Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease

Nat Commun. 2020 Sep 4;11(1):4417. doi: 10.1038/s41467-020-18233-x.

Abstract

COVID-19 was declared a pandemic on March 11 by WHO, due to its great threat to global public health. The coronavirus main protease (Mpro, also called 3CLpro) is essential for processing and maturation of the viral polyprotein, therefore recognized as an attractive drug target. Here we show that a clinically approved anti-HCV drug, Boceprevir, and a pre-clinical inhibitor against feline infectious peritonitis (corona) virus (FIPV), GC376, both efficaciously inhibit SARS-CoV-2 in Vero cells by targeting Mpro. Moreover, combined application of GC376 with Remdesivir, a nucleotide analogue that inhibits viral RNA dependent RNA polymerase (RdRp), results in sterilizing additive effect. Further structural analysis reveals binding of both inhibitors to the catalytically active side of SARS-CoV-2 protease Mpro as main mechanism of inhibition. Our findings may provide critical information for the optimization and design of more potent inhibitors against the emerging SARS-CoV-2 virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / pharmacology
  • Betacoronavirus / drug effects*
  • Betacoronavirus / enzymology
  • Binding Sites / drug effects
  • COVID-19
  • COVID-19 Drug Treatment
  • Catalytic Domain
  • Chlorocebus aethiops
  • Coronavirus 3C Proteases
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / virology*
  • Crystallography, X-Ray
  • Cysteine Endopeptidases / chemistry
  • Cysteine Endopeptidases / metabolism
  • Disease Models, Animal
  • High-Throughput Screening Assays
  • Models, Molecular
  • Pandemics
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / virology*
  • Proline / analogs & derivatives*
  • Proline / pharmacology
  • Protease Inhibitors / pharmacology*
  • Pyrrolidines / pharmacology*
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors
  • RNA-Dependent RNA Polymerase / chemistry
  • RNA-Dependent RNA Polymerase / metabolism
  • SARS-CoV-2
  • Sulfonic Acids
  • Vero Cells
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry
  • Viral Nonstructural Proteins / metabolism
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Protease Inhibitors
  • Pyrrolidines
  • Sulfonic Acids
  • Viral Nonstructural Proteins
  • N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide
  • Proline
  • RNA-Dependent RNA Polymerase
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases
  • GC376