Discovery of M Protease Inhibitors Encoded by SARS-CoV-2

Antimicrob Agents Chemother. 2020 Aug 20;64(9):e00872-20. doi: 10.1128/AAC.00872-20. Print 2020 Aug 20.

Abstract

The coronavirus (CoV) disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is a health threat worldwide. Viral main protease (Mpro, also called 3C-like protease [3CLpro]) is a therapeutic target for drug discovery. Herein, we report that GC376, a broad-spectrum inhibitor targeting Mpro in the picornavirus-like supercluster, is a potent inhibitor for the Mpro encoded by SARS-CoV-2, with a half-maximum inhibitory concentration (IC50) of 26.4 ± 1.1 nM. In this study, we also show that GC376 inhibits SARS-CoV-2 replication with a half-maximum effective concentration (EC50) of 0.91 ± 0.03 μM. Only a small portion of SARS-CoV-2 Mpro was covalently modified in the excess of GC376 as evaluated by mass spectrometry analysis, indicating that improved inhibitors are needed. Subsequently, molecular docking analysis revealed that the recognition and binding groups of GC376 within the active site of SARS-CoV-2 Mpro provide important new information for the optimization of GC376. Given that sufficient safety and efficacy data are available for GC376 as an investigational veterinary drug, expedited development of GC376, or its optimized analogues, for treatment of SARS-CoV-2 infection in human is recommended.

Keywords: COVID-19; GC376; M protease; Mpro; SARS-CoV-2; antiviral research.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology
  • Betacoronavirus / drug effects*
  • Betacoronavirus / pathogenicity
  • Catalytic Domain
  • Chlorocebus aethiops
  • Coronavirus 3C Proteases
  • Cysteine Endopeptidases / chemistry*
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism
  • Gene Expression
  • Molecular Docking Simulation
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Conformation, beta-Strand
  • Protein Interaction Domains and Motifs
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • SARS-CoV-2
  • Sulfonic Acids
  • Thermodynamics
  • Vero Cells
  • Viral Nonstructural Proteins / antagonists & inhibitors
  • Viral Nonstructural Proteins / chemistry*
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism
  • Virus Replication / drug effects

Substances

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