A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

Matthew Mahoney, Vishnu C. Damalanka, Michael A. Tartell, Dong hee Chung, Andre Luiz Lourenço, Dustin Pwee, Anne E. Mayer Bridwell, Markus Hoffmann, Jorine Voss, Partha Karmakar, Nurit P. Azouz, Andrea M. Klingler, Paul W. Rothlauf, Cassandra E. Thompson, Melody Lee, Lidija Klampfer, Christina L. Stallings, Marc E. Rothenberg, Stefan Pohlmann, Sean P.J. WhelanAnthony J. O’Donoghue, Charles S. Craik, James W. Janetka

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC50 (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC50 (half-maximal effective concentration) of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV-SARS-CoV-2 chimeric virus, and an EC50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East respiratory syndrome coronavirus (MERS-CoV) cell entry with an EC50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice, with a half-life of 8.6 h in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.

Original languageEnglish
Article numbere2108728118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number43
DOIs
StatePublished - Oct 26 2021

Keywords

  • Antiviral
  • COVID-19
  • PS-SCL
  • Protease inhibitor
  • Structure-based drug discovery

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