Lambert Kristiansen Sørensen

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Markus Hoffmann, German Primate Center – Leibniz Institute for Primate Research, University of Göttingen
  • ,
  • Heike Hofmann-Winkler, German Primate Center – Leibniz Institute for Primate Research
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  • Joan C. Smith, Cold Spring Harbor Laboratory, Google, Inc.
  • ,
  • Nadine Krüger, German Primate Center – Leibniz Institute for Primate Research
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  • 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
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  • Simon Olsson, Free University of Berlin, Chalmers University of Technology
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  • Olga Danov, Fraunhofer Institute for Toxicology and Experimental Medicine
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  • Danny Jonigk, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover Medical School
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  • Takashi Yamazoe, Ono Pharmaceutical Co., Ltd.
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  • Katsura Yamatsuta, Ono Pharmaceutical Co., Ltd.
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  • Hirotaka Mizuno, Ono Pharmaceutical Co., Ltd.
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  • Stephan Ludwig, Westfälische Wilhelms-Universität, Münster
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  • 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.

Original languageEnglish
Article number103255
JournalEBioMedicine
Volume65
DOIs
Publication statusPublished - Mar 2021

    Research areas

  • Camostat, FOY-251, GBPA, SARS-CoV-2, TMPRSS2

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