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Small- molecule inhibitor for blocking combination of COVID-19 spinous protein and human angiotensin converting enzyme 2 and application thereof

A COVID-19, small molecule inhibitor technology, applied in the fields of peptide/protein components, active ingredients of hydroxyl compounds, medical preparations containing active ingredients, etc. question

Active Publication Date: 2021-03-09
DALIAN UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For the vast number of susceptible people, the current protective products such as masks and alcohol-containing disinfection products are broad-spectrum protection, and there is no protective product that is highly effective and specific to block virus infection on the market

Method used

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  • Small- molecule inhibitor for blocking combination of COVID-19 spinous protein and human angiotensin converting enzyme 2 and application thereof
  • Small- molecule inhibitor for blocking combination of COVID-19 spinous protein and human angiotensin converting enzyme 2 and application thereof
  • Small- molecule inhibitor for blocking combination of COVID-19 spinous protein and human angiotensin converting enzyme 2 and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1: preliminary screening of compound

[0040] Virtual screening was carried out with the laboratory's own 145 molecular databases and 1913 marketed small molecule drugs as screening objects. The virtual screening software used in this embodiment is Discovery Studio. According to the virtual screening scores, a list of potential molecules is selected based on the molecular structure characteristics. In this embodiment, the compounds shown in the following table 1 are selected, wherein, the disulfonated derivatives of luteolin MXCS-diSO 3 Na (DUT202001, DUT202002) was synthesized by the following example 2, resveratrol analogs (DUT202003), quercetin disulfonated derivatives (DUT202004) were owned by the laboratory, cerulein DUT202005, acarbose DUT202006 , Aliskiren (DUT202007) and the luteolin used in the examples are all purchased commercially.

[0041] Table 1 Compound information

[0042]

[0043]

Embodiment 2

[0044] Example 2: DUT202001[2-(4,5-dihydroxyphenyl)-5,7-dihydroxy-benzo-γ-pyrone-3', 6-sodium disulfonate (also known as: Mignonette Sulfonate-3′,6-sodium disulfonate)] and DUT202002[2-(4,5-dihydroxyphenyl)-5,7-dihydroxy-benzo-γ-pyrone-3′,8- Synthesis of sodium disulfonate (also known as: luteolin-3', 8-sodium disulfonate)]

[0045] Measure 4mL of concentrated sulfuric acid into a 50mL chicken heart bottle, cool in an ice-water bath to 0°C, add 1.0g of luteolin powder in batches under stirring, heat up after the addition, react at 30°C for 72h, and transfer the reaction solution into 50mL Stir the saturated sodium chloride aqueous solution, and a large amount of solids precipitate out. Let stand until the solids are completely precipitated, filter under reduced pressure, wash the filter cake with saturated sodium chloride solution (5mL×3), and filter until dry to obtain a khaki-yellow product. Add 40 mL of deionized water to dissolve the product, adjust the pH value to 6-7 wi...

Embodiment 3

[0048] Example 3: Activity test for blocking the binding of the receptor binding domain (RBD) of the COVID-19 spike protein to human angiotensin-converting enzyme 2 (hACE2)

[0049] Experimental materials: Compounds DUT202001 and DUT202002 (synthesized in Example 2), DUT202003 and DUT202004 (owned by the laboratory); compounds DUT202005, DUT202006 and DUT202007 (purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.); SARS-CoV-2S, pAX2, pHB and ACE2-pcDNA3 (Zhongke Presun Technology Co., Ltd.); 293T cells (Shanghai Heyuan Biotechnology Co., Ltd.). The pCMV-SNAP-hACE2 plasmid, SNAP-561 fluorescent dye and RBD541-Halo-640dye were from Xu Zhaochao's research group at Dalian Institute of Chemical Physics, Chinese Academy of Sciences.

[0050] Specifically, the test steps are as follows:

[0051]1) Select the luteolin disulfonated derivative MXCS-diSO with a virtual screening normalized FitValue scoring value of 0.3966 in Example 1 3 Na(DUT202001), luteolin disulfonated...

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Abstract

The invention belongs to the technical field of biology and medicine, and relates to a small-molecule inhibitor for blocking combination of COVID-19 spinous protein and human angiotensin converting enzyme 2 and application of the small-molecule inhibitor. The small molecular inhibitor which has an inhibiting effect on the combination of the COVID-19 spinous protein and the human angiotensin converting enzyme 2 and blocks the COVID-19 transferred into cells within the range of 0.5-500 mu M is found through virtual screening, experiments of blocking the combination of the COVID-19 spinous protein and the human angiotensin converting enzyme 2 and antiviral transcription experiments, The small-molecule inhibitor can be used for preparing medicines for preventing and treating novel coronavirusinfection.

Description

technical field [0001] The invention belongs to the technical field of biology and medicine, and relates to a small molecule inhibitor that blocks the combination of COVID-19 spike protein and human angiotensin-converting enzyme 2 and its application, specifically, relates to the efficient and specific prevention and treatment of novel coronavirus infection compounds and their applications. Background technique [0002] Novel coronavirus pneumonia, referred to as "new coronary pneumonia", is a type of acute infectious disease caused by 2019 novel coronavirus (COVID-19) infection. After a person is infected with the new coronavirus, the main symptoms include respiratory symptoms, fever, cough, shortness of breath, and dyspnea. In more severe cases, the infection can lead to pneumonia, severe acute respiratory syndrome, kidney failure, and even death. Currently, there is a lack of effective antiviral drugs against pathogens for diseases caused by novel coronaviruses. For the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/30A61P31/14A61P11/00A61K31/7036A61K31/165A61K31/352A61K31/05A61K38/08
CPCC07D311/30A61P31/14A61P11/00A61K31/7036A61K31/165A61K31/352A61K31/05A61K38/08A61K2300/00
Inventor 李悦青苗露赵伟杰徐兆超潘霞周伟孙萌萌左雨薇
Owner DALIAN UNIV OF TECH
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