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

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dc.citation.articleNumber103255en_US
dc.citation.journalTitleEBioMedicineen_US
dc.citation.volumeNumber65en_US
dc.contributor.authorHoffmann, Markusen_US
dc.contributor.authorHofmann-Winkler, Heikeen_US
dc.contributor.authorSmith, Joan C.en_US
dc.contributor.authorKrüger, Nadineen_US
dc.contributor.authorArora, Prernaen_US
dc.contributor.authorSørensen, Lambert K.en_US
dc.contributor.authorSøgaard, Ole S.en_US
dc.contributor.authorHasselstrøm, Jørgen Boen_US
dc.contributor.authorWinkler, Michaelen_US
dc.contributor.authorHempel, Timen_US
dc.contributor.authorRaich, Lluísen_US
dc.contributor.authorOlsson, Simonen_US
dc.contributor.authorDanov, Olgaen_US
dc.contributor.authorJonigk, Dannyen_US
dc.contributor.authorYamazoe, Takashien_US
dc.contributor.authorYamatsuta, Katsuraen_US
dc.contributor.authorMizuno, Hirotakaen_US
dc.contributor.authorLudwig, Stephanen_US
dc.contributor.authorNoé, Franken_US
dc.contributor.authorKjolby, Madsen_US
dc.contributor.authorBraun, Arminen_US
dc.contributor.authorSheltzer, Jason M.en_US
dc.contributor.authorPöhlmann, Stefanen_US
dc.date.accessioned2021-06-07T20:22:18Zen_US
dc.date.available2021-06-07T20:22:18Zen_US
dc.date.issued2021en_US
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.en_US
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.en_US
dc.identifier.digital1-s2-0-S2352396421000487-mainen_US
dc.identifier.doihttps://doi.org/10.1016/j.ebiom.2021.103255en_US
dc.identifier.urihttps://hdl.handle.net/1911/110664en_US
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.rightsThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)en_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/)en_US
dc.titleCamostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activityen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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