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Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity

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DOI

  • Markus Hoffmann, German Primate Center – Leibniz Institute for Primate Research, University of Göttingen
  • ,
  • Heike Hofmann-Winkler, German Primate Center – Leibniz Institute for Primate Research
  • ,
  • Joan C. Smith, Cold Spring Harbor Laboratory, Google, Inc.
  • ,
  • Nadine Krüger, German Primate Center – Leibniz Institute for Primate Research
  • ,
  • Prerna Arora, German Primate Center – Leibniz Institute for Primate Research, University of Göttingen
  • ,
  • Lambert K. Sørensen
  • Ole S. Søgaard
  • Jørgen Bo Hasselstrøm
  • Michael Winkler, German Primate Center – Leibniz Institute for Primate Research
  • ,
  • Tim Hempel, Free University of Berlin
  • ,
  • Lluís Raich, Free University of Berlin
  • ,
  • Simon Olsson, Free University of Berlin, Chalmers University of Technology
  • ,
  • Olga Danov, Fraunhofer Institute for Toxicology and Experimental Medicine
  • ,
  • Danny Jonigk, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover Medical School
  • ,
  • Takashi Yamazoe, Ono Pharmaceutical Co., Ltd.
  • ,
  • Katsura Yamatsuta, Ono Pharmaceutical Co., Ltd.
  • ,
  • Hirotaka Mizuno, Ono Pharmaceutical Co., Ltd.
  • ,
  • Stephan Ludwig, Westfälische Wilhelms-Universität, Münster
  • ,
  • Frank Noé, Free University of Berlin, Rice University
  • ,
  • Mads Kjolby
  • Armin Braun, Fraunhofer Institute for Toxicology and Experimental Medicine
  • ,
  • Jason M. Sheltzer, Cold Spring Harbor Laboratory
  • ,
  • Stefan Pöhlmann, German Primate Center – Leibniz Institute for Primate Research, University of Göttingen

Background: Antivirals 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. Methods: We 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. Findings: We 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. Interpretation: Our 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. Funding: NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation.

OriginalsprogEngelsk
Artikelnummer103255
TidsskriftEBioMedicine
Vol/bind65
DOI
StatusUdgivet - mar. 2021

Bibliografisk note

Funding Information:
We are grateful for in-depth discussions with Katarina Elez, Tuan Le, Moritz Hoffmann (FU Berlin) and the members of the JEDI COVID-19 grand challenge. We further thank Inga Nehlmeier for excellent technical support. Research in the Sheltzer Lab was supported by NIH grants 1DP5OD021385 and R01CA237652-01, a Damon Runyon-Rachleff Innovation award, an American Cancer Society Research Scholar Grant, and a grant from the New York Community Trust. The No? lab was supported by Deutsche Forschungsgemeinschaft DFG (SFB/TRR 186, Project A12), the European Commission (ERC CoG 772230 "ScaleCell"), the Berlin Mathematics center MATH+ (AA1-6) and the federal ministry of education and research BMBF (BIFOLD). The P?hlmann lab was supported by the Bundesministerium f?r Bildung und Forschung (RAPID Consortium, 01KI1723D; RENACO consortium, 01KI20328A; SARS_S1S2, 01KI20396 ), Deutsche Forschungsgemeinschaft (PO 716/11-1) and the Country of Lower Saxony. The Kjolby lab was supported by the Lundbeck Foundation (M.K. O.S.) and the Novo Nordisk Foundation (M.K.). The work in the Braun lab was partly funded by the Fraunhofer Internal Programs under Grant No. Anti-Corona 840260 DRECOR (Drug Repurposing for Corona).

Publisher Copyright:
© 2021 The Authors

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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