A gsdmd inhibitor

An inhibitor and competitive inhibition technology, applied in the field of biomedicine to achieve the effects of reducing cell pyroptosis, inhibiting cell pyroptosis, preventing and treating atherosclerosis and sepsis

Active Publication Date: 2022-03-11
ZHONGSHAN HOSPITAL FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] The preventive effect of GSDMD polypeptide inhibitor on atherosclerosis:

[0051] 1. 5-week-old ApoE- / - mice were fed with high-fat diet (21% fat, 0.15% cholesterol), and the samples were collected at 6, 8, 11, 14, and 18 weeks of age, and Western Blot was used to detect the 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 (as shown in the appendix). image 3 ), suggesting that the activation level of Caspase-1 / GSDMD pathway may play an important role in the progression of atherosclerosis.

[0052] 2. The 5-week-old ApoE- / - mice were fed with high-fat diet for 9 weeks, and then 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); the GSDMD inhibitor group was treated with Z-LLSD-FMK (GSMDD inhibitor, intrape...

Embodiment 2

[0055] The preventive effect of GSDMD polypeptide inhibitor on sepsis:

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

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Abstract

The invention relates to a GSDMD inhibitor, which belongs to the technical field of biomedicine. GSDMD is a key molecule mediating pyroptosis, which is involved in the development of atherosclerosis and sepsis. The present invention designs a polypeptide inhibitor for GSDMD, which can combine with Caspase1 and caspase4 / 5 / 11, and competitively inhibit the shearing effect of these enzymes on GSDMD, thereby significantly inhibiting the vascular tissue of atherosclerosis model mice The activation level of GSDMD in the medium can reduce vascular inflammation and inhibit the progression of atherosclerosis, significantly reduce the activation level of GSDMD in the spleen tissue of sepsis model mice, reduce the level of systemic inflammation and improve the survival rate of mice. The GSDMD polypeptide inhibitor of the invention can be used as a potential drug for the prevention and treatment of atherosclerosis and sepsis.

Description

technical field [0001] The invention relates to a GSDMD inhibitor, belonging to the technical field of biomedicine. Background technique [0002] Atherosclerotic cardio-cerebrovascular disease (ASCVD), including coronary heart disease and stroke, is the first 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. Although the primary and secondary prevention of cardiovascular disease has been gradually strengthened, with the aggravation of aging, the prevalence of Morbidity and mortality are still on the rise, which leads to an increasing disease burden in my country. Atherosclerosis is the main pathological basis of ASCVD. Therefore, it is particularly important to clarify the occurrence and development mechanism of atherosclerosis and develop drugs that can delay or even reverse the prog...

Claims

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Application Information

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Patent Type & Authority Patents(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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