. Such expression control regions that decrease expression in response to a signal are often referred to as repressible. Typically, the amount of increase or decrease conferred by such elements is proportional to the amount of signal present; the greater the amount of signal, the greater the increase or decrease in expression.

[0498] In embodiments, the present disclosure contemplates the use of inducible promoters capable of effecting high level of expression transiently in response to a cue. For example, when in the proximity of a tumor cell, a cell transformed with an expression vector forthe peptide or the derivative thereof (and / or additional agents) comprising such an expression control sequence is induced to transiently produce a high level of the agent by exposing the transformed cell to an appropriate cue. Illustrative inducible expression control regions include those comprising an inducible promoter that is stimulated with a cue such as a small molecule chemical compound. Particular examples can be found, for example, in U.S. Patent Nos. 5,989,910, 5,935,934, 6,015,709, and 6,004,941, each of which is incorporated herein by reference in its entirety.

[0499] Expression control regions and locus control regions include full-length promoter sequences, such as native promoter and enhancer elements, as well as subsequences or polynucleotide variants which retain all or part of full-length or non-variant function. As used herein, the term "functional" and grammatical variants thereof, when used in reference to a nucleic acid sequence, subsequence or fragment, means that the sequence has one or more functions of native nucleic acid sequence (e.g., non-variant or unmodified sequence).

[0500] As used herein, “operable linkage’’ refers to a physical juxtaposition of the components so described as to permit them to function in their intended manner. In the example of an expression control element in operable linkage with a nucleic acid, the relationship is such that the control element modulates expression of the nucleic acid. Typically, an expression control region that modulates transcription is juxtaposed near the 5' end of the transcribed nucleic acid ( / .e., “upstream”). Expression control regions can also be located at the 3’ end of the transcribed sequence ( / .e., “downstream”) or within the transcript (e.g., in an intron). Expression control elements can be located at a distance away from the transcribed sequence (e.g., 100 to 500, 500 to 1000, 2000 to 5000, or more nucleotides from the nucleic acid). A specific example of an expression control element is a promoter, which is usually located 5' of the transcribed sequence. Another example of an expression control element is an enhancer, which can be located 5' or 3' of the transcribed sequence, or within the transcribed sequence.

[0501] Expression systems functional in human cells are well known in the art and include viral systems. Generally, a promoter functional in a human cell is any DNA sequence capable of binding mammalian RNA polymerase and initiating the downstream (3') transcription of a coding sequence into mRNA. A promoter will have a transcription initiating region, which is usually placed proximal to the 5' end of the coding sequence, and typically a TATA box located 25-30 base pairs upstream of the transcription initiation site. The TATA box is thought to direct RNA polymerase II to begin RNA synthesis at the correct site. A promoter will also typically contain an upstream promoter element (enhancer element), typically located within 100 to 200 base pairs upstream of the TATA box. An upstream promoter element determines the rate at which transcription is initiated and can act in either orientation. Of particular use as promoters are the promoters from mammalian viral genes, since the viral genes are often highly expressed and have a broad host range. Examples include the SV40 early promoter, mouse mammary tumor virus LTR promoter, adenovirus major late promoter, herpes simplex virus promoter, and the CMV promoter.

[0502] Typically, transcription termination and polyadenylation sequences recognized by mammalian cells are regulatory regions located 3' to the translation stop codon and thus, together with the promoter elements, flank the coding sequence. The 3’ terminus of the mature mRNA is formed by site-specific post-translational cleavage and polyadenylation. Examples of transcription terminator and polyadenylation signals include those derived from SV40. Introns may also be included in expression constructs.

[0503] There are a variety of techniques available for introducing nucleic acids into viable cells. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, polymer-based systems, DEAE-dextran, viral transduction, the calcium phosphate precipitation method, etc. For in vivo gene transfer, a number of techniques and reagents may also be used, including liposomes; natural polymer-based delivery vehicles, such as chitosan and gelatin; viral vectors are also suitable for in vivo transduction. In some situations, it is desirable to provide a targeting agent, such as an antibody or ligand specific for a tumor cell surface membrane protein. Where liposomes are employed, proteins which bind to a cell surface membrane protein associated with endocytosis may be used for targeting and / orto facilitate uptake, e.g., capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, proteins thattarget intracellular localization and enhance intracellular half-life. The technique of receptor-mediated endocytosis is described, for example, by Wu et al., J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Natl. Acad. Sci. USA 87, 3410-3414 (1990).

[0504] Where appropriate, gene delivery agents such as, e.g., integration sequences can also be employed. Numerous integration sequences are known in the art (see, e.g., Nunes-Duby et al., Nucleic Acids Res. 26:391-406, 1998; Sadwoski, J. Bacterio!., 165:341-357, 1986; Bestor, Cell, 122(3): 322-325, 2005; Plasterk et al., TIG 15:326-332, 1999; Kootstra et al., Ann. Rev. Pharm. Toxicol., 43:413-439, 2003). These include recombinases and transposases. Examples include Cre (Sternberg and Hamilton, J. Mol. Biol., 150:467-486, 1981), lambda (Nash, Nature, 247, 543-545, 1974), Flp (Broach, ef al., Cell, 29:227-234, 1982), R (Matsuzaki, et al., J. Bacteriology, 172:610-618, 1990), cpC31 (see, e.g., Groth et al., J. Mol. Biol. 335:667- 678, 2004), sleeping beauty, transposases of the mariner family (Plasterk et al., supra), and components for integrating viruses such as AAV, retroviruses, and antiviruses having components that provide for virus integration such as the LTR sequences of retroviruses or lentivirus and the ITR sequences of AAV (Kootstra et al., Ann. Rev. Pharm. Toxicol., 43:413-439, 2003). In addition, direct and targeted genetic integration strategies may be used to insert nucleic acid sequences encoding the peptides or the derivatives thereof including CRISPR / CAS9, zinc finger, TALEN, and meganuclease gene-editing technologies.

[0505] In aspects, the disclosure provides expression vectors for the expression of the peptides or the derivatives thereof (and / or additional agents) that are viral vectors. Many viral vectors useful for gene therapy are known (see, e.g., Lundstrom, Trends Biotechnol. , 21 : 1 17, 122, 2003. Illustrative viral vectors include those selected from Antiviruses (LV), retroviruses (RV), adenoviruses (AV), adeno-associated viruses (AAV), and a viruses, though other viral vectors may also be used. For in vivo uses, viral vectors that do not integrate into the host genome are suitable for use, such as a viruses and adenoviruses. Illustrative types of a viruses include Sindbis virus, Venezuelan equine encephalitis (VEE) virus, and Semliki Forest virus (SFV). For in vitro uses, viral vectors that integrate into the host genome are suitable, such as retroviruses, AAV, and Antiviruses. In embodiments, the disclosure provides methods of transducing a human cell in vivo, comprising contacting a solid tumor in vivo with a viral vector of the disclosure.

[0506] In embodiments, the present disclosure provides a host cell, comprising the expression vector comprising the peptide or the derivative thereof described herein.

[0507] Expression vectors can be introduced into host cells for producing the present fusion proteins. Cells may be cultured in vitro or genetically engineered, for example. Useful mammalian host cells include, without limitation, cells derived from humans, monkeys, and rodents (see, for example, Kriegler in “Gene Transfer and Expression: A Laboratory Manual,” 1990, New York, Freeman & Co.). These include monkey kidney cell lines transformed by SV40 (e.g., COS-7, ATCC CRL 1651); human embryonic kidney lines (e.g., 293, 293- EBNA, or 293 cells subcloned for growth in suspension culture, Graham ef al., J Gen Virol 1977, 36:59); baby hamster kidney cells (e.g., BHK, ATCC CCL 10); Chinese hamster ovary-cells-DHFR (e.g., CHO, Urlaub and Chasin, Proc Natl Acad Sci USA 1980, 77:4216); DG44 CHO cells, CHO-K1 cells, mouse sertoli cells (Mather, Biol Reprod ] 980, 23:243-251); mouse fibroblast cells (e.g., NIH-3T3), monkey kidney cells (e.g., CV1 ATCC CCL 70); African green monkey kidney cells, (e.g., VERO-76, ATCC CRL-1587); human cervical carcinoma cells (e.g., HELA, ATCC CCL 2); canine kidney cells (e.g., MDCK, ATCC CCL 34); buffalo rat liver cells (e.g., BRL 3A, ATCC CRL 1442); human lung cells (e.g., W138, ATCC CCL 75); human liver cells (e.g., Hep G2, HB 8065); and mouse mammary tumor cells (e.g., MMT 060562, ATCC CCL51). Illustrative cancer cell types for expressing the peptides or the derivatives thereof described herein include mouse fibroblast cell line, NIH3T3, mouse Lewis lung carcinoma cell line, LLC, mouse mastocytoma cell line, P815, mouse lymphoma cell line, EL4 and its ovalbumin transfectant, E.G7, mouse melanoma cell line, B16F10, mouse fibrosarcoma cell line, MC57, and human small cell lung carcinoma cell lines, SCLC#2 and SCLC#7.

[0508] Host cells can be obtained from normal or affected subjects, including healthy humans, cancer patients, and patients with an infectious disease, private laboratory deposits, public culture collections such as the American Type Culture Collection, or from commercial suppliers.

[0509] Cells that can be used for production of the present fusion proteins in vitro, ex vivo, and / or in vivo include, without limitation, epithelial cells, endothelial cells, keratinocytes, fibroblasts, muscle cells, hepatocytes; blood cells such as T lymphocytes, B lymphocytes, monocytes, macrophages, neutrophils, eosinophils, megakaryocytes, granulocytes; various stem or progenitor cells, in particular hematopoietic stem or progenitor cells (e.g., as obtained from bone marrow), umbilical cord blood, peripheral blood, fetal liver, etc. The choice of cell type depends on the type of tumor or infectious disease being treated or prevented, and can be determined by one of skill in the art.

[0510] Where necessary, the formulations comprising the peptide or the derivative thereof, or the isolated polynucleotide (and / or additional agents) can also include a solubilizing agent. Also, the agents can be delivered with a suitable vehicle or delivery device as known in the art. Combination therapies outlined herein can be co-delivered in a single delivery vehicle or delivery device. Compositions for administration can optionally include a local anesthetic such as, for example, lignocaine to lessen pain at the site of the injection.

[0511] The formulations comprising the peptide or the derivative thereof (and / or additional agents) of the present disclosure may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional methods known in the art)

[0512] In embodiments, any fusion protein, or the isolated polynucleotide or mmRNA (and / or additional agents) described herein is formulated in accordance with routine procedures as a composition adapted for a mode of administration described herein.

[0513] Routes of administration include, for example: intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin. In embodiments, the administering is effected orally or by parenteral injection. In some instances, administration results in the release of any agent described herein into the bloodstream, or alternatively, the agent is administered directly to the site of active disease.

[0514] Any fusion protein, or the isolated polynucleotide (and / or additional agents) described herein can be administered orally. Such fusion proteins (and / or additional agents) can also be administered by any other convenient route, for example, by intravenous infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and can be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer.

[0515] In embodiments, the pharmaceutical composition is formulated for parenteral administration. In embodiments, the pharmaceutical composition is formulated for intradermal, intramuscular, intraperitoneal, intraarticular, intravenous, subcutaneous, intraarterial or transdermal administration.

[0516] Dosage forms suitable for parenteral administration (e.g., intravenous, intramuscular, intraperitoneal, subcutaneous and intra-articular injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions (e.g., lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art.

[0517] The dosage of any fusion protein, or the isolated polynucleotide or mmRNA (and / or additional agents) described herein as well as the dosing schedule can depend on various parameters, including, but not limited to, the disease being treated, the subject’s general health, and the administering physician’s discretion. Any fusion protein described herein, can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of an additional agent, to a subject in need thereof. In embodiments any fusion protein and additional agent described herein are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, 1 day apart, 2 days apart, 3 days part, 4 days apart, 5 days apart, 6 days apart, 1 week apart, 2 weeks apart, 3 weeks apart, or 4 weeks apart.

[0518] The dosage of any fusion protein, or the isolated polynucleotide or mmRNA (and / or additional agents) described herein can depend on several factors including the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the subject to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular subject may affect dosage used. Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific combination of the agents being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the particular disease being treated, the severity of the disorder, and the anatomical location of the disorder. Some variations in the dosage can be expected.

[0519] In embodiments, delivery can be in a vesicle, in particular a liposome (see Langer, 1990, Science 249:1527- 1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989).

[0520] Any fusion protein, or the isolated polynucleotide (and / or additional agents) described herein can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591 ,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms can be useful for providing controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Controlled- or sustained- release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, stimulation by an appropriate wavelength of light, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

[0521] In embodiments, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 ; see also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351 ; Howard et al., 1989, J. Neurosurg. 71 :105).

[0522] In embodiments, a controlled-release system can be placed in proximity of the target area to be treated, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussed in the review by Langer, 1990, Science 249:1527-1533) may be used.

[0523] Administration of any fusion protein, or the isolated polynucleotide or mmRNA (and / or additional agents) described herein can, independently, be one to four times daily or one to four times per month or one to six times per year or once every two, three, four or five years. Administration can be for the duration of one day or one month, two months, three months, six months, one year, two years, three years, and may even be for the life of the subject.

[0524] The dosage regimen utilizing any fusion protein, or the isolated polynucleotide or mmRNA (and / or additional agents) described herein can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; the pharmacogenomic makeup of the individual; and the specific compound of the disclosure employed. Any fusion protein (and / or additional agents) described herein can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, any fusion protein (and / or additional agents) described herein can be administered continuously rather than intermittently throughout the dosage regimen. Methods of Treatment or Prevention

[0525] In aspects, the present disclosure provides a method of treating or preventing hyperglycemia, diabetes, obesity or metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a cardiometabolic disease, or liver fibrosis or for reducing blood glucose, or for reducing fed and fasting blood glucose, or for reducing cardiovascular risk, or for decreasing body weight, decreasing food intake, decreasing blood glucose, decreasing liver adiposity, decreasing liver weight, decreasing subcutaneous white adipose tissue (sWAT), or for increasing glucose tolerance in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein.

[0526] In aspects, the present disclosure provides a method of treating or preventing hyperglycemia, diabetes, obesity or metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a cardiometabolic disease, or liver fibrosis or for reducing blood glucose, or for reducing fed and fasting blood glucose, or for reducing cardiovascular risk, or for decreasing body weight, decreasing food intake, decreasing blood glucose, decreasing liver adiposity, decreasing liver weight, decreasing subcutaneous white adipose tissue (sWAT), or for increasing glucose tolerance in a subject in need thereof, the method comprising administering to the subject the isolated polynucleotide of any of the embodiments disclosed herein.

[0527] In aspects, the present disclosure provides a method of treating or preventing hyperglycemia, diabetes, obesity or metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a cardiometabolic disease, or liver fibrosis or for reducing blood glucose, or for reducing fed and fasting blood glucose, or for reducing cardiovascular risk, or for decreasing body weight, decreasing food intake, decreasing blood glucose, decreasing liver adiposity, decreasing liver weight, decreasing subcutaneous white adipose tissue (sWAT), or for increasing glucose tolerance in a subject in need thereof, the method comprising administering to the subject the expression vector of any of the embodiments disclosed herein.

[0528] In aspects, the present disclosure provides a method of treating or preventing hyperglycemia, diabetes, obesity or metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a cardiometabolic disease, or liver fibrosis or for reducing blood glucose, or for reducing fed and fasting blood glucose, or for reducing cardiovascular risk, or for decreasing body weight, decreasing food intake, decreasing blood glucose, decreasing liver adiposity, decreasing liver weight, decreasing subcutaneous white adipose tissue (sWAT), or for increasing glucose tolerance in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any of the embodiments disclosed herein.

[0529] In aspects, the present disclosure provides a method of treating or preventing hyperglycemia in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any ofthe embodiments disclosed herein, or the expression vector of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein.

[0530] In aspects, the present disclosure provides a method of treating or preventing diabetes in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, or the expression vector of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein.

[0531] In aspects, the present disclosure provides a method of treating or preventing obesity in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, or the expression vector of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein.

[0532] In aspects, the present disclosure provides a method of treating or preventing metabolic syndrome in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, or the expression vector of any ofthe embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein.

[0533] In aspects, the present disclosure provides a method for reducing blood glucose in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, or the expression vector of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein. In aspects, the present disclosure provides a method for reducing fed and fasting blood glucose in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, or the expression vector of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein.

[0534] In aspects, the present disclosure provides a method for reducing cardiovascular risk in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, or the expression vector of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein.

[0535] In aspects, the present disclosure provides a method for decreasing body weight in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, or the expression vector of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein.

[0536] In aspects, the present disclosure provides a method for decreasing food intake in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, or the expression vector of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein.

[0537] In aspects, the present disclosure provides a method for decreasing liver adiposity in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, or the expression vector of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein.

[0538] In aspects, the present disclosure provides a method for decreasing liver weight in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, or the expression vector of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein. In aspects, the present disclosure provides a method for decreasing subcutaneous white adipose tissue (sWAT) in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, or the expression vector of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein.

[0539] In aspects, the present disclosure provides a method for increasing glucose tolerance in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any of the embodiments disclosed herein, the isolated polynucleotide of any of the embodiments disclosed herein, or the expression vector of any of the embodiments disclosed herein, or the pharmaceutical composition of any of the embodiments disclosed herein.

[0540] In embodiments, the subject selected for the treatment with the compositions comprising the peptide or the derivative thereof disclosed herein or the polynucleotides encoding the peptide or the derivative thereof disclosed herein based on diagnosis symptoms selected from one or more of the subject suffers from one or more symptoms selected from increased urination, increased thirst, increased hunger, increased food intake, increased weight, obesity, weight loss, blurry vision, numbing or tingling hands or feet, very dry skin, increased infections, and diabetic sores. In embodiments, the subject is asymptomatic. In embodiments, the patient has type 1 diabetes. In embodiments, the patient has type 2 diabetes. In embodiments, the patient has gestational diabetes or steroid-induced diabetes.

[0541] In embodiments, the peptide or the derivative thereof disclosed herein or the polynucleotides encoding the peptide or the derivative thereof disclosed herein is administered to a patient that has one or more of an average hemoglobin A1c value of more than about 10%, or more than about 11%, or more than about 12%, or more than about 13%, or more than about 14%, or more than about 15%) at the start of treatment with conventional diabetic therapy. In embodiments, the peptide or the derivative thereof disclosed herein or the polynucleotides encoding the peptide or the derivative thereof disclosed herein is administered to a patient that has an average glucose of more than about 200 mg / dl, or more than about 210 mg / dl, or more than about 220 mg / dl, or more than about 230 mg / dl, or more than about 240 mg / dl, or more than about 250 mg / dl at the start of treatment with conventional diabetic therapy. In various embodiments, the conventional diabetic therapy is any one of those described herein, including, for example, insulin therapy and non-insulin diabetes agent therapy. In embodiments, the treatment comprises one or more of a decrease of the blood glucose level, stimulation of peripheral glucose disposal, and inhibition of hepatic glucose production. These biological activities can be assayed in vitro using known methodologies. For example, the effect of the peptide or the derivative thereof disclosed herein or the polynucleotides encoding the peptide or the derivative thereof disclosed herein on glucose uptake in 3T3-L1 adipocytes can be measured and compared with that of insulin. Pretreatment of the cells with a biologically active analog may generally produce a dose-dependent increase in 2- deoxyglucose uptake. The ability of the peptide or the derivative thereof disclosed herein or the polynucleotides encoding the peptide or the derivative thereof disclosed herein to regulate glucose production may be measured in any number of cell types, for example, H4lle hepatoma cells. In this assay, pretreatment with a biologically active analog may generally result in a dose-dependent inhibition of the amount of glucose released.

[0542] In embodiments, the peptide or the derivative thereof disclosed herein or the polynucleotides encoding the peptide or the derivative thereof disclosed herein is administered as an anti-diabetic regimen that decreases blood glucose levels; stimulates peripheral glucose disposal; and / or inhibits hepatic glucose production. In embodiments, the treatment regimen comprises administering the peptide or the derivative thereof disclosed herein or the polynucleotides encoding the peptide or the derivative thereof disclosed herein on an insulinlike regimen. For example, in embodiments, the peptide or the derivative thereof disclosed herein or the polynucleotides encoding the peptide or the derivative thereof disclosed herein is administered once in the morning or the evening (e.g., at bedtime), or in a twice-daily regimen (e.g., pre-breakfast and pre-evening meal, or as a continuous administration (e.g., analogously to administration of insulin via an insulin pump).

[0543] In embodiments, the peptide or the derivative thereof disclosed herein or the polynucleotides encoding the peptide or the derivative thereof disclosed herein administration is effective for providing glycemic control. Glycemic control refers to the typical levels of blood sugar (glucose) in a person with diabetes mellitus. Many of the long-term complications of diabetes, including microvascular complications, result from many years of hyperglycemia. Good glycemic control is an important goal of diabetes care. Because blood sugar levels fluctuate throughout the day and glucose records are imperfect indicators of these changes, the percentage of hemoglobin which is glycosylated is used as a proxy measure of long-term glycemic control in research trials and clinical care of people with diabetes. In this test, the hemoglobin A1c or glycosylated hemoglobin reflects average glucose values over the preceding 2-3 months. In non-diabetic persons with normal glucose metabolism glycosylated hemoglobin levels are usually about 4-6%...

Claims

CLAIMSWhat is claimed is:1 . A peptide or a derivative thereof, wherein the peptide comprises a general formula (I):N-L1-[Aaa]1-[Aaa]2-[Aaa]3-Gly-Thr-Phe-Thr-Ser-Asp-[Aaa]4-Ser-[Aaa]5-[Aaa]6-[Aaa]7-[Aaa]8- [Aaa]9-[Aaa]10-[Aaa]11-[Aaa]12-[Aaa]13-[Aaa]14-Phe-[Aaa]15-[Aaa]16-[Aaa]17-Leu-[Aaa]18- [Aaa]19-[Aaa]20-Gly-Pro-[Aaa]21-[Aaa]22-[Aaa]23-[Aaa]24-Pro-Pro-Pro-[Aaa]25-L2-C(I) wherein:N is the N-terminus;L1 and / or L2 are independently present or absent; and L1 and / or L2, if present, are each independently selected from a carrier protein, a tag, and a polymer, optionally wherein the L1 and / or L2 further comprise a linker that adjoins the carrier protein, tag, or polymer with the peptide;[Aaa]1 is His;[Aaa]2 is Ser or Gly;[Aaa]3 is His or Pro;[Aaa]4 is Phe or lie;[Aaa]5 is Leu or Vai;[Aaa]6 is Ala;[Aaa]7 is Leu or lie;[Aaa]8 is Asp or Glu;[Aaa]9 is Lys or Glu;[Aaa]10 is Gin;[Aaa]11 is Arg;[Aaa]12 is Gin;[Aaa]13 is Ala or Gin;[Aaa]14 is Glu;[Aaa]15 is lie or Leu;[Aaa]16 is Asp or Glu;[Aaa]17 is Trp;[Aaa]18 is Arg or Gly;[Aaa]19 is Ala;[Aaa]20 is Gly or Ala;[Aaa]21 is Pro or Ser;[Aaa]22 is Ser or Thr;[Aaa]23 is Gly or Ala;[Aaa]24 is Arg or Lys;[Aaa]25 is Arg or Lys; andC is the C-terminus.

2. A peptide or a derivative thereof, wherein the peptide comprises formula (II):N-L1 -[Aaa]1-[Aaa]2-[Aaa]3-Gly-Thr-Phe-Thr-Ser-Asp-[Aaa]4-Ser-[Aaa]5-[Aaa]6-[Aaa]7-[Aaa]8-[Aaa]9-[Aaa]10-[Aaa]11-[Aaa]12-[Aaa]13-[Aaa]14-Phe-[Aaa]15-[Aaa]16-[Aaa]17-Leu-[Aaa]18-[Aaa]19-[Aaa]20-Gly-Pro-[Aaa]21-[Aaa]22-[Aaa]23-[Aaa]24-Pro-Pro-Pro-[Aaa]25-L2-C(II) wherein:N is the N-terminus;L1 and / or L2 are independently present or absent; and L1 and / or L2, if present, are each independently selected from a carrier protein, a tag, and a polymer;[Aaa] 1 is a positively charged amino acid residue selected from His, Lys, and Arg;[Aaa]2 is a polar and neutral of charge hydrophilic amino acid selected from Ser, Asn, Gin, Thr, andPro, or a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met;[Aaa] 3 is a positively charged amino acid residue selected from His, Lys, and Arg, or a polar and neutral of charge hydrophilic amino acid selected from Pro Ser, Asn, Gin, and Thr;[Aaa]4 is a hydrophobic, aromatic amino acid selected from Phe, Trp, and Tyr, or a hydrophobic, aliphatic amino acid selected from lie, Gly, Ala, Leu, Met, and Vai;[Aaa]5 is a hydrophobic, aliphatic amino acid selected from Leu, Vai, lie, Gly, Ala, and Met;[Aaa]6 is a hydrophobic, aliphatic amino acid selected from Ala, Gly, Vai, lie, Leu, and Met;[Aaa]7 is a hydrophobic, aliphatic amino acid selected from Leu, lie, Vai, Gly, Ala, and Met;[Aaa]8 is a polar and negatively charged hydrophilic amino acid selected from Asp and Glu;[Aaa]9 is: a polar and positively charged hydrophilic amino acid selected from Lys, His, and Arg, or a polar and negatively charged hydrophilic amino acid selected from Glu, and Asp;[Aaa] 10 is a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro;[Aaa] 11 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His;[Aaa] 12 is a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro;[Aaa] 13 is a hydrophobic, aliphatic amino acid selected from Ala, Vai, Gly, Leu, lie, and Met, or a polar and neutral of charge hydrophilic amino acid selected from Gin, Asn, Ser, Thr, and Pro;[Aaa] 14 is a polar and negatively charged hydrophilic amino acid selected from Glu, and Asp;[Aaa] 15 is a hydrophobic, aliphatic amino acid selected from lie, Leu, Vai, Ala, Gly, and Met;[Aaa] 16 is a polar and negatively charged hydrophilic amino acid selected from Asp, and Glu;[Aaa] 17 is hydrophobic, aromatic amino acid selected from Trp, Phe, and Tyr;[Aaa] 18 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His, or a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met;[Aaa] 19 is a hydrophobic, aliphatic amino acid selected from Ala, Gly, Vai, Leu, lie, and Met;[Aaa]20 is a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met;[Aaa]21 is a polar and neutral of charge hydrophilic amino acid selected from Pro, Ser, Gin, Asn, and Thr;[Aaa]22 is a polar and neutral of charge hydrophilic amino acid selected from Ser, Thr, Gin, Asn, and Pro;[Aaa]23 a hydrophobic, aliphatic amino acid selected from Gly, Ala, Vai, Leu, lie, and Met;[Aaa]24 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His;[Aaa]25 is a polar and positively charged hydrophilic amino acid selected from Arg, Lys, and His; andC is the C-terminus.

3. The peptide or the derivative thereof of claim 2, wherein:[Aaa]1 is His;[Aaa]2 is Ser or Gly;[Aaa]3 is His or Pro;[Aaa]4 is Phe or lie;[Aaa]5 is Leu or Vai;[Aaa]6 is Ala;[Aaa]7 is Leu or lie;[Aaa]8 is Asp or Glu;[Aaa]9 is Lys or Glu;[Aaa]10 is Gin;[Aaa]11 is Arg;[Aaa]12 is Gin;[Aaa]13 is Ala or Gin;[Aaa]14 is Glu;[Aaa]15 is lie or Leu;[Aaa]16 is Asp or Glu;[Aaa]17 is Trp;[Aaa]18 is Arg or Gly;[Aaa]19 is Ala;[Aaa]20 is Gly or Ala;[Aaa]21 is Pro or Ser;[Aaa]22 is Ser or Thr;[Aaa]23 is Gly or Ala;[Aaa]24 is Arg or Lys; and / or[Aaa]25 is Arg or Lys.

4. The peptide or the derivative thereof of any one of claim 1 to 3, wherein the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60 to 69.

5. The peptide or the derivative thereof of claim 4, wherein the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60 to 69,or a variant thereof having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations with respect to an amino acid sequence selected from SEQ ID NOs: 60 to 69.

6. The peptide or the derivative thereof of claim 5, wherein the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 68 and SEQ ID NO: 69, or a variant thereof having 1 or 2 amino acid mutations with respect to an amino acid sequence selected from SEQ ID NOs: 60, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 68 and SEQ ID NO: 69.

7. The peptide or the derivative thereof of claim 6, wherein the peptide or the derivative thereof comprises an amino acid sequence that is selected from the amino acid sequence of SEQ ID NOs: 60, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 68 and SEQ ID NO: 69.

8. The peptide or the derivative thereof any one of claims 1 to 7, wherein the peptide or the derivative thereof comprises a carrier protein selected from Fc domain, albumin, transferrin, or elastin-like protein, Keyhole Limpet Hemocyanin (KLH), ovalbulin, or a variant thereof.

9. The peptide or the derivative thereof of claim 8, wherein the carrier protein comprises an Fc domain selected from an IgG Fc domain, an IgA Fc domain, an IgM Fc domain, an IgE Fc domain, and an IgD Fc domain, or a variant thereof.

10. The peptide or the derivative thereof of claim 9, wherein the carrier protein comprises the IgG Fc domain selected from an lgG1 Fc domain, an I gG2 Fc domain, an I gG3 Fc domain, and an I gG4 Fc domain, or a variant thereof.

11. The peptide or the derivative thereof of claim 10, wherein the carrier protein comprises the IgG Fc domain is selected from a human I gG1 Fc domain, and a human I gG4 Fc domain, or a variant thereof.

12. The peptide or the derivative thereof of claim 11, wherein the human lgG1 Fc domain comprises a hinge-CH2-CH3-Fc domain derived from human I gG1 or a derivative thereof.

13. The peptide or the derivative thereof of claim 11, wherein the human lgG4 Fc domain comprises a hinge-CH2-CH3-Fc domain derived from human I gG4 or a derivative thereof.

14. The peptide or the derivative thereof any one of claims 7 to 13, wherein the peptide or the derivative thereof further comprises a linker that adjoins the carrier protein with the peptide or the derivative thereof.

15. The peptide or the derivative thereof of claim 14, wherein the peptide linker is rigid or flexible.

16. The peptide or the derivative thereof any one of claims 1 to 15, wherein the peptide or the derivative thereof further comprises a glycosyl moiety.

17. The peptide or the derivative thereof of claim 16, wherein the glycosyl moiety is an N-linked glycosyl moiety.

18. The peptide or the derivative thereof of claim 16, wherein the glycosyl moiety is an O-linked glycosyl moiety.

19. The peptide or the derivative thereof any one of claims 1 to 18, wherein the peptide or the derivative thereof comprises one or more N-linked glycosylation consensus sites and / or O-linked glycosylation consensus sites.

20. The peptide or the derivative thereof any one of claims 1 to 19, wherein the peptide or the derivative thereof is biosynthesized as a single polypeptide chain.21 . The peptide or the derivative thereof any one of claims 1 to 20, wherein the peptide or the derivative thereof is biosynthesized from a single open reading frame.

22. The peptide or the derivative thereof any one of claims 1 to 21 , wherein the peptide or the derivative thereof is prepared using an expression system.

23. The peptide or the derivative thereof of claim 22, wherein the expression system is selected from bacterial, yeast, invertebrate, vertebrate, and plant expression system.

24. The peptide or the derivative thereof any one of claims 1 to 23, wherein the peptide or the derivative thereof further comprises a non-natural amino acid selected from an amino isobutyric acid (Aib), a D-amino acid, and those comprising a modification selected from N-methylation (Nm), Ca-methylation (Cm), (CH2NH) reduced amide bonds (Rd), and a peptoids (Pp)).

25. The peptide or the derivative thereof any one of claims 1 to 24, wherein the peptide or the derivative thereof comprises a polymer.

26. The peptide or the derivative thereof of claim 25, wherein the polymer is selected from poly (alkyl ene oxide) (e.g., polyethylene glycol (PEG)), poly(N-vinylpyrrolidone), poly(vinyl alcohol), poly(glycerol), poly(zwitterions), poly(carbonates), polyoxazoline, poly(acryloylmorpholine), poly(oxazolines), poly(sacharrides), and a combination thereof.

27. The peptide or the derivative thereof of claim 26, wherein the polymer is polyethylene glycol (PEG).

28. The peptide or the derivative thereof of claim 27, wherein one or more amino acids present in the peptide or the derivative thereof is PEGylated.

29. The peptide or the derivative thereof of claim 28, wherein the one or more PEGylated amino acids are located inside the carrier protein.

30. The peptide or the derivative thereof of any one of claims 27 to 29, wherein the PEGylation is conducted using a succinimidyl ester, an aldehyde, a maleimide, and / or a p-nitrophenyl carbonate ester reagent.31 . The peptide or the derivative thereof of any one of claims 27 to 30, wherein one or more Lys residues, one or more Ser residues, one or more Tyr residues, one or more His residues, one or more Cys residues, the N-terminus and / or the C-terminus are PEGylated.

32. The peptide or the derivative thereof of any one of claims 27 to 31, wherein the one or more PEGylated amino acids comprise a Lys residue.

33. The peptide or the derivative thereof of claim 32, wherein the PEGylation is conducted via amine conjugation.

34. The peptide or the derivative thereof of any one of claims 27 to 33, wherein the one or more PEGylated amino acids comprise a Gin residue.

35. The peptide or the derivative thereof of claim 34, wherein the PEGylation is conducted via transglutaminase (TGase) mediated enzymatic conjugation.

36. The peptide or the derivative thereof of any one of claims 27 to 35, wherein the one or more PEGylated amino acids comprise a Cys residue.

37. The peptide or the derivative thereof of claim 36, wherein the PEGylation is conducted via thiol conjugation.

38. The peptide or the derivative thereof of any one of claims 1 to 37, wherein the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on glucagon-like peptide- 1 receptor (GLP-1 R), glucagon-like peptide-2 receptor (GLP-2R), gastric inhibitory peptide receptor (GIPR), and / or glucagon receptor (GCGR).

39. The peptide or the derivative thereof of any one of claims 1 to 38, wherein the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R and GCGR.

40. The peptide or the derivative thereof of any one of claims 1 to 38, wherein the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R and GIPR.

41. The peptide or the derivative thereof of any one of claims 1 to 38, wherein the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R and GLP-2R.

42. The peptide or the derivative thereof of any one of claims 1 to 38, wherein the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GIPR and GCGR.

43. The peptide or the derivative thereof of any one of claims 1 to 38, wherein the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-2R and GIPR.

44. The peptide or the derivative thereof of any one of claims 1 to 38, wherein the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-2R and GCGR.

45. The peptide or the derivative thereof of any one of claims 1 to 38, wherein the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R, GIPR and GCGR.

46. The peptide or the derivative thereof of any one of claims 1 to 38, wherein the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R, GLP-2R and GCGR.

47. The peptide or the derivative thereof of any one of claims 1 to 38, wherein the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R, GLP-2R and GIPR.

48. The peptide or the derivative thereof of any one of claims 1 to 38, wherein the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-2R, GIPR and GCGR.

49. The peptide or the derivative thereof of any one of claims 1 to 38, wherein the peptide or the derivative thereof has independently an agonistic activity or an antagonistic activity on GLP-1 R, GLP-2R, GIPR and GCGR.

50. The peptide or the derivative thereof of any one of claims 1 to 49, wherein the peptide or the derivative thereof exhibits an EC50 value for GLP-1 R in the range of 100 pM to 1000 nM, as determined by a cell-based assay.

51. The peptide or the derivative thereof of any one of claims 1 to 50, wherein the peptide or the derivative thereof exhibits an EC50 value for GLP-1 R in the range of 2 nM to 100 nM, as determined by a cellbased assay, optionally wherein the peptide or the derivative thereof exhibits an I C50 value for GLP-1 R in the range of 10 pM to 10 pM, as determined by a cell-based assay.

52. The peptide or the derivative thereof of any one of claims 1 to 51 , wherein the peptide or the derivative thereof exhibits an EC50 value for GIPR in the range of 100 pM to 1000 nM, as determined by a cell-based assay.

53. The peptide or the derivative thereof of any one of claims 1 to 52, wherein the peptide or the derivative thereof exhibits an EC50 value for GIPR in the range of 100 pM to 2 nM, as determined by a cellbased assay.

54. The peptide or the derivative thereof of any one of claims 1 to 53, wherein the peptide or the derivative thereof exhibits an IC50 value for GIPR in the range of 10 pM to 10 pM, as determined by a cellbased assay.

55. The peptide or the derivative thereof of any one of claims 1 to 54, wherein the peptide or the derivative thereof exhibits an EC50 value for GCGR in the range of 100 pM to 1000 nM, as determined by a cell-based assay.

56. The peptide or the derivative thereof of any one of claims 1 to 55, wherein the peptide or the derivative thereof exhibits an EC50 value for GCGR in the range of 2 nM to 100 nM, as determined by a cellbased assay.

57. The peptide or the derivative thereof of any one of claims 1 to 56, wherein the peptide or the derivative thereof exhibits an IC50 value for GCGR in the range of 10 pM to 10 pM, as determined by a cellbased assay.

58. The peptide or the derivative thereof of any one of claims 1 to 57, wherein the peptide or the derivative thereof exhibits: an EC50 value for GCGR in the range of 10 pM to 10 pM, as determined by a cell-based assay or an I C50 value for GCGR in the range of 10 pM to 10 pM, as determined by a cell-based assay.

59. A fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 60, or a variant thereof having an amino acidsequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 60.

60. The fusion protein of claim 59, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 60.

61. A fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 61, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 61.

62. The fusion protein of claim 61, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 61.

63. A fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 62, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 62.

64. The fusion protein of claim 63, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 62.

65. A fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 63, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 63.

66. The fusion protein of claim 65, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 63.

67. A fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 64, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 64.

68. The fusion protein of claim 67, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 64.

69. A fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 65, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 65.

70. The fusion protein of claim 69, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 65.

71. A fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1 , GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 66, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 66.

72. The fusion protein of claim 71, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 66.

73. A fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 67, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selectedfrom substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 67.

74. The fusion protein of claim 73, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 67.

75. A fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 68, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 68.

76. The fusion protein of claim 75, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 68.

77. A fusion protein comprising a hinge CH2-CH3-Fc domain fused to a peptide or a derivative thereof having agonistic or antagonistic activity on the receptors of GLP-1, GLP-2, GIP, and / or glucagon, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 69, or a variant thereof having an amino acid sequence having about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more amino acid mutations, independently selected from substitutions, insertions, deletions, and truncations, with respect to the amino acid sequence selected from SEQ ID NO: 69.

78. The fusion protein of claim 77, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 69.

79. The fusion protein of any one of claims 59 to 78, wherein the hinge CH2-CH3-Fc domain is derived from IgG, IgM, IgA, IgD, or IgE.

80. The fusion protein of claim 79, wherein the IgG is selected from IgG 1 , lgG2, 1 gG3, and I gG4.81 . The fusion protein of any one of claims 59 to 80, wherein the hinge CH2-CH3-Fc domain is derived from lgG1.

82. The fusion protein of claim 81 , wherein the I gG 1 is human I gG 1 .

83. The fusion protein of claim 81 or claim 82, wherein the hinge CH2-CH3-Fc domain comprises an amino acid sequence that is at least about 95%, or at least about 97%, or at least about 97%, or at least about 98% or at least 99% identical to the amino acid sequence of SEQ ID NO: 4.

84. The fusion protein of any one of claims 59 to 80, wherein the hinge-CH2-CH3 Fc domain is derived from I gG4.

85. The fusion protein of claim 84, wherein the lgG4 is human I gG4.

86. The fusion protein of claim 84 or claim 85, wherein the hinge CH2-CH3-Fc domain comprises an amino acid sequence that is at least about 95%, or at least about 97%, or at least about 97%, or at least about 98% or at least 99% identical to the amino acid sequence SEQ ID NO: 1 , SEQ ID NO: 2, or SEQ ID NO: 3.

87. The fusion protein of any one of claims 59 to 86, wherein the hinge CH2-CH3-Fc domain is fused to the peptide or a derivative thereof via a linker.

88. The fusion protein of claim 84, wherein the linker has an amino acid sequence selected from SEQ ID NOs: 5 to 53.

89. An isolated polynucleotide encoding the peptide or the derivative thereof of any one of claims 1 to 23 or 39 to 58 or the fusion protein of any one of claims 59 to 88.

90. The isolated polynucleotide of claim 89, wherein the isolated polynucleotide is DNA.91 . The isolated polynucleotide of claim 89, wherein the nucleic acid is RNA.

92. The isolated polynucleotide of claim 89, wherein the isolated polynucleotide is selected from mRNA, circular RNA (circRNA) and self-amplifying RNA (saRNA), optionally wherein the polynucleotide is modified.

93. The isolated polynucleotide of claim 92, wherein the mRNA a modified mRNA (mmRNA).

94. The isolated polynucleotide of claim 93, wherein the mmRNA comprises at least one nucleoside modification selected from pseudouridine, N1-methylpseudouridine, 5-methylcytosine, 5-methoxyuridine, pyridin-4-one ribonucleoside, 5-aza-uridine, 2-thio-5-aza-uridine, 2-thiouridine, 4-thio-pseudouridine, 2-thio- pseudouridine, 5-hydroxyuridine, 3-methyluridine, 5-carboxymethyl-uridine, 1-carboxymethyl-pseudouridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyluridine, 1-taurinomethyl-pseudouridine, 5- taurinomethyl-2-thio-uridine, 1-taurinomethyl-4-thio-uridine, 5-methyl-uridine, 1-methyl-pseudouridine, 4- thio-1-methyl-pseudouridine, 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1 -methyl-1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio- dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2- thio-pseudouridine, 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine, 5-formylcytidine, N4-methylcytidine, 5-hydroxymethylcytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo- pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio-pseudoisocytidine, 4-thio-1 -methylpseudoisocytidine, 4-thio-1-methyl-1-deaza-pseudoisocytidine, 1 -methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy- cytidine, 2-methoxy-5-methyl-cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy- 1-methyl- pseudoisocytidine, 2-aminopurine, 2, 6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza- 2-aminopurine, 7-deaza-8-aza-2-aminopurine, 7-deaza-2, 6-diaminopurine, 7-deaza-8-aza-2,6- diaminopurine, 1 -methyladenosine, N6-methyladenosine, N6-isopentenyladenosine, N6-(cis- hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine, N6- glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosine, 2-methylthio-N6-threonyl carbamoyladenosine, N6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, and 2-methoxy- adenine, inosine, 1 -methyl-inosine, wyosine, wybutosine, 7-deaza-guanosine, 7-deaza-8-aza-guanosine, 6- thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyl-guanosine, 6-thio-7- methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1 -methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosine, 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2- methyl-6-thio-guanosine, and N2,N2-dimethyl-6-thio-guanosine, and combinations thereof.

95. The isolated polynucleotide of claim 93 or claim 94, wherein the mmRNA further comprises a 5'-cap and / or a poly A tail.

96. An expression vector comprising the isolated polynucleotide of claim 89 or claim 90.

97. A expression vector of claim 96, wherein the expression vector is a mammalian expression vector.

98. A host cell comprising the isolated polynucleotide of any one of claim 89 or claim 90, or the expression vector of claim 96 or claim 97.

99. A pharmaceutical composition comprising the peptide or the derivative thereof of any one of claims 1 to 58 or the fusion protein of any one of claims 59 to 88, or the isolated polynucleotide of any one of claim 89 to 95, or the expression vector of claim 96 or claim 67, or the host cell of claim 98.

100. A pharmaceutical composition comprising the mmRNA of any one of claims 93 to 95, and a pharmaceutically acceptable carrier.

101. The pharmaceutical composition of claim 99 or claim 100, wherein the carrier is a lipidoid, a liposome, a lipoplex, a lipid nanoparticle, a polymeric nanoparticle, a peptide, a protein, a cell, a nanoparticle mimic, a nanotube, or a conjugate.

102. The pharmaceutical composition of claim 101 , wherein the pharmaceutical composition is formulated as a lipid nanoparticle (LNPs), a lipoplex, or a liposome.

103. The pharmaceutical composition of claim 102, wherein the pharmaceutical composition is formulated as a lipid nanoparticle (LNPs).

104. The pharmaceutical composition of claim 103, wherein the lipid nanoparticles comprise lipids selected from an ionizable lipid (e.g, an ionizable cationic lipid selected from DLin-DMA, DLin-K-DMA, DLin- KC2-DMA, DLin-MC3-DMA, 98N12-5, and C12-200); a structural lipid (e.g., distearoylphosphatidylcholine (DSPC)); cholesterol, and a polyethyleneglycol (PEG)-lipid (e.g, a PEG-diacylglycerol (DAG), a PEG- dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide (Cer), or a mixture thereof, or a PEG- dilauryloxypropyl (C12, a PEG-dimyristyloxypropyl (C14), a PEG-dipalmityloxypropyl (C16), or a PEG- distearyloxypropyl (C18)); 1 ,2-dioleoyl-3-trimethylammoniumpropane (DOTAP); dioleoylphosphatidylethanolamine (DOPE); and the mmRNA.

105. The pharmaceutical composition of claim 104, wherein the lipid nanoparticles comprise (a) a cationic lipid comprising from 50 mol % to 85 mol % of the total lipid present in the particle; (b) a non-cationic lipid comprising from 13 mol % to 49.5 mol % of the total lipid present in the particle; and (c) a conjugated lipid that inhibits aggregation of particles comprising from 0.5 mol % to 2 mol % of the total lipid present in the particle.

106. The pharmaceutical composition of claim 104 or claim 105, wherein the lipid nanoparticles comprise a lipid selected from SM-102, DLin-DMA, DLin-K-DMA, DLin-KC2-DMA, DLin-MC3-DMA, 98N12-5, and C12- 200; a cholesterol; and a PEG-lipid.

107. The pharmaceutical composition of any one of claims 104 to 106, wherein the pharmaceutical composition is formulated for parenteral administration.

108. The pharmaceutical composition of claim 107, wherein the pharmaceutical composition is formulated for intradermal, intramuscular, intraperitoneal, intraarticular, intravenous, subcutaneous, intraarterial or transdermal administration.

109. A method of treating or preventing hyperglycemia, diabetes, obesity or metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), a cardiometabolic disease, or liver fibrosis or for reducing blood glucose, or for reducing fed and fasting blood glucose, or for reducing cardiovascular risk, or for decreasing body weight, decreasing food intake, decreasing blood glucose, decreasing liver adiposity, decreasing liver weight, decreasing subcutaneous white adipose tissue (sWAT), or for increasing glucose tolerance in a subject in need thereof, the method comprising administering to the subject the peptide or the derivative thereof of any one of claims 1 to 58 or the fusion protein of any one of claims 59 to 88, or the isolated polynucleotide of any one of claim 89 to 95, or the expression vector of claim 96 or claim 97, or the host cell of claim 98, or the pharmaceutical composition of claim 99 to 108.

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