Search

CN-122011123-A - GLP-1R/GIPR/GCGR triple receptor agonist and application thereof

CN122011123ACN 122011123 ACN122011123 ACN 122011123ACN-122011123-A

Abstract

The invention provides a polypeptide with GLP-1R/GIPR/GCGR triple receptor agonistic activity or pharmaceutically acceptable salt thereof, has obvious triple receptor agonistic activity of glucagon-like peptide-1 (GLP-1), gastric Inhibitory Polypeptide (GIP) and glucagon (GCG) and DPP-IV enzyme digestion resistance, and can be used for preparing a pharmaceutical composition for preventing or treating metabolic diseases such as type I diabetes, type II diabetes, gestational diabetes, obesity, nonalcoholic fatty liver disease (NAFLD), obesity, hyperlipidemia and the like.

Inventors

  • ZHANG CHI
  • LU WEI
  • YAN YIRAN
  • LI XIULING

Assignees

  • 上海生物制品研究所有限责任公司

Dates

Publication Date
20260512
Application Date
20260306

Claims (10)

  1. 1. A polypeptide or a pharmaceutically acceptable salt thereof, wherein the polypeptide has an amino acid sequence according to formula (I): Xaa 1 Xaa 2 Xaa 3 GTFTSDXaa 10 SXaa 12 YLXaa 15 Xaa 16 RAAXaa 20 DFVQWLLDGGPSXaa 33 GAPPPXaa 39 (I) Wherein, the Xaa1 is M or H or Y, Xaa2 is S, V, aib or A, Xaa3 is Q or M, Xaa10 is K or Y, or modified K or Y, Xaa12 is Y or K, Xaa15 is D or H, and, Xaa16 is either I or E, Xaa20 is Y or Q, and is, Xaa33 is S or T, Xaa39 is S or T, And The amino acid sequence of the formula (I) is not the amino acid sequence shown in SEQ ID NO. 2, The polypeptide or a pharmaceutically acceptable salt thereof has both activity of binding to and activating glucagon-like peptide-1 (GLP-1) receptor, gastric Inhibitory Polypeptide (GIP) receptor and glucagon (GCG) receptor.
  2. 2. The polypeptide of claim 1, wherein the polypeptide has high GLP-1R selectivity, and the "high GLP-1R selectivity" means that the GLP-1R selectivity of the polypeptide is Y1≤2 under the same reaction conditions, Wherein, the YA is the agonistic activity of the polypeptide to be tested on GLP-1R, YB is the agonistic activity of the polypeptide to be tested on GCGR.
  3. 3. The polypeptide of claim 1, wherein the polypeptide is a modified polypeptide or an unmodified polypeptide.
  4. 4. The polypeptide of claim 3, wherein the amino acid sequence of the modified polypeptide has covalently attached thereto a side chain selected from the group consisting of long chain fatty acids, polyethylene glycol chains, hydrophilic polymers, hydrophilic spacer arms, glycosylated side chains, cholesterol groups, fatty diacid side chains, hydrophobic alkyl chains, polypeptide or protein fusion tags, or combinations thereof, preferably long chain fatty acids.
  5. 5. The polypeptide of claim 4, wherein the long chain fatty acid is selected from the group consisting of an n-hexadecanoyl (C16) chain, or an octadecanedioyl (C18) chain, or a combination thereof, preferably an n-hexadecanoyl (C16) chain.
  6. 6. The polypeptide of claim 1, wherein the amino acid sequence of the polypeptide has the following core amino acid mutations relative to SEQ ID No. 2: S33T and S39T.
  7. 7. The polypeptide of claim 1, wherein the amino acid sequence of the polypeptide has the following core amino acid mutations H1M, aib2S, Q3M, Q20Y, S T and S39T relative to SEQ ID NO. 2.
  8. 8. The polypeptide of claim 1 or 7, wherein the polypeptide has an amino acid sequence as set forth in SEQ ID No. 20.
  9. 9. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises: (1) The polypeptide or a pharmaceutically acceptable salt thereof according to claim 1, and (2) A pharmaceutically acceptable carrier.
  10. 10. Use of a polypeptide according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition.

Description

GLP-1R/GIPR/GCGR triple receptor agonist and application thereof Technical Field The invention belongs to the field of biological medicine, and particularly relates to a GLP-1R/GIPR/GCGR triple receptor agonist and application thereof. Background Diabetes is a health problem to be solved worldwide, is a metabolic disease characterized by persistent hyperglycemia, causes serious damage to multiple organ systems, and causes various complications. The prevalence of obesity is also expanding and the risk of various chronic and debilitating diseases is increasing, including but not limited to diabetes, hypertension and dyslipidemia. Therefore, developing innovative therapeutic drugs and therapeutic strategies for obesity and diabetes and its complications is of great importance for improving human health. At present, drugs with certain therapeutic effects on obesity and diabetes have been developed and applied to clinical treatment, including single-molecule single-receptor agonists targeting GLP-1R, such as liraglutide (Liraglutide) and semraglutide (Semaglutide), and single-molecule double-receptor agonists targeting GLP-1R/GIPR (such as telipopeptide) and GLP-1R/GCGR (such as cocoa-degree peptide (Cotadutide)), but the two drugs generally show insufficient agonistic efficacy, short half-life, low stability and bioavailability, and have limitations such as dose-dependent gastrointestinal side effects. The new generation of metabolic drugs for diabetes, obesity and the like at present mainly focuses on research of single-molecule pleiotropic receptor agonists, such as GLP-1R/GIPR/GCGR triple receptor agonists. Ruitalu peptide (Retatrutide) is the fastest GLP-1R/GIPR/CGCR triple receptor agonist, and has been subjected to three-phase clinical test, the half life period of the Ruitalu peptide is prolonged to 6 days, and the Ruitalu peptide has good blood glucose and weight reducing effects, but mild to moderate gastrointestinal reactions are usually present. Although GLP-1R/GIPR/GCGR triple receptor agonists of different amino acid sequences have been developed in the prior art, there are still a number of disadvantages. Therefore, research and development of GLP-1R/GIPR/GCGR triple receptor agonists with novel structure, higher bioavailability, better treatment effect, higher stability and lower production cost and fewer side effects can remarkably improve blood sugar control and weight control efficiency, provides a safer and more effective treatment method for metabolic diseases such as obesity, diabetes and the like and complications thereof, and is an important problem to be solved in the field. Disclosure of Invention The invention provides a GLP-1R/GIPR/GCGR triple receptor agonist or pharmaceutically acceptable salt thereof and application thereof. In a first aspect of the present invention there is provided a polypeptide having an amino acid sequence of formula (I): Xaa1Xaa2Xaa3GTFTSDXaa10SXaa12YLXaa15Xaa16RAAXaa20DFVQWLLDGGPSXaa33GAPPPXaa39 (I) Wherein, the Xaa1 is M or H or Y, Xaa2 is S, V, aib or A, Xaa3 is Q or M, Xaa10 is K or Y, or modified K or Y, Xaa12 is Y or K, Xaa15 is D or H, and, Xaa16 is either I or E, Xaa20 is Y or Q, and is, Xaa33 is S or T, Xaa39 is S or T, And The amino acid sequence of the formula (I) is not the amino acid sequence shown in SEQ ID NO. 2, The polypeptide or a pharmaceutically acceptable salt thereof has both activity of binding to and activating glucagon-like peptide-1 (GLP-1) receptor, gastric Inhibitory Polypeptide (GIP) receptor and glucagon (GCG) receptor. In another preferred embodiment, the polypeptide has a high GLP-1R selectivity. In another preferred embodiment, the term "GLP-1R high selectivity" means that the GLP-1R selectivity of the polypeptide is Y1≤2 under the same reaction conditions, Wherein, the YA is the agonistic activity of the polypeptide to be tested on GLP-1R, YB is the agonistic activity of the polypeptide to be tested on GCGR. In another preferred embodiment, Y1 is equal to or less than 1.5, preferably equal to or less than 1, and more preferably equal to or less than 0.5. In another preferred embodiment, the reaction conditions are a polypeptide concentration of 10 -5~10-12 mol/L, a reaction temperature of 37℃and a reaction time of 4 hours. In another preferred embodiment, Y1 is 0.0001 to 2, preferably 0.001 to 1.5, more preferably 0.01 to 1. In another preferred embodiment, the polypeptide is a modified polypeptide or an unmodified polypeptide. In another preferred embodiment, the amino acid sequence of the modified polypeptide has covalently attached thereto a side chain selected from the group consisting of long chain fatty acids, polyethylene glycol chains, hydrophilic polymers, hydrophilic spacer arms, glycosylated side chains, cholesterol groups, fatty diacid side chains, hydrophobic alkyl chains, polypeptide or protein fusion tags, or combinations thereof, preferably long chain fatty acids. In another preferred embodiment, the long chai