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Novel application of compound in prevention and/or treatment of diseases caused by coronavirus infection

A coronavirus, disease technology, applied in medicinal chemistry

Active Publication Date: 2021-01-19
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This poses a challenge to traditional screening methods

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  • Novel application of compound in prevention and/or treatment of diseases caused by coronavirus infection
  • Novel application of compound in prevention and/or treatment of diseases caused by coronavirus infection
  • Novel application of compound in prevention and/or treatment of diseases caused by coronavirus infection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 protein-protein interaction test

[0035] Protein-protein interactions of ACE2 and RBD proteins were determined using NTA chips using a Biacore S200 instrument. The running buffer was HBS-T+ buffer (10mM HEPES, 150mM NaCl, 0.05% tween 20, pH 8.0, 0.22μm microporous membrane filtration). The ligand is ACE2-His, the concentration is 10 mg / mL, and the capture time is 100 seconds. A series of S-RBD-mFc solutions at concentrations of 3.13, 6.25, 12.5, 25, 50, and 100 nM were prepared, flowed over the captured ACE2-His surface, and the response units (RUs) obtained were recorded. The flow rate was set at 30 μL / min, the binding time was 120 s, and the dissociation time was 500 s. 350mM EDTA is the regeneration solution, and the regeneration time is 60 seconds.

[0036] The experimental results showed that the amount of ACE2 captured by different cycles was relatively stable (the response was about 143RU, and the deviation did not exceed 2RU). In addition, the sen...

Embodiment 2

[0037] Example 2 Establishment of Amino Coupling Method SPR Screening Model

[0038] RBD and ACE2 proteins were immobilized on the CM5 chip by amino coupling method. The chip is first activated by contact with a mixture of EDC and NHS. Then RBD and ACE2-His proteins with concentrations of 20 μg / mL and 16 μg / mL were dissolved in sodium acetate solution (pH 5.0 and pH 4.5, respectively), and flowed over the surface of the chip, and finally immobilized on the Fc2 and ACE2-His of the CM5 chip, respectively. on Fc4. Finally, the chip was blocked with ethanolamine.

[0039] It has been measured that the coupling amount of RBD protein is about 8500RUs, and the coupling amount of ACE2 protein is about 9100RUs. When about 20nM of ACE2 or RBD was passed through the chip immobilized with RBD or ACE2, the response signals were 242RUs and 319RUs, respectively. The above results indicated that both target proteins could maintain their activity after immobilization.

Embodiment 3

[0040] Embodiment 3 active compound screening

[0041] The whole process of compound screening is divided into three steps: library clearing, binding level screening and affinity determination. All experiments were carried out using Biacore T200 or Biacore S200 instruments with a flow rate of 30 μL / min, and the data were analyzed using Biacore T200 / S200 evaluation software. HBS-T+ buffer (10 mM HEPES, 150 mM NaCl, 0.05% tween 20, 5% DMSO, pH 8.0, 0.22 μm Millipore membrane filtration) was used as the running buffer. Compounds were first diluted to 100 μM and finally diluted to 25 μM or 10 μM in 5% DMSO running buffer.

[0042] Based on the difference in solubility, the library was cleared by flowing the compound at a concentration of 25 μM or 10 μM over the surface of the chip. A total of 13 high-viscosity compounds were excluded by clearing the library. Compounds that pass through the library are then screened for binding levels in order to identify compounds that bind to ...

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Abstract

The invention finds that the norzerelaldehyde and the cediranib can effectively block the combination of RBD and ACE2 protein, so that the norzerelaldehyde and the cediranib can be applied to prevention and / or treatment of diseases caused by coronavirus infection.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to small molecule inhibitors targeting SARS-CoV-2 RBD and / or human ACE2 protein. Background technique [0002] Novel coronavirus disease 2019 (COVID-19) caused by novel coronavirus (SARS-CoV-2) infection [1,2] . Infection with SARS-CoV-2 can cause symptoms such as fever, dry cough, and difficulty breathing. Unlike SARS, COVID-19 may transform into a chronic disease similar to influenza and coexist with humans for a long time. To date, the number of confirmed COVID-19 cases worldwide has exceeded 16.3 million and continues to rise [3] . [0003] Scientists now have detailed biological information about SARS-CoV-2 [4-7] . The S protein mainly binds to the membrane receptor angiotensin-converting enzyme 2 (ACE2) on the host cell to promote the entry of the virus into the host cell [8,9] . Among them, the receptor binding domain (RBD) of S protein is directly involved in the r...

Claims

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Application Information

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IPC IPC(8): A61K31/56A61K31/517A01N37/42A01N43/54A61P31/14A01P1/00
CPCA01N37/42A01N43/54A61K31/517A61K31/56A61P31/14
Inventor 山广志朱志玲仇小丹李玉环吴硕左利民赵婷刘伊彤
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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