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

Nat Commun. 2020 Aug 27;11(1):4282. doi: 10.1038/s41467-020-18096-2.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • A549 Cells
  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Betacoronavirus / drug effects*
  • Betacoronavirus / enzymology
  • Binding Sites
  • Chlorocebus aethiops
  • Coronavirus 3C Proteases
  • Coronavirus, Feline / drug effects*
  • Coronavirus, Feline / enzymology
  • Crystallography, X-Ray
  • Cysteine Endopeptidases / chemistry
  • Cytopathogenic Effect, Viral / drug effects
  • Drug Repositioning
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Prodrugs
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology
  • SARS Virus / drug effects
  • SARS Virus / enzymology
  • SARS-CoV-2
  • Vero Cells
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • GC376
  • Prodrugs
  • Protease Inhibitors
  • Pyrrolidines
  • Viral Nonstructural Proteins
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases