Synergistic inhibition of SARS-CoV-2 cell entry by otamixaban and covalent protease inhibitors: pre-clinical assessment of pharmacological and molecular properties

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dc.citation.firstpage12600en_US
dc.citation.journalTitleChemical Scienceen_US
dc.citation.lastpage12609en_US
dc.citation.volumeNumber12en_US
dc.contributor.authorHempel, Timen_US
dc.contributor.authorElez, Katarinaen_US
dc.contributor.authorKrüger, Nadineen_US
dc.contributor.authorRaich, Lluísen_US
dc.contributor.authorShrimp, Jonathan H. en_US
dc.contributor.authorDanov, Olgaen_US
dc.contributor.authorJonigk, Dannyen_US
dc.contributor.authorBraun, Arminen_US
dc.contributor.authorShen, Minen_US
dc.contributor.authorHall, Matthew D. en_US
dc.contributor.authorPöhlmann, Stefanen_US
dc.contributor.authorHoffmann, Markusen_US
dc.contributor.authorNoé, Franken_US
dc.date.accessioned2021-10-26T16:40:37Zen_US
dc.date.available2021-10-26T16:40:37Zen_US
dc.date.issued2021en_US
dc.description.abstractSARS-CoV-2, the cause of the COVID-19 pandemic, exploits host cell proteins for viral entry into human lung cells. One of them, the protease TMPRSS2, is required to activate the viral spike protein (S). Even though two inhibitors, camostat and nafamostat, are known to inhibit TMPRSS2 and block cell entry of SARS-CoV-2, finding further potent therapeutic options is still an important task. In this study, we report that a late-stage drug candidate, otamixaban, inhibits SARS-CoV-2 cell entry. We show that otamixaban suppresses TMPRSS2 activity and SARS-CoV-2 infection of a human lung cell line, although with lower potency than camostat or nafamostat. In contrast, otamixaban inhibits SARS-CoV-2 infection of precision cut lung slices with the same potency as camostat. Furthermore, we report that otamixaban's potency can be significantly enhanced by (sub-) nanomolar nafamostat or camostat supplementation. Dominant molecular TMPRSS2-otamixaban interactions are assessed by extensive 109 μs of atomistic molecular dynamics simulations. Our findings suggest that combinations of otamixaban with supplemental camostat or nafamostat are a promising option for the treatment of COVID-19.en_US
dc.identifier.citationHempel, Tim, Elez, Katarina, Krüger, Nadine, et al.. "Synergistic inhibition of SARS-CoV-2 cell entry by otamixaban and covalent protease inhibitors: pre-clinical assessment of pharmacological and molecular properties." <i>Chemical Science,</i> 12, (2021) Royal Society of Chemistry: 12600-12609. https://doi.org/10.1039/D1SC01494C.en_US
dc.identifier.doihttps://doi.org/10.1039/D1SC01494Cen_US
dc.identifier.urihttps://hdl.handle.net/1911/111596en_US
dc.language.isoengen_US
dc.publisherRoyal Society of Chemistryen_US
dc.rightsThis Open Access Article is licensed under a Creative Commons Attribution-Non Commercial 3.0 Unported Licenceen_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc/3.0/en_US
dc.titleSynergistic inhibition of SARS-CoV-2 cell entry by otamixaban and covalent protease inhibitors: pre-clinical assessment of pharmacological and molecular propertiesen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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