Structure-Based Design of a Dual-Targeted Covalent Inhibitor Against Papain-like and Main Proteases of SARS-CoV-2

J Med Chem. 2022 Dec 22;65(24):16252-16267. doi: 10.1021/acs.jmedchem.2c00954. Epub 2022 Dec 12.


The two proteases, PLpro and Mpro, of SARS-CoV-2 are essential for replication of the virus. Using a structure-based co-pharmacophore screening approach, we developed a novel dual-targeted inhibitor that is equally potent in inhibiting PLpro and Mpro of SARS-CoV-2. The inhibitor contains a novel warhead, which can form a covalent bond with the catalytic cysteine residue of either enzyme. The maximum rate of the covalent inactivation is comparable to that of the most potent inhibitors reported for the viral proteases and covalent inhibitor drugs currently in clinical use. The covalent inhibition appears to be very specific for the viral proteases. The inhibitor has a potent antiviral activity against SARS-CoV-2 and is also well tolerated by mice and rats in toxicity studies. These results suggest that the inhibitor is a promising lead for development of drugs for treatment of COVID-19.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • COVID-19*
  • Cysteine Endopeptidases / chemistry
  • Mice
  • Molecular Docking Simulation
  • Papain
  • Peptide Hydrolases
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Protease Inhibitors / therapeutic use
  • Rats
  • SARS-CoV-2*
  • Viral Nonstructural Proteins
  • Viral Proteases


  • Papain
  • Cysteine Endopeptidases
  • Viral Nonstructural Proteins
  • Peptide Hydrolases
  • Viral Proteases
  • Antiviral Agents
  • Protease Inhibitors