CN-122011124-A - GLP-1R/GIPR/GCGR triple receptor agonist and application thereof

Abstract

The invention provides a GLP-1R/GIPR/GCGR triple receptor agonist and application thereof. Specifically, the invention provides a polypeptide with GLP-1R/GIPR/GCGR triple receptor agonistic activity or pharmaceutically acceptable salt thereof, which has obvious triple agonistic activity of a glucagon-like peptide-1 (GLP-1) receptor, a Gastric Inhibitory Polypeptide (GIP) receptor and a glucagon (GCG) receptor, 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

• YAN YIRAN
• ZHANG CHI
• 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 having GLP-1R/GIPR/GCGR triple receptor agonistic activity, or a pharmaceutically acceptable salt thereof, characterized in that the polypeptide has an amino acid sequence represented by the following formula (I): Xaa 1 Xaa 2 MGTFTSDKSKYLDERAAYDFVQWLLDGGPSTGAPPPT(I) Wherein, the Xaa 1 is H or M, Xaa 2 is V, aib or S.
2. 2. The polypeptide of claim 1, wherein the polypeptide is a modified polypeptide or an unmodified polypeptide.
3. 3. The polypeptide of claim 2, 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, or combinations thereof, preferably long chain fatty acids.
4. 4. A polypeptide according to claim 3, 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.
5. 5. The polypeptide of claim 4, wherein said covalent linkage is via a gamma-carboxylic acid linkage.
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: Q3M, Q20Y, S T and S39T.
7. 7. 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: H1M, aib2S, Q3M, Q20Y, S T and S39T.
8. 8. 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: Aib2V, Q3M, Q20Y, S T and S39T.
9. 9. The polypeptide of claim 1, wherein the polypeptide comprises an amino acid sequence as set forth in any one of SEQ ID NOs 6, 8, 9, and wherein the 10 th position of the polypeptide is a modified K.
10. 10. 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.

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 Obesity is a health problem that needs to be addressed in the 21 st century, and severe obesity can lead to insulin resistance and, in turn, diabetes. Diabetes is a metabolic disease characterized by sustained hyperglycemia, which can cause serious damage to multiple organ systems for a long period of time, causing various complications. As the prevalence of obesity continues to expand, the risk of various chronic and debilitating diseases is also 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 the problems of insufficient agonistic efficacy, poor glucose control and weight reduction effects and the like. 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. Ruitalutide (Ruitalutide) is the fastest GLP-1R/GIPR/CGCR triple receptor agonist, has been put into a three-phase clinical test at present, has a half-life period prolonged to 6 days and has good hypoglycemic and weight-reducing effects, so GLP-1R/GIPR/GCGR triple receptor agonists with different amino acid sequences have been developed in the prior art, but still have a plurality of defects. Therefore, the invention has urgent need to develop GLP-1R/GIPR/GCG triple receptor agonists with excellent GLP-1R/GIPR/GCG triple receptor agonism and excellent glucose control and weight reduction effects. 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 GLP-1R/GIPR/GCGR triple receptor agonistic activity, or a pharmaceutically acceptable salt thereof, said polypeptide having an amino acid sequence represented by the following formula (I): Xaa1Xaa2MGTFTSDKSKYLDERAAYDFVQWLLDGGPSTGAPPPT(I) Wherein, the Xaa 1 is H or M, Xaa 2 is V, aib or S. 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, or combinations thereof, preferably long chain fatty acids. In another preferred embodiment, 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. In another preferred embodiment, the covalent linkage is via a gamma-carboxylic acid linkage. In another preferred embodiment, the polypeptide or pharmaceutically acceptable salt thereof has the activity of binding to and activating glucagon-like peptide-1 (GLP-1) receptor, gastric Inhibitory Polypeptide (GIP) receptor and glucagon (GCG) receptor simultaneously. In another preferred embodiment, the polypeptide consists of an amino acid sequence represented by the following formula (I). In another preferred embodiment, the structure of the polypeptide is as shown in formula (I). In another preferred embodiment, xaa 1 is H and Xaa 2 is Aib. In another preferred embodiment, xaa 1 is M and Xaa 2 is Aib or V. In another preferred embodiment, the covalent linkage at position 10K at the N-terminus in the amino acid sequence of the polypeptide additionally comprises a long chain fatty acid selected from the group consisting of gamma-glutamyl (gamma Glu), 8-amino-3, 6-dioxaoctanoic acid (AEEA), or oligoethylene glycol (OEG), or a combination thereof, preferably 8-amino-3, 6-dioxaoctanoic acid (AEEA) or gamma-glutamyl (gamma Glu). In another preferred embodiment, the polypeptide has the amino acid sequence shown in SEQ ID NO. 6. In another preferred embodiment, the polypeptide has anti-DPP-IV enzyme cleavage activity. In another preferred embodiment, the pharmaceutically acceptable salt is an alkali metal salt (e.g., sodium