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

  • J Med Chem. 2022 Feb 24;65(4):2866-2879. doi: 10.1021/acs.jmedchem.1c00566.
Sarah Huff  1 ,  Indrasena Reddy Kummetha  1 ,  Shashi Kant Tiwari  1 ,  Matthew B Huante  2 ,  Alex E Clark  3 ,  Shaobo Wang  1 ,  William Bray  1 ,  Davey Smith  3 ,  Aaron F Carlin  3 ,  Mark Endsley  2 ,  Tariq M Rana  1  3
Affiliations
  • 1. Division of Genetics, Department of Pediatrics, Center for Drug Discovery Innovation, Program in Immunology, Institute for Genomic Medicine, 9500 Gilman Drive MC 0762, La Jolla, California 92093, United States.
  • 2. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, United States.
  • 3. Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, 9500 Gilman Drive MC 0762, La Jolla, California 92093, United States.
PMID: 34570513 DOI: 10.1021/acs.jmedchem.1c00566
Abstract

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.

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