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Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication

Journal Article · · Nature Communications
 [1];  [2];  [3];  [4];  [3];  [5];  [5];  [3];  [3];  [5];  [4];  [6];  [3];  [4]
  1. Univ. of Alberta, Edmonton, AB (Canada). Dept. of Chemistry; OSTI
  2. Univ. of Alberta, Edmonton, AB (Canada). Dept. of Biochemistry. Membrane Protein Disease Research Group
  3. Univ. of Alberta, Edmonton, AB (Canada). Dept. of Chemistry
  4. Univ. of Alberta, Edmonton, AB (Canada). Dept. of Biochemistry. Membrane Protein Disease Research Group
  5. Univ. of Alberta, Edmonton, AB (Canada). Dept. of Medical Microbiology and Immunology and Li Ka Shing Institute of Virology
  6. Univ. of Alberta, Edmonton, AB (Canada). Dept. of Medical Microbiology and Immunology; Univ. of Alberta, Edmonton, AB (Canada). Li Ka Shing Institute of Virology
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The main protease, Mpro (or 3CLpro) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the Mpro from both SARS-CoV and SARS-CoV-2 with IC50 values in the nanomolar range. Crystal structures of SARS-CoV-2 Mpro with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19.
Research Organization:
Stanford Univ., CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
1816374
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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