Novel oligopeptide COX53-64 for inhibiting glucose-induced insulin secretion and application of novel oligopeptide COX53-64

Abstract

Hyperinsulinemia is a pathogenesis basis of coronary heart disease, hypertension, hyperlipidemia, type II diabetes and obesity, and is also one of reasons for complications of the coronary heart disease, hypertension, hyperlipidemia, type II diabetes and obesity. At present, no good coping method exists. The invention discloses an oligopeptide with activity of inhibiting glucose-induced insulin secretion. The polypeptide COX52-69 with the function of inhibiting insulin secretion is subjected to gradual truncation and functional experiments, a key active fragment which still keeps the function of inhibiting insulin secretion is screened, and the sequence of the key active fragment is LPAGWVLSHLDS (namely a continuous fragment obtained after amino acid is gradually removed from the sequence of the original polypeptide COX52-69, and the key active fragment is called COX53-64). Experiments show that the novel oligopeptide fragment can still inhibit glucose-induced insulin secretion in an in-vitro model. The novel oligopeptide provided by the invention has fewer amino acids and is easier to synthesize and modify, so that the cost is saved to a greater extent, and the novel oligopeptide can be applied to development of drugs for treating hyperinsulin and metabolic disorder related diseases caused by hyperinsulin.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a polypeptide fragment capable of inhibiting glucose-induced insulin secretion, its derivatives, a pharmaceutical composition containing the polypeptide fragment, and its use in the prevention or treatment of diseases related to abnormal insulin secretion (such as diabetic complications, hyperinsulinemia, etc.). Background Technology

[0002] Hyperinsulinemia is a syndrome characterized by excessively high levels of insulin in the blood. There are two types of hyperinsulinemia: hyperinsulinemia with normal blood glucose levels and congenital hyperinsulinemia. Insulin maintains blood glucose balance by promoting glucose uptake in insulin-sensitive tissues, reducing glucose production in the liver, kidneys, and small intestine, and stimulating the synthesis of fatty acids and glycogen. However, excessive insulin can lead to obesity, type 2 diabetes, atherosclerosis, and many other complications, posing a significant threat to human health. Therefore, developing drugs that can regulate (especially inhibit) glucose-induced insulin secretion is of great clinical significance. Currently, the selection of drugs for directly inhibiting insulin secretion in clinical practice is limited. Previous laboratory studies have found that a polypeptide named COX52-69, isolated from porcine small intestine, has inhibitory activity against glucose-induced insulin secretion. However, the full-length COX52-69 polypeptide still suffers from drawbacks such as high synthesis cost, poor stability, and complex structure, which hinders structure-activity relationship studies. To develop candidate molecules with greater clinical application potential, we optimized the structure of the original polypeptide and identified the minimum active core fragment necessary for its function. Summary of the Invention

[0003] This invention involves cleaving the original polypeptide COX52-69 to provide a novel short peptide, LPAGWVLSHLDS (COX53-64), which has fewer amino acids, a simpler structure, and lower synthesis costs, while retaining the active function of the original polypeptide. Technical solution

[0004] The sequence of the proto-peptide COX52-69 (discovered by our laboratory and previously patented) was screened by progressively shortening it from the N-terminus and C-terminus.

[0005] Experiments were conducted on peptides of different lengths to screen for active fragments that inhibit glucose-induced insulin secretion.

[0006] The polypeptide fragments provided by this invention have shorter sequences than the original full-length polypeptides, significantly reducing chemical synthesis costs, increasing yield, and making them easier to mass-produce and control in terms of quality.

[0007] This core active fragment identifies the key regions where the original peptide functions, laying the foundation for subsequent rational drug design and optimization of its activity, stability, or pharmacokinetic properties through amino acid substitution and other methods.

[0008] This fragment retains its original biological activity, providing a new candidate molecular entity for the development of novel insulin secretion regulators. Attached Figure Description

[0009] Figure 1 This provides the amino acid sequence information for the linear peptide COX53-64.

[0010] Figure 2 This study, using ELISA to measure insulin release from pancreatic β-cells treated with different fragments of the linear peptide, found that the linear peptide from the fifth fragment can effectively inhibit hyperglycemia-induced insulin secretion.

Claims

1. A synthetic polypeptide, characterized in that, The polypeptide has the activity of inhibiting glucose-induced insulin secretion, and the amino acid sequence thereof comprises LPAGWVLSHLDS (COX53-64); the synthetic polypeptide is characterized in that the polypeptide has the activity of inhibiting glucose-induced insulin secretion, and the amino acid sequence thereof comprises LPAGWVLSHLDS (COX53-64).

2. The polypeptide of claim 1, wherein, The polypeptide also has the activity of inhibiting glucose-induced insulin secretion when the amino acid sequence comprises LLPAGWVLSHLDSY (linear peptide 6).

3. The polypeptide of claims 1-2, wherein A modified peptide with the intermediate amino acid modified, i.e. LPAGWV-[N-Me-Leu]-SHLDS, is used to increase the oral stability thereof.

4. The polypeptide according to claims 1-3, characterized in that, The polypeptide is a pharmaceutically acceptable salt, ester, amide or acetylated derivative thereof.

5. The polypeptide according to any one of claims 1-4 or use according to claim for the preparation of a medicament for inhibiting insulin secretion.

6. The polypeptide according to any one of claims 1-4 or use according to claim for the preparation of a medicament for the complications associated with hyperinsulinism.

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