3CL Protease Inhibitors with an Electrophilic Arylketone Moiety as Anti-SARS-CoV-2 Agents

J Med Chem. 2022 Feb 24;65(4):2926-2939. doi: 10.1021/acs.jmedchem.1c00665. Epub 2021 Jul 27.


The novel coronavirus, SARS-CoV-2, has been identified as the causative agent for the current coronavirus disease (COVID-19) pandemic. 3CL protease (3CLpro) plays a pivotal role in the processing of viral polyproteins. We report peptidomimetic compounds with a unique benzothiazolyl ketone as a warhead group, which display potent activity against SARS-CoV-2 3CLpro. The most potent inhibitor YH-53 can strongly block the SARS-CoV-2 replication. X-ray structural analysis revealed that YH-53 establishes multiple hydrogen bond interactions with backbone amino acids and a covalent bond with the active site of 3CLpro. Further results from computational and experimental studies, including an in vitro absorption, distribution, metabolism, and excretion profile, in vivo pharmacokinetics, and metabolic analysis of YH-53 suggest that it has a high potential as a lead candidate to compete with COVID-19.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • COVID-19 / metabolism
  • COVID-19 Drug Treatment
  • Chlorocebus aethiops
  • Coronavirus 3C Proteases / antagonists & inhibitors*
  • Coronavirus 3C Proteases / isolation & purification
  • Coronavirus 3C Proteases / metabolism
  • Cysteine Proteinase Inhibitors / chemical synthesis
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Humans
  • Ketones / chemistry
  • Ketones / pharmacology*
  • Male
  • Microbial Sensitivity Tests
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Conformation
  • Peptidomimetics / chemical synthesis
  • Peptidomimetics / chemistry
  • Peptidomimetics / pharmacology*
  • Rats
  • Rats, Wistar
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / enzymology
  • Vero Cells


  • Antiviral Agents
  • Cysteine Proteinase Inhibitors
  • Ketones
  • Peptidomimetics
  • 3C-like protease, SARS coronavirus
  • Coronavirus 3C Proteases