1. Academic Validation
  2. BC-11 is a covalent TMPRSS2 fragment inhibitor that impedes SARS-CoV-2 host cell entry

BC-11 is a covalent TMPRSS2 fragment inhibitor that impedes SARS-CoV-2 host cell entry

  • Arch Pharm (Weinheim). 2023 Jan;356(1):e2200371. doi: 10.1002/ardp.202200371.
Aurélien F A Moumbock 1 Hoai T T Tran 2 Evelyn Lamy 2 Stefan Günther 1
Affiliations

Affiliations

  • 1 Faculty of Chemistry and Pharmacy, Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
  • 2 Molecular Preventive Medicine, Faculty of Medicine, University Medical Center, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
Abstract

Host cell entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is facilitated via priming of its spike glycoprotein by the human transmembrane Protease serine 2 (TMPRSS2). Although camostat and nafamostat are two highly potent covalent TMPRSS2 inhibitors, they nevertheless did not hold promise in COVID-19 clinical trials, presumably due to their short plasma half-lives. Herein, we report an integrative chemogenomics approach based on computational modeling and in vitro enzymatic assays, for repurposing serine-targeted covalent inhibitors. This led to the identification of BC-11 as a covalent TMPRSS2 inhibitor displaying a unique selectivity profile for serine proteases, ascribable to its boronic acid warhead. BC-11 showed modest inhibition of SARS-CoV-2 (omicron variant) spike pseudotyped particles in a cell-based entry assay, and a combination of BC-11 and AHN 1-055 (a spike glycoprotein inhibitor) demonstrated better viral entry inhibition than either compound alone. Given its low molecular weight and good activity against TMPRSS2, BC-11 qualifies as a good starting point for further structural optimizations.

Keywords

BC-11; CovPDB; SARS-CoV-2 cell entry; TMPRSS2; targeted covalent inhibitor.

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