Application of GLP-1R/GCGR double-target agonist polypeptide to treatment of fatty liver diseases, hyperlipidemia and arteriosclerosis

一种双激动剂、脂肪肝病的技术，应用在生物化学领域，能够解决mPEG毒性忽视等问题，达到抑制和改善肝纤维化及肝硬化、改善肝脏脂肪样变性和非酒精性脂肪肝病、抑制和肝脏脂肪样变性和非酒精性脂肪肝病的效果

Active Publication Date: 2016-10-26
SHENZHEN TURIER BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Toxicity of mPEG is currently largely ignored

Method used

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  • Application of GLP-1R/GCGR double-target agonist polypeptide to treatment of fatty liver diseases, hyperlipidemia and arteriosclerosis
  • Application of GLP-1R/GCGR double-target agonist polypeptide to treatment of fatty liver diseases, hyperlipidemia and arteriosclerosis
  • Application of GLP-1R/GCGR double-target agonist polypeptide to treatment of fatty liver diseases, hyperlipidemia and arteriosclerosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0223] Embodiment 1, the synthesis of polypeptide compound

[0224] Material:

[0225] All amino acids were purchased from NovaBiochem. Unless otherwise specified, all other reagents were of analytical grade and purchased from Sigma. A Protein Technologies PRELUDE 6-channel peptide synthesizer was used. A Phenomenex Luna C18 preparative column (46mm x 250mm) was used to purify the peptides. The high-performance liquid chromatograph is a product of Waters Company. Mass spectrometry was performed using an Agilent mass spectrometer.

[0226] Taking polypeptide compound 6 as an example to illustrate the synthetic method of the polypeptide compound of the present invention:

[0227] Structure sequence:

[0228] His-(D-Ser)-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Lys(PEG 2 -PEG 2 -γGlu-CO(CH 2 ) 14 CH 3 )-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser- NH 2

[0229] a) Main peptide chain assembly:

[0230] A...

Embodiment 2

[0260] Example 2 In vitro inhibitory effect of GLP-1R / GCGR dual agonist polypeptide on liver fibrosis

[0261] The human hepatic stellate cell line LX-2 was selected to study and observe the effect of different doses of the test substance on the expression of the activation marker α-SMA of LX-2 cells.

[0262] Human hepatic stellate cells LX-2 were plated on a 35mm cell culture dish and cultured with DMEM (high glucose) + 10% FBS + 1% double antibody medium (Thermo Fisher) at 37°C, 5% CO 2 Under the conditions, when the cells grow to 70% confluency, there is no serum overnight. The next morning, the cells are treated with the above compound 1-37 (dissolved in PBS) for 48 hours, and then the cell protein is extracted for Western Blot. β-actin is used as an internal reference, and Image J 1.50i grayscale analysis of the expression levels of α-SMA and β-actin. Negative control only added the same volume of PBS as the experimental group.

[0263] Compounds 2, 5, 16, and 19 at 0....

Embodiment 3

[0269] Embodiment 3, GLP-1R / GCGR double agonist polypeptide to CCl 4 Improved therapeutic effect of induced liver fibrosis in mice

[0270] SPF-grade healthy C57 mice, 6-8 weeks old, weighing 20-25g, were provided by the Guangdong Provincial Experimental Animal Center, and experiments were carried out in the SPF-grade laboratory of the Experimental Animal Center of Guangdong Pharmaceutical University. C57 mice were divided into control group, liver fibrosis model group and treatment group, with 8 mice in each group. Mice were injected intraperitoneally with 20% CCl 4 (2mL / kg, diluted 1:4 with olive oil), 2 times a week for 6 weeks, to form a stable animal model of liver fibrosis. In the treatment group, one of the compounds 2, 6 and 22 was injected subcutaneously at 500 μg / kg body weight at the same time, once every other day for 6 weeks. The control group was given olive oil with the same volume and frequency until the end of the 6-week experiment. After the experiment, m...

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Abstract

The invention relates to application of a polypeptide compound having double agonist effects on a glucagon-like peptide-1 receptor and a glucagon receptor. The polypeptide compound has the characteristics of high enzymolysis stability, high bioactivity, no adverse reaction, etc., can alleviate abnormal rise in the levels of total cholesterol and triglyceride in blood induced by diabetes and high-meal diet, lowers the level of liver enzyme, improves liver damage and fibrosis stage and is applicable to prevention or treatment of diseases like non-alcoholic fatty liver diseases, hyperlipidemia and arteriosclerosis.

Description

technical field [0001] The invention belongs to the technical field of biochemistry, and in particular relates to a class of GLP-1R / GCGR dual-target agonist polypeptides. The present invention also relates to the preventive and / or therapeutic use of the above-mentioned dual-target agonist polypeptide for diseases such as non-alcoholic fatty liver disease, hyperlipidemia, and arteriosclerosis. Background technique [0002] Non-alcoholic fatty liver disease (NAFLD) is a progressive and complex liver disease caused by non-alcoholic excess: from steatosis, non-alcoholic hepatitis (NASH), further development to liver fibrosis (Fibrosis) and liver cirrhosis (Cirrhosis) ), and eventually develop into hepatocellular carcinoma or liver failure. The global prevalence of NAFLD has doubled in the past 30 years: Among them, the number of NAFLD patients in China has reached 270 million. Steatosis alone was not associated with increased short-term morbidity or mortality, whereas patients...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605A61K38/26A61P1/16A61P3/06A61P9/10
CPCC07K14/605A61K38/00A61P1/16A61P3/08A61P3/06A61K38/26A61K9/19A61K9/0019A61K9/08A61K47/44C07K14/575A61K38/22
Inventor 蒋先兴王锐
Owner SHENZHEN TURIER BIOTECH CO LTD
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