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

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

  • Proc Natl Acad Sci U S A. 2021 Oct 26;118(43):e2108728118. doi: 10.1073/pnas.2108728118.
Matthew Mahoney 1 2,  Vishnu C Damalanka 1,  Michael A Tartell 3 4,  Dong Hee Chung 5,  André Luiz Lourenço 5,  Dustin Pwee 6,  Anne E Mayer Bridwell 3,  Markus Hoffmann 7 8,  Jorine Voss 1,  Partha Karmakar 1,  Nurit P Azouz 9,  Andrea M Klingler 9,  Paul W Rothlauf 3 4,  Cassandra E Thompson 3,  Melody Lee 5,  Lidija Klampfer 2,  Christina L Stallings 3,  Marc E Rothenberg 9,  Stefan Pöhlmann 7 8,  Sean P J Whelan 3,  Anthony J O'Donoghue 6,  Charles S Craik 5,  James W Janetka 10 2
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110.
  • 2 ProteXase Therapeutics, Inc., Saint Louis, MO 63108.
  • 3 Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110.
  • 4 Program in Virology, Harvard Medical School, Boston, MA 02115.
  • 5 Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158.
  • 6 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093.
  • 7 Infection Biology Unit, German Primate Center, Leibniz Institute for Primate Research, Göttingen 37077, Germany.
  • 8 Faculty of Biology and Psychology, Georg-August University Göttingen, Göttingen 37077, Germany.
  • 9 Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
  • 10 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110; [email protected].
PMID: 34635581 DOI: 10.1073/pnas.2108728118
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.

Keywords

COVID-19; PS-SCL; antiviral; protease inhibitor; structure-based drug discovery.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-148072
    99.20%, TMPRSS2 Inhibitor