Proc Natl Acad Sci U S A . A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells

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Proc Natl Acad Sci U S A


. 2021 Oct 26;118(43):e2108728118.
doi: 10.1073/pnas.2108728118.
A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells


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

• 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.