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

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.

• 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 4 Pg. 2866-2879 (02 24 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 34570513 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Benzothiazoles
• Cysteine Proteinase Inhibitors
• 3C-like proteinase, SARS-CoV-2
• Coronavirus 3C Proteases

Topics

• Animals
• Antiviral Agents (chemical synthesis, chemistry, pharmacology)
• Benzothiazoles (chemistry, pharmacology)
• COVID-19 (metabolism)
• Chlorocebus aethiops
• Coronavirus 3C Proteases (antagonists & inhibitors, isolation & purification, metabolism)
• Crystallography, X-Ray
• Cysteine Proteinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Discovery
• Fluorescence Resonance Energy Transfer
• Humans
• Microbial Sensitivity Tests
• Molecular Docking Simulation
• Molecular Structure
• SARS-CoV-2 (drug effects, enzymology)
• Vero Cells
• Virus Replication (drug effects)
• COVID-19 Drug Treatment