Pegylation hypoglycemic polypeptide and preparation method and application thereof

Abstract

The invention discloses pegylation hypoglycemic polypeptide. The pegylation hypoglycemic polypeptide has an amino acid sequence as shown by the sequence 1 (SQDID NO:1): His-Gly-Glu-Gly-Xaa1-Phe-Thr-Ser-Asp-Leu-Ser-Xaa2-Xaa3-Xaa4-Glu-Glu-Glu-Ala-Va1-Xaa5-Leu-Phe-I le-Glu-Trp-Leu-Xaa6-Xaa7-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Xaa8; and a side-chain hydrosulfide group of C-terminal amino acidXaa8 of the hypoglycemic polypeptide is in covalent linkage with polyethylene glycol. The GLP-1 receptor stimulating agent activity of the pegylation hypoglycemic polypeptide is higher than that of aGLP-1 prototype molecule. A peptide sequence of the molecule does not contain recognition sites of dipeptidyl peptidase and neutral peptidase and has high stability. Besides, due to the masking action of the polyethylene glycol, the immunogenicity of a modified peptide molecule is basically eliminated, and when the polyethylene glycol of which the molecular weight is over 20 kDa is adopted to perform modification, the pharmacokinetic half-life of the pegylation hypoglycemic polypeptide can be over 48 hours.

Description

technical field [0001] The invention relates to a pegylated hypoglycemic polypeptide and its use as a drug for treating diabetes. Background technique [0002] Diabetes mellitus is a metabolic disease of multiple etiologies characterized by chronic hyperglycemia accompanied by disturbances in carbohydrate, fat and protein metabolism due to defects in insulin secretion and / or action. Diabetes can be easily divided into type 1 and type 2. Type 1 diabetes is insulin-dependent; type 2 diabetes is insulin-independent. Type 2 diabetes accounts for 90%-95% of the numerous diabetic patients. [0003] The incidence of diabetes is increasing year by year. According to WHO statistics, the current incidence of diabetes is 2.8%, and it is expected that this value will increase to 4.8% by 2030. According to the CDCP report of the United States, diabetic patients account for 6.8% of the entire American population, and 90-95% of them are type 2 diabetic patients. With the improvement o...

AI Technical Summary

Problems solved by technology

These effects make GLP-1 an ideal drug candidate molecule for the treatment of diabetes, but the GLP-1 prototype molecule has not been used clinically for many years, mainly because GLP-1 has a very short action time in the body and its plasma half-life is less than 2 minutes. After intravenous administration, it is quickly inactivated by endogenous dipeptidyl peptidase (DPP4) cutting off 2 amino acids from the N-terminus, and the fragment GLP-1 (9-36) produced after enzymatic hydrolysis is the natural GLP-1 Antagonists, which further inhibited the effect of GLP-1

Second, the modified polypeptide has certain immunogenicity, and the polypeptide needs to be administered repeatedly for a long time in the treatment of diabetes, and the problem of immunogenicity becomes particularly serious

Third, there are many problems in the physical and chemical properties of the modified or allosteric polypeptide molecules obtained by structural modification (for example, the use of fatty acid modification will lead to a decrease in water solubility)

Fourth, the duration of the hypoglycemic effect of many modified polypeptides in vivo is still not long enough (for example, the in vivo half-life of exendin-4 that is already on the market is only about 2.4 hours)

However, the molecules finally obtained in previous studies either had the problem of increased stability but decreased activity, or had the problem of increased activity but decreased stability

So far, no ideal molecular structure with high agonist activity, low immunogenicity and long action time in vivo has been reported in literature or patent applications

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