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

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

  • bioRxiv. 2020 Aug 5;2020.08.05.237651. doi: 10.1101/2020.08.05.237651.
Markus Hoffmann 1 2,  Heike Hofmann-Winkler 1,  Joan C Smith 3 4,  Nadine Krüger 1,  Lambert K Sørensen 5,  Ole S Søgaard 6 7,  Jørgen Bo Hasselstrøm 5,  Michael Winkler 1,  Tim Hempel 8 9,  Lluís Raich 8,  Simon Olsson 8,  Takashi Yamazoe 10,  Katsura Yamatsuta 10,  Hirotaka Mizuno 10,  Stephan Ludwig 11 12,  Frank Noé 8 9 13,  Jason M Sheltzer 4,  Mads Kjolby 14 15,  Stefan Pöhlmann 1 2
Affiliations

Affiliations

  • 1 Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, 37077 Göttingen, Germany.
  • 2 Faculty of Biology and Psychology, University Göttingen, 37073 Göttingen, Germany.
  • 3 Google, Inc., New York City, NY 10011, USA.
  • 4 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
  • 5 Department of Forensic Medicine, Aarhus University, Denmark.
  • 6 Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark.
  • 7 Department of Infectious Diseases, Aarhus University Hospital, 8200 Aarhus, Denmark.
  • 8 Freie Universität Berlin, Department of Mathematics and Computer Science, Berlin, Germany.
  • 9 Freie Universität Berlin, Department of Physics, Berlin, Germany.
  • 10 Discovery Technology Research Laboratories, Ono Pharmaceutical Co., Ltd., Osaka 618-8585, Japan.
  • 11 Institute of Virology (IVM), Westfälische Wilhelms-Universität, 48149 Münster, Germany.
  • 12 Cluster of Excellence "Cells in Motion", Westfälische Wilhelms-Universität, 48149 Münster, Germany.
  • 13 Rice University, Department of Chemistry, Houston, TX, USA.
  • 14 Danish Diabetes Academy and DANDRITE, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
  • 15 Department of Clinical Pharmacology, Aarhus University Hospital, 8200 Aarhus, Denmark.
PMID: 32793911 DOI: 10.1101/2020.08.05.237651
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.

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