A head-to-head comparison of the inhibitory activities of 15 peptidomimetic SARS-CoV-2 3CLpro inhibitors

Bioorg Med Chem Lett. 2021 Sep 15:48:128263. doi: 10.1016/j.bmcl.2021.128263. Epub 2021 Jul 14.


The COVID-19 pandemic caused by SARS-CoV-2 has created an unprecedented global health emergency. As of July 2021, only three antiviral therapies have been approved by the FDA for treating infected patients, highlighting the urgent need for more antiviral drugs. The SARS-CoV-2 3CL protease (3CLpro) is deemed an attractive drug target due to its essential role in viral polyprotein processing and pathogenesis. Indeed, a number of peptidomimetic 3CLpro inhibitors armed with electrophilic warheads have been reported by various research groups that can potentially be developed for treating COVID-19. However, it is currently impossible to compare their relative potencies due to the different assays employed. To solve this, we conducted a head-to-head comparison of fifteen reported peptidomimetic inhibitors in a standard FRET-based SARS-CoV-2 3CLpro inhibition assay to compare and identify potent inhibitors for development. Inhibitor design and the suitability of various warheads are also discussed.

Keywords: 3CLpro; Cysteine protease inhibitors; Mpro; Peptidomimetic inhibitors; SARS-CoV-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry*
  • Antiviral Agents / metabolism
  • Coronavirus 3C Proteases / antagonists & inhibitors*
  • Coronavirus 3C Proteases / metabolism
  • Cysteine Proteinase Inhibitors / chemistry*
  • Cysteine Proteinase Inhibitors / metabolism
  • Enzyme Assays
  • Fluorescence Resonance Energy Transfer
  • Inhibitory Concentration 50
  • Peptidomimetics / chemistry*
  • Peptidomimetics / metabolism
  • Protein Binding
  • SARS-CoV-2 / enzymology*


  • Antiviral Agents
  • Cysteine Proteinase Inhibitors
  • Peptidomimetics
  • 3C-like proteinase, SARS-CoV-2
  • Coronavirus 3C Proteases