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Insulin amyloid polypeptide inhibitor, preparation method and application thereof

A technology of amyloid polypeptide and inhibitor, applied in the field of polypeptide compounds for the treatment of diabetes

Inactive Publication Date: 2015-02-04
刘旭
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite this, there are no well-developed amylin inhibitors available for the prevention or treatment of diabetes

Method used

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  • Insulin amyloid polypeptide inhibitor, preparation method and application thereof
  • Insulin amyloid polypeptide inhibitor, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0011] Chemical Synthesis of Peptides

[0012] Inhibitor 2 was prepared by Fmoc-protected solid-phase synthesis technique. The synthesis reaction was carried out from the C-terminus to the N-terminus according to the inhibitor 2 sequence, and there were free amino groups on Rink amide MBHA resin and Fmoc-Gly-Wang resin as carriers (available from Advanced Chem Tech). During each ligation step, the amino acid residues are activated, and there are 4 times as many HBTU, HOBt, DIEA and Fmoc-amino acids as there are free amino groups on the carrier in the activation mixture. Use 6-chloro-1-hydroxybenzotriazole and N,N-diisopropylcarbodiimide as condensing agents to carry out connection reaction. After each amino acid connection reaction, use pyridine / acetic acid / N-methyl A mixture of imidazole (4:1:0.5) was used to block the unconnected free amino group, and the blocking reaction was 10 minutes. Before the next amino acid is connected, the Fmoc-group on the carrier must be remove...

Embodiment 2

[0015] In Vitro Apoptosis Assay by Amylin Inhibitor 2

[0016] In this experiment, the effect of insulin amyloid peptide inhibitor 2 on inhibiting the apoptosis of insulinoma cells (INS-1 cells) was studied. After the cells were treated with 10 μmol / L insulin-like amyloid polypeptide, many green bright spots appeared after TUNEL staining compared with the medium control group, indicating that there were apoptotic cells in the system. When 20 μmol / L insulin-amyloid peptide inhibitor 2 was co-incubated with insulin-amyloid peptide, microscopic examination showed fewer green highlights than the control group with insulin-like amyloid peptide alone. After counting and counting the photographs, it was found that the apoptosis rate of cells treated with 10 μmol / L insulin-like amyloid polypeptide was about 65.0%, while the apoptosis rate of cells treated with 20 μmol / L inhibitor 2 and insulin-like amyloid polypeptide was reduced to 30.2% (p<0.05). And there was no significant diffe...

Embodiment 3

[0018] In vivo hypoglycemic experiment of amylin inhibitor 2

[0019] Kunming mice were fed with high-fat and high-sugar to a body weight of 18-22 g, half male and half female, fasted for 24 hours before the experiment, and intraperitoneally injected with streptozotocin (STZ) 50 mg / kg (1% citrate buffer). liquid solution preparation). One week later, blood glucose (BS) was measured by blood collection from the tail vein of the mice. If the BS was higher than 16mmol / L, the modeling was successful. After modeling, the mice were divided into 3 groups, 10 in each group. Diabetes model group (DM group): subcutaneous injection of the same amount of PBS buffer; control group (insulin): 20 μg / kg subcutaneous injection (dissolved in 0.1mol / L PBS buffer), twice a day for 9 consecutive days; sample group (Amylin inhibitor 2): the same as the control group; another 10 normal mice were taken as the blank group. On the 9th day after administration, blood was taken from the tail vein to me...

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Abstract

Insulin amyloid polypeptide inhibitor, preparation method and application thereof. The invention relates to the field of drugs and particularly relates to an inhibitor 1 compound which can treat diabetes. A sequence of the inhibitor 2 is VLSVAALNHLDKATPIESH. A preparation method of the inhibitor 2 is carried out through Fmoc-protected solid-phase synthetic technology, with Rink amide MBHA resin and Fmoc-Gly-Wang resin as supporters, with 6-chloro-1-hydroxylbenzotriazole and N,N-diisopropyl carbodiimide as condensing agents, and with trifluoroacetic acid as a cutting reagent. The invention also provides an application of the inhibitor 2 for preventing or treating diabetes and complications thereof, wherein the complications comprise diabetic nephropathy, diabetic hypertension, diabetic eye diseases and diabetic neurogenic lesion. The inhibitor 2 can be employed for preventing or treating the diabetes and the complications thereof through various dosing methods, such as subcutaneous injection or intramuscular injection, intravenous injection or intravenous drip, and oral medication, such as pills, capsules, nasal spray agents and the like. The islet amyloid polypeptide inhibitor 2 can targetedly inhibit generation of islet amyloid polypeptide, thereby preventing or treating diabetes.

Description

Technical field: [0001] The invention relates to the field of medicine, in particular to a polypeptide compound for treating diabetes. Background technique [0002] Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia. It is a syndrome of glucose, protein and lipid metabolism disorders caused by insufficient insulin or defects in insulin cell metabolism. In recent years, the number of diabetic patients has gradually increased, and is divided into type I diabetes and type II diabetes. Among them, the number of patients with type II diabetes accounts for 85-90% of the total number of diabetes, which seriously threatens the health and life of patients. If diabetes is not well controlled, it may cause many complications, such as diabetic nephropathy, retinopathy, high blood pressure, etc. [0003] Recent studies have shown that in the pathogenesis of type 2 diabetes, increasing β-cell apoptosis is the main cause of β-cell decline and hyperglycemia....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08C07K1/06C07K1/04A61K38/10A61P3/10A61P27/02A61P25/00A61P9/12A61P13/12
Inventor 罗瑞雪
Owner 刘旭
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