Structure-Guided Design of Potent Spirocyclic Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3C-like Protease

J Med Chem. 2022 Jun 9;65(11):7818-7832. doi: 10.1021/acs.jmedchem.2c00224. Epub 2022 May 31.


The worldwide impact of the ongoing COVID-19 pandemic on public health has made imperative the discovery and development of direct-acting antivirals aimed at targeting viral and/or host targets. SARS-CoV-2 3C-like protease (3CLpro) has emerged as a validated target for the discovery of SARS-CoV-2 therapeutics because of the pivotal role it plays in viral replication. We describe herein the structure-guided design of highly potent inhibitors of SARS-CoV-2 3CLpro that incorporate in their structure novel spirocyclic design elements aimed at optimizing potency by accessing new chemical space. Inhibitors of both SARS-CoV-2 3CLpro and MERS-CoV 3CLpro that exhibit nM potency and high safety indices have been identified. The mechanism of action of the inhibitors and the structural determinants associated with binding were established using high-resolution cocrystal structures.

Publication types

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

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • COVID-19*
  • Coronavirus 3C Proteases
  • Cysteine Endopeptidases / metabolism
  • Hepatitis C, Chronic*
  • Humans
  • Pandemics
  • Peptide Hydrolases
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • SARS-CoV-2


  • Antiviral Agents
  • Protease Inhibitors
  • Peptide Hydrolases
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases