A Novel Class of TMPRSS2 Inhibitors Potently Block SARS-CoV-2 and MERS-CoV Viral Entry and Protect Human Epithelial Lung Cells

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2021 Oct 12

PMID 34635581

Citations 53

Authors

Matthew Mahoney

Vishnu C Damalanka

Michael A Tartell

Dong Hee Chung

Andre Luiz Lourenco

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 Whelan

Anthony J ODonoghue

Charles S Craik

James W Janetka

Affiliations

Soon will be listed here.

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 IC (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC (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 EC 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 EC 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.

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