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

View ORCID ProfileMarkus Hoffmann, Heike Hofmann-Winkler, Joan C. Smith, Nadine Krüger, Lambert K. Sørensen, Ole S. Søgaard, Jørgen Bo Hasselstrøm, Michael Winkler, Tim Hempel, Lluís Raich, Simon Olsson, Takashi Yamazoe, Katsura Yamatsuta, Hirotaka Mizuno, Stephan Ludwig, Frank Noé, Jason M. Sheltzer, Mads Kjolby, View ORCID ProfileStefan Pöhlmann
doi: https://doi.org/10.1101/2020.08.05.237651
Markus Hoffmann
1Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research, 37077 Göttingen, Germany
2Faculty of Biology and Psychology, University Göttingen, 37073 Göttingen, Germany
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  • For correspondence: spoehlmann@dpz.eu mhoffmann@dpz.eu
Heike Hofmann-Winkler
1Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research, 37077 Göttingen, Germany
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Joan C. Smith
3Google, Inc., New York City, NY 10011, USA
4Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Nadine Krüger
1Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research, 37077 Göttingen, Germany
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Lambert K. Sørensen
5Department of Forensic Medicine, Aarhus University, Denmark
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Ole S. Søgaard
6Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark
7Department of Infectious Diseases, Aarhus University Hospital, 8200 Aarhus, Denmark
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Jørgen Bo Hasselstrøm
5Department of Forensic Medicine, Aarhus University, Denmark
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Michael Winkler
1Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research, 37077 Göttingen, Germany
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Tim Hempel
8Freie Universität Berlin, Department of Mathematics and Computer Science, Berlin, Germany
9Freie Universität Berlin, Department of Physics, Berlin, Germany
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Lluís Raich
8Freie Universität Berlin, Department of Mathematics and Computer Science, Berlin, Germany
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Simon Olsson
8Freie Universität Berlin, Department of Mathematics and Computer Science, Berlin, Germany
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Takashi Yamazoe
10Discovery Technology Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka 618-8585, Japan
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Katsura Yamatsuta
10Discovery Technology Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka 618-8585, Japan
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Hirotaka Mizuno
10Discovery Technology Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka 618-8585, Japan
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Stephan Ludwig
11Institute of Virology (IVM), Westfälische Wilhelms-Universität, 48149 Münster, Germany
12Cluster of Excellence “Cells in Motion”, Westfälische Wilhelms-Universität, 48149 Münster, Germany
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Frank Noé
8Freie Universität Berlin, Department of Mathematics and Computer Science, Berlin, Germany
9Freie Universität Berlin, Department of Physics, Berlin, Germany
13Rice University, Department of Chemistry, Houston, TX, USA
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Jason M. Sheltzer
4Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
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Mads Kjolby
14Danish Diabetes Academy and DANDRITE, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
15Department of Clinical Pharmacology, Aarhus University Hospital, 8200 Aarhus, Denmark
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Stefan Pöhlmann
1Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research, 37077 Göttingen, Germany
2Faculty of Biology and Psychology, University Göttingen, 37073 Göttingen, Germany
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  • ORCID record for Stefan Pöhlmann
  • For correspondence: spoehlmann@dpz.eu mhoffmann@dpz.eu
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Abstract

Antiviral therapy is urgently needed to combat the coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The protease inhibitor camostat mesylate inhibits SARS-CoV-2 infection of lung cells by blocking the virus-activating host cell protease TMPRSS2. Camostat mesylate has been approved for treatment of pancreatitis in Japan and is currently being repurposed for COVID-19 treatment. However, potential mechanisms of viral resistance as well as camostat mesylate metabolization and antiviral activity of metabolites are unclear. Here, we show that SARS-CoV-2 can employ TMPRSS2-related host cell proteases for activation and that several of them are expressed in viral target cells. However, entry mediated by these proteases was blocked by camostat mesylate. The camostat metabolite GBPA inhibited the activity of recombinant TMPRSS2 with reduced efficiency as compared to camostat mesylate and was rapidly generated in the presence of serum. Importantly, the infection experiments in which camostat mesylate was identified as a SARS-CoV-2 inhibitor involved preincubation of target cells with camostat mesylate in the presence of serum for 2 h and thus allowed conversion of camostat mesylate into GBPA. Indeed, when the antiviral activities of GBPA and camostat mesylate were compared in this setting, no major differences were identified. Our results indicate that use of TMPRSS2-related proteases for entry into target cells will not render SARS-CoV-2 camostat mesylate resistant. Moreover, the present and previous findings suggest that the peak concentrations of GBPA established after the clinically approved camostat mesylate dose (600 mg/day) will result in antiviral activity.

Competing Interest Statement

J.C.S. is a co-founder of Meliora Therapeutics and is an employee of Google, Inc. This work was performed outside of her affiliation with Google and used no proprietary knowledge or materials from Google. J.M.S. has received consulting fees from Ono Pharmaceuticals, is a member of the Advisory Board of Tyra Biosciences, and is a co-founder of Meliora Therapeutics. As part of its mission the Deutsches Primatenzentrum (German Primate Center) performs services for the scientific community including services for pharmaceutical companies resulting in fees being paid to the German Primate Center.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity
Markus Hoffmann, Heike Hofmann-Winkler, Joan C. Smith, Nadine Krüger, Lambert K. Sørensen, Ole S. Søgaard, Jørgen Bo Hasselstrøm, Michael Winkler, Tim Hempel, Lluís Raich, Simon Olsson, Takashi Yamazoe, Katsura Yamatsuta, Hirotaka Mizuno, Stephan Ludwig, Frank Noé, Jason M. Sheltzer, Mads Kjolby, Stefan Pöhlmann
bioRxiv 2020.08.05.237651; doi: https://doi.org/10.1101/2020.08.05.237651
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Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity
Markus Hoffmann, Heike Hofmann-Winkler, Joan C. Smith, Nadine Krüger, Lambert K. Sørensen, Ole S. Søgaard, Jørgen Bo Hasselstrøm, Michael Winkler, Tim Hempel, Lluís Raich, Simon Olsson, Takashi Yamazoe, Katsura Yamatsuta, Hirotaka Mizuno, Stephan Ludwig, Frank Noé, Jason M. Sheltzer, Mads Kjolby, Stefan Pöhlmann
bioRxiv 2020.08.05.237651; doi: https://doi.org/10.1101/2020.08.05.237651

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