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

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...

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Autores principales: Hoffmann, Markus, Hofmann-Winkler, Heike, Smith, Joan C., Krüger, Nadine, Sørensen, Lambert K., Søgaard, Ole S., Hasselstrøm, Jørgen Bo, Winkler, Michael, Hempel, Tim, Raich, Lluís, Olsson, Simon, Yamazoe, Takashi, Yamatsuta, Katsura, Mizuno, Hirotaka, Ludwig, Stephan, Noé, Frank, Sheltzer, Jason M., Kjolby, Mads, Pöhlmann, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418737/
https://www.ncbi.nlm.nih.gov/pubmed/32793911
http://dx.doi.org/10.1101/2020.08.05.237651
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author Hoffmann, Markus
Hofmann-Winkler, Heike
Smith, Joan C.
Krüger, Nadine
Sørensen, Lambert K.
Søgaard, Ole S.
Hasselstrøm, Jørgen Bo
Winkler, Michael
Hempel, Tim
Raich, Lluís
Olsson, Simon
Yamazoe, Takashi
Yamatsuta, Katsura
Mizuno, Hirotaka
Ludwig, Stephan
Noé, Frank
Sheltzer, Jason M.
Kjolby, Mads
Pöhlmann, Stefan
author_facet Hoffmann, Markus
Hofmann-Winkler, Heike
Smith, Joan C.
Krüger, Nadine
Sørensen, Lambert K.
Søgaard, Ole S.
Hasselstrøm, Jørgen Bo
Winkler, Michael
Hempel, Tim
Raich, Lluís
Olsson, Simon
Yamazoe, Takashi
Yamatsuta, Katsura
Mizuno, Hirotaka
Ludwig, Stephan
Noé, Frank
Sheltzer, Jason M.
Kjolby, Mads
Pöhlmann, Stefan
author_sort Hoffmann, Markus
collection PubMed
description 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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spelling pubmed-74187372020-08-13 Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity Hoffmann, Markus Hofmann-Winkler, Heike Smith, Joan C. Krüger, Nadine Sørensen, Lambert K. Søgaard, Ole S. Hasselstrøm, Jørgen Bo Winkler, Michael Hempel, Tim Raich, Lluís Olsson, Simon Yamazoe, Takashi Yamatsuta, Katsura Mizuno, Hirotaka Ludwig, Stephan Noé, Frank Sheltzer, Jason M. Kjolby, Mads Pöhlmann, Stefan bioRxiv Article 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. Cold Spring Harbor Laboratory 2020-08-05 /pmc/articles/PMC7418737/ /pubmed/32793911 http://dx.doi.org/10.1101/2020.08.05.237651 Text en http://creativecommons.org/licenses/by-nc-nd/4.0/It is made available under a CC-BY-NC-ND 4.0 International license (http://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Article
Hoffmann, Markus
Hofmann-Winkler, Heike
Smith, Joan C.
Krüger, Nadine
Sørensen, Lambert K.
Søgaard, Ole S.
Hasselstrøm, Jørgen Bo
Winkler, Michael
Hempel, Tim
Raich, Lluís
Olsson, Simon
Yamazoe, Takashi
Yamatsuta, Katsura
Mizuno, Hirotaka
Ludwig, Stephan
Noé, Frank
Sheltzer, Jason M.
Kjolby, Mads
Pöhlmann, Stefan
Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity
title Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity
title_full Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity
title_fullStr Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity
title_full_unstemmed Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity
title_short Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity
title_sort camostat mesylate inhibits sars-cov-2 activation by tmprss2-related proteases and its metabolite gbpa exerts antiviral activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418737/
https://www.ncbi.nlm.nih.gov/pubmed/32793911
http://dx.doi.org/10.1101/2020.08.05.237651
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