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

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dc.citation.articleNumber103255
dc.citation.journalTitleEBioMedicine
dc.citation.volumeNumber65
dc.contributor.authorHoffmann, Markus
dc.contributor.authorHofmann-Winkler, Heike
dc.contributor.authorSmith, Joan C.
dc.contributor.authorKrüger, Nadine
dc.contributor.authorArora, Prerna
dc.contributor.authorSørensen, Lambert K.
dc.contributor.authorSøgaard, Ole S.
dc.contributor.authorHasselstrøm, Jørgen Bo
dc.contributor.authorWinkler, Michael
dc.contributor.authorHempel, Tim
dc.contributor.authorRaich, Lluís
dc.contributor.authorOlsson, Simon
dc.contributor.authorDanov, Olga
dc.contributor.authorJonigk, Danny
dc.contributor.authorYamazoe, Takashi
dc.contributor.authorYamatsuta, Katsura
dc.contributor.authorMizuno, Hirotaka
dc.contributor.authorLudwig, Stephan
dc.contributor.authorNoé, Frank
dc.contributor.authorKjolby, Mads
dc.contributor.authorBraun, Armin
dc.contributor.authorSheltzer, Jason M.
dc.contributor.authorPöhlmann, Stefan
dc.date.accessioned2021-06-07T20:22:18Z
dc.date.available2021-06-07T20:22:18Z
dc.date.issued2021
dc.description.abstractBackground: 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.
dc.identifier.citationHoffmann, Markus, Hofmann-Winkler, Heike, Smith, Joan C., et al.. "Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity." <i>EBioMedicine,</i> 65, (2021) Elsevier: https://doi.org/10.1016/j.ebiom.2021.103255.
dc.identifier.digital1-s2-0-S2352396421000487-main
dc.identifier.doihttps://doi.org/10.1016/j.ebiom.2021.103255
dc.identifier.urihttps://hdl.handle.net/1911/110664
dc.language.isoeng
dc.publisherElsevier
dc.rightsThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/)
dc.titleCamostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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