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

Sarah Huff, Indrasena Reddy Kummetha, Shashi Kant Tiwari, Matthew B. Huante, Alex E. Clark, Shaobo Wang, William Bray, Davey Smith, Aaron F. Carlin, Mark Endsley, Tariq M. Rana

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2866-2879
Number of pages14
JournalJournal of medicinal chemistry
Volume65
Issue number4
DOIs
StatePublished - Feb 24 2022

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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