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

Authors
  • Huff, Sarah
  • Kummetha, Indrasena Reddy
  • Tiwari, Shashi Kant
  • Huante, Matthew B
  • Clark, Alex E
  • Wang, Shaobo
  • Bray, William
  • Smith, Davey
  • Carlin, Aaron F
  • Endsley, Mark
  • Rana, Tariq M
Publication Date
Feb 01, 2022
Source
eScholarship - University of California
Keywords
License
Unknown
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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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