Lead compounds for the development of SARS-CoV-2 3CL protease inhibitors

Nat Commun. 2021 Apr 1;12(1):2016. doi: 10.1038/s41467-021-22362-2.


We report the identification of three structurally diverse compounds - compound 4, GC376, and MAC-5576 - as inhibitors of the SARS-CoV-2 3CL protease. Structures of each of these compounds in complex with the protease revealed strategies for further development, as well as general principles for designing SARS-CoV-2 3CL protease inhibitors. These compounds may therefore serve as leads for the basis of building effective SARS-CoV-2 3CL protease inhibitors.

Publication types

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

MeSH terms

  • COVID-19 / drug therapy*
  • Coronavirus 3C Proteases / antagonists & inhibitors*
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical
  • Humans
  • Pyrrolidines / pharmacology
  • SARS-CoV-2 / drug effects*
  • Sulfonic Acids
  • Virus Replication / drug effects*


  • Pyrrolidines
  • Sulfonic Acids
  • 3C-like protease, SARS coronavirus
  • Coronavirus 3C Proteases
  • GC376