Affordable Access

Publisher Website

Discovery and Mechanism of SARS-CoV-2 Main Protease Inhibitors

  • Huff, Sarah1
  • Kummetha, Indrasena Reddy1
  • Tiwari, Shashi Kant1
  • Huante, Matthew B.2
  • Clark, Alex E.3
  • Wang, Shaobo1
  • Bray, William1
  • Smith, Davey3
  • Carlin, Aaron F.3
  • Endsley, Mark2
  • Rana, Tariq M.1, 3
  • 1 Institute for Genomic Medicine, United States , (United States)
  • 2 University of Texas Medical Branch, United States , (United States)
  • 3 University of California San Diego, United States , (United States)
Published Article
Journal of Medicinal Chemistry
American Chemical Society
Publication Date
Sep 27, 2021
DOI: 10.1021/acs.jmedchem.1c00566
PMID: 34570513
PMCID: PMC8491550
PubMed Central
  • Article


The emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify a 2-phenyl-1,2-benzoselenazol-3-one class of compounds targeting the SARS-CoV-2 main protease (Mpro). FRET-based screening against recombinant SARS-CoV-2 Mpro identified six compounds that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 Mpro can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit Mpro competitively. Lead E24 inhibited viral replication with a nanomolar EC50 value (844 nM) in SARS-CoV-2-infected Vero E6 cells and was further confirmed to impair SARS-CoV-2 replication in human lung epithelial cells and human-induced pluripotent stem cell-derived 3D lung organoids. Altogether, these studies provide a structural framework and mechanism of Mpro inhibition that should facilitate the design of future COVID-19 treatments.

Report this publication


Seen <100 times