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GSDMD inhibitor and application thereof in prevention and treatment of atherosclerosis and sepsis

A technology for atherosclerosis and sepsis, applied in the field of biomedicine, to prevent and treat atherosclerosis and sepsis, reduce pyroptosis, and inhibit pyroptosis

Active Publication Date: 2020-12-04
ZHONGSHAN HOSPITAL FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to solve the technical problem of utilizing the polypeptide inhibitor against GSDMD as a potential drug for preventing and treating atherosclerosis and sepsis

Method used

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  • GSDMD inhibitor and application thereof in prevention and treatment of atherosclerosis and sepsis
  • GSDMD inhibitor and application thereof in prevention and treatment of atherosclerosis and sepsis
  • GSDMD inhibitor and application thereof in prevention and treatment of atherosclerosis and sepsis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Prevention and treatment effect of GSDMD polypeptide inhibitor on atherosclerosis:

[0051] 1. The 5-week-old ApoE- / - mice were fed with high-fat diet (21% fat, 0.15% cholesterol), and samples were taken at 6, 8, 11, 14, and 18 weeks of age, and the Western Blot method was used to detect blood vessels. The activation levels of Caspase-1 and GSDMD; it was found that with the progression of atherosclerosis, the activation levels of Caspase-1 and GSDMD in vascular tissue increased significantly (see attached image 3 ), suggesting that the activation level of Caspase-1 / GSDMD pathway may play an important role in the process of atherosclerosis.

[0052] 2. After 5 weeks old ApoE- / - mice were fed with high-fat diet for 9 weeks, the control group was given control solvent; the Caspase-1 inhibitor group was given Z-YVAD-FMK (Caspase-1 inhibitor, intraperitoneal injection , 200 μg / day); GSDMD inhibitor group received Z-LLSD-FMK (GSDMD inhibitor, intraperitoneal injection, 200 ...

Embodiment 2

[0055] Prevention and treatment effect of GSDMD polypeptide inhibitor on sepsis:

[0056] Using 10-week-old C57 mice, the control group was given a control solvent; the Caspase-1 inhibitor group was given Z-YVAD-FMK (caspase-1 inhibitor, intraperitoneal injection, 200 μg / day); the GSDMD inhibitor group was given Z -LLSD-FMK (GSDMD inhibitor, intraperitoneal injection, 200 μg / day) or Caspase-1 inhibitor plus GSDMD inhibitor group with Z-YVAD-FMK+Z-LLSD-FMK (intraperitoneal injection, each 200 μg / day) Intervention for 5 days, intraperitoneal injection of LPS (20mg / kg) at the same time on the 5th day; the results found that compared with the control group, Caspase-1 inhibitor group, GSDMD inhibitor group and Caspase-1 inhibitor + GSDMD inhibitor Both groups significantly improved the survival rate of mice, decreased plasma LDH and HMGB1 levels, and there was no significant difference among the inhibitor groups (such as Figure 7 ). At the same time, the activation level of Casp...

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Abstract

The invention relates to a GSDMD inhibitor and application thereof in prevention and treatment of atherosclerosis and sepsis, and belongs to the technical field of biological medicines. GSDMD is a keymolecule for mediating cell scorch, and the cell scorch participates in occurrence and development of atherosclerosis and sepsis diseases. A polypeptide inhibitor is designed for the GSDMD, and the inhibitor can be combined with Caspase1 and Caspase4 / 5 / 11 to competitively inhibit the shearing effect of the enzymes on the GSDMD, so that the activation level of the GSDMD in vascular tissues of an atherosclerosis model mouse is remarkably inhibited, vascular inflammation is reduced, the development of atherosclerosis is inhibited, the activation level of the GSDMD in spleen tissues of a sepsis model mouse is remarkably reduced, the level of systemic inflammation is reduced, and the survival rate of the mouse is improved. The GSDMD polypeptide inhibitor can be used as a potential medicine forpreventing and treating atherosclerosis and sepsis.

Description

technical field [0001] The invention relates to a GSDMD inhibitor and its application in the prevention and treatment of atherosclerosis and sepsis, belonging to the technical field of biomedicine. Background technique [0002] Atherosclerotic cardiovascular and cerebrovascular disease (ASCVD), including coronary heart disease and stroke, is the number one cause of death in my country and even in the world. According to the "China Cardiovascular Disease Report 2017", the number of patients with coronary heart disease and stroke in my country is as high as 11 million and 13 million respectively. The morbidity and mortality are still on the rise, which has led to an increasing burden of disease in our country. Atherosclerosis is the main pathological basis of ASCVD. Therefore, it is particularly important to clarify the mechanism of occurrence and development of atherosclerosis and develop drugs that can delay or even reverse the progression of atherosclerosis for the effectiv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/02A61K38/07A61P9/10A61P31/04
CPCA61P9/10A61P31/04A61K38/07
Inventor 姜红刘明张宝丽于鹏苏恩勇
Owner ZHONGSHAN HOSPITAL FUDAN UNIV
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