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

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Publication Year:
2021
Authors:
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
PubMed ID:
34570513
Funding Grants:
Public Summary:
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 (M(pro)). FRET-based screening against recombinant SARS-CoV-2 M(pro) identified six compounds that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 M(pro) can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit M(pro) 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 M(pro) inhibition that should facilitate the design of future COVID-19 treatments
Scientific 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 (M(pro)). FRET-based screening against recombinant SARS-CoV-2 M(pro) identified six compounds that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 M(pro) can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit M(pro) 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 M(pro) inhibition that should facilitate the design of future COVID-19 treatments.