• Markus Hoffmann, Heike Hofmann-Winkler, Joan C Smith, Nadine Krüger, Prerna Arora, Lambert K Sørensen, Ole S Søgaard, Jørgen Bo Hasselstrøm, Michael Winkler, Tim Hempel, Lluís Raich, Simon Olsson, Olga Danov, Danny Jonigk, Takashi Yamazoe, Katsura Yamatsuta, Hirotaka Mizuno, Stephan Ludwig, Frank Noé, Mads Kjolby, Armin Braun, Jason M Sheltzer, and Stefan Pöhlmann.
• Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, 37077 Göttingen, Germany; Faculty of Biology and Psychology, University Göttingen, 37073 Göttingen, Germany. Electronic address: mhoffmann@dpz.eu.
• EBioMedicine. 2021 Mar 1; 65: 103255.

BackgroundAntivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated.MethodsWe used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA.FindingsWe show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity.InterpretationOur results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA.FundingNIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation.Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

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