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CSE (Cystathionine gamma-Lyase) enzyme activator and application thereof in drug for diseases related to CSE/H2S system

A technology for circulatory system diseases and diseases, applied in respiratory system diseases, urinary system diseases, cardiovascular system diseases, etc., can solve the problems of poor drugability, short metabolic half-life, high toxicity, etc., to reduce hypertension, inhibit vascular inflammation, The effect of increasing expression

Inactive Publication Date: 2019-04-26
FUWAI HOSPITAL CHINESE ACAD OF MEDICAL SCI & PEKING UNION MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Many drugs have shortcomings such as short metabolic half-life in vivo, high toxicity, and poor druggability, and there is still a long way to go before they can be used in the treatment of cardiovascular diseases.
[0007] Existing H 2 S donors are direct exogenous donors of H 2 S, rarely interfering with endogenous H from other perspectives 2 Drugs that generate S and then increase the level of hydrogen sulfide in the body

Method used

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  • CSE (Cystathionine gamma-Lyase) enzyme activator and application thereof in drug for diseases related to CSE/H2S system
  • CSE (Cystathionine gamma-Lyase) enzyme activator and application thereof in drug for diseases related to CSE/H2S system
  • CSE (Cystathionine gamma-Lyase) enzyme activator and application thereof in drug for diseases related to CSE/H2S system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1 There is an intermolecular interaction between demethylated gentianoside and CSE, and the key binding site is Leu91

[0058] The present invention downloads the crystal file (PDB_ID: 3COG) of human source CSE from the protein database RCSB.org, removes unnecessary parts with text editing software (VI), adopts molecular docking technology, and can be screened from the natural product database (CNPD) Natural small molecule compounds that interact with CSE. The compound demethyl gentianolin (norswertianolin, NW) was obtained after screening.

[0059] NWs were exported from the CNPD database and saved as 3D structures with Discovery Studio Visualizer 4.1. The structure of NW was optimized with Gaussian software and used to make force field templates. Autodock Vina was used to dock CSE and NW to obtain the initial complex structure, and NAMD2.9 was used to calculate the molecular dynamics of 20ns and calculate the RMSD. Judging from the results of RMSD, the dyna...

Embodiment 2

[0068] Example 2 Demethyl daisy leaf gentianoside glycoside increases H 2 S yield

[0069] In order to study the influence of NW on the activity of CSE, the present invention chooses to first observe the effect of NW on the isolated tissue homogenate H 2 The effect of S yield. The inventors respectively selected normal SD rat heart, blood vessel, kidney and liver tissues to study the effect of different concentration gradients of NW on tissue homogenate H 2 The effect of S yield.

[0070] The methylene blue method was used to detect the yield of hydrogen sulfide. First, weigh 200mg rat heart, add 2ml 50mM pH6.8 potassium phosphate buffer (1:10 ratio) to homogenate. Centrifuge at 12000 rpm at 4°C for 10 min, and take the supernatant. Prepare 10ml working solution, the composition is containing 2mM pyridoxal phosphate, 100mM pH7.4 potassium phosphate buffer solution of 10mM cysteine ​​(now ready to use, add 12.1mg cysteine ​​to 10ml potassium phosphate buffer solution, 5.3 ...

Embodiment 3

[0075] Example 3 Gentianoside demethylated daisy leaf gentianoside can relieve renal ischemia-reperfusion injury

[0076] Renal ischemia-reperfusion injury is one of the main causes of acute renal failure, and it is common in clinical shock or during kidney transplantation and partial nephrectomy. Studies have shown that H 2 S can effectively alleviate renal ischemia-reperfusion injury, and H in kidney tissue of CSE knockout mice 2 The production of S is reduced, and the injury and mortality after ischemia-reperfusion are also greatly increased. Therefore, exogenously provided H 2 S or H 2 S donor may be used as an effective method to reduce ischemia-reperfusion injury in kidney transplantation and other operations.

[0077] The inventors took SD rats and divided them into three groups: a sham operation group (Sham group), a renal ischemia-reperfusion group (I / R group), and a renal ischemia-reperfusion treatment group given NW (I / R+NW group). In the Sham group, only the l...

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Abstract

The invention discloses application of NW (Norswertianolin) in preparing a drug for preventing or treating diseases related to a CSE (Cystathionine gamma-Lyase) / H2S system. An inventor discovers thatNW is capable of combining CSE, promoting CSE enzyme activity and increasing generation of heart, blood vessel and kidney endogenous H2S, and is a new CSE enzyme activator. The NW is capable of activating a blood vessel CSE / H2S system, remarkably reducing high blood pressure, reducing vascular remodeling, inhibiting vascular inflammation, reducing atherosclerotic plaque, activating a kidney CSE / H2S system and reducing kidney ischemia reperfusion injury, so that the NW can be used for treating the diseases related to CSE / H2S.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a CSE enzyme activator and its combination with CSE / H 2 S system-related disease drug application. Background technique [0002] Hydrogen sulfide (H 2 S), as the third gas signal molecule after nitric oxide (NO) and carbon monoxide (CO), is widely involved in the regulation of physiological functions of multiple systems such as nerves, cardiovascular, digestion, and respiration. Cystathionine gamma-lyase (CSE) is the key to the production of H 2 The key enzyme of S, its main reaction substrate is cysteine. In the cardiovascular system, CSE / H 2 S can lower blood pressure, alleviate atherosclerosis, and improve the ischemia-reperfusion injury of the heart and kidney. In a variety of cardiovascular disease models, such as spontaneously hypertensive rat models, atherosclerosis models, and ischemia-reperfusion models, H 2 The content of S decreased significantly, and the exo...

Claims

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Application Information

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IPC IPC(8): A61K31/7048A61P9/12A61P9/10A61P9/00A61P9/04A61P11/00A61P11/06A61P1/04A61P1/16A61P13/12A61P1/00A61P13/00A61P3/10A61P15/10A61P15/00A61P27/02A61P19/02A61P19/00
CPCA61K31/7048A61P1/00A61P1/04A61P1/16A61P3/10A61P9/00A61P9/04A61P9/10A61P9/12A61P11/00A61P11/06A61P13/00A61P13/12A61P15/00A61P15/10A61P19/00A61P19/02A61P27/02
Inventor 耿彬杜从阔
Owner FUWAI HOSPITAL CHINESE ACAD OF MEDICAL SCI & PEKING UNION MEDICAL COLLEGE
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