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DHODH inhibitor of anti-RNA virus drug and application of DHODH inhibitor

A technology of RNA virus and DHODH, which can be applied in the direction of antiviral agents, resistance to vector-borne diseases, medical preparations containing active ingredients, etc., and can solve problems such as less work and less effort

Pending Publication Date: 2021-10-01
EAST CHINA UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the former type of drugs usually cause drug resistance and toxicity, the development of broad-spectrum antiviral drugs targeting the host has always been the goal pursued in the field of new anti-infective drugs. However, since such drugs target the host, it is also a double-edged Sword, more consideration needs to be given to safety issues and poor in vitro-in vivo drug effect conversion issues, so the research and development of such drugs often achieve twice the result with half the effort and less effort

Method used

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  • DHODH inhibitor of anti-RNA virus drug and application of DHODH inhibitor
  • DHODH inhibitor of anti-RNA virus drug and application of DHODH inhibitor
  • DHODH inhibitor of anti-RNA virus drug and application of DHODH inhibitor

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Effect test

Embodiment 1

[0062] Embodiment 1. The inhibitory activity and cytotoxicity evaluation of the compound of the present invention to 2019 new coronavirus (2019-nCoV), Ebola virus, avian influenza virus A / GuangZhou / 99 (H9N2)

[0063] Materials and methods: Buquina is commercially available with a purity of over 98%, and DHODH inhibitors are purchased from compound libraries or reagent companies.

[0064] Detection methods and results:

[0065] 1. Anti-2019 novel coronavirus (2019-nCoV) drug efficacy experiment detected by fluorescent quantitative PCR method:

[0066]References (Wu Zhong, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Research (2020), 1–3, Zhou, P., et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature 2020) method, infected with 2019BetaCoV / Wuhan / WIV04 / 2019 strain) infection amount MOI=0.03 on Vero E6 cells (ATCC-1586), and added different dilutions of drugs at the s...

Embodiment 2

[0087] Example 2 Inhibitory activity of compounds of the present invention to H3N2, H1N1, H7N9

[0088] Materials and methods: DHODH inhibitors were purchased from compound libraries or reagent companies.

[0089] Detection method and results: Activity test for inhibiting virus replication at the cellular level

[0090] Determination of drug IC50 (half inhibitory concentration): MDCK cells or Vero cells or RD cells were plated on a 96-well plate, cultured for 12 hours and grown to more than 90% for later use. Drugs were serially diluted 2-fold (1×10-1 to 1×10-10). The monolayer of MDCK cells was sucked off the culture medium, washed once with PBS, 50 μl of drug solution of corresponding dilution was added to each well, and 50 μl of virus solution containing 100 times TCID50 was added to each well, and four replicate wells were made for each dilution. 37°C, 5% CO 2After culturing for 3-5 days, observe the production of CPE (cytopathic), record the number of positive wells th...

Embodiment 3

[0103] Embodiment 3. The antiviral activity evaluation of the combination of the compound of the present invention and other antiviral drugs

[0104] The inventors further tested some higher active DHODH inhibitors and other antiviral drugs of the prior art, including lopinavir, ritonavir, ribavirin, remdesivir, oseltamivir, One or more combinations of Tamiflu, Laninamivir, Peramivir and Chloroquine (Chloroquine Phosphate).

[0105] It was found that some highly active DHODH inhibitors combined with these antiviral drugs can produce better therapeutic effects; Chloroquine phosphate) combined treatment effect is relatively better.

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Abstract

The invention discloses multiple DHODH inhibitors, or pharmaceutically acceptable salts of the DHODH inhibitors in drugs for treating RNA (Ribonucleic Acid) virus infection. The drugs have broad-spectrum and excellent anti-RNA virus activity, and have low toxicity to normal cells.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry; specifically, the present invention relates to the application of a DHODH inhibitor in the preparation of a medicament for treating RNA virus infection and in the treatment of viral infection. Background technique [0002] Dihydroorotate dehydrogenase (DHODH), an iron-containing flavin-dependent mitochondrial enzyme, is a key enzyme in pyrimidine synthesis in nucleic acids, and catalyzes the fourth rate-limiting reaction in the de novo pyrimidine biosynthesis pathway[ 7-10]. There are two ways to obtain pyrimidine nucleotides in the human body, de novo synthesis and salvage synthesis. Resting lymphocytes in the human body mainly obtain the pyrimidine nucleotides required for cell metabolism through the salvage synthesis pathway. However, in the state of immune activation, the demand of lymphocytes for pyrimidine nucleotides can reach more than 8 times that in the resting state. At thi...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/277A61P31/14A61P31/18A61P31/16A61P31/20A61P31/22
CPCA61K45/00A61K31/277A61P31/14A61P31/18A61P31/16A61P31/20A61P31/22Y02A50/30
Inventor 李洪林徐可李诗良朱丽丽赵振江
Owner EAST CHINA UNIV OF SCI & TECH
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