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.firstpage12600
dc.citation.journalTitleChemical Science
dc.citation.lastpage12609
dc.citation.volumeNumber12
dc.contributor.authorHempel, Tim
dc.contributor.authorElez, Katarina
dc.contributor.authorKrüger, Nadine
dc.contributor.authorRaich, Lluís
dc.contributor.authorShrimp, Jonathan H. 
dc.contributor.authorDanov, Olga
dc.contributor.authorJonigk, Danny
dc.contributor.authorBraun, Armin
dc.contributor.authorShen, Min
dc.contributor.authorHall, Matthew D. 
dc.contributor.authorPöhlmann, Stefan
dc.contributor.authorHoffmann, Markus
dc.contributor.authorNoé, Frank
dc.date.accessioned2021-10-26T16:40:37Z
dc.date.available2021-10-26T16:40:37Z
dc.date.issued2021
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.
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.
dc.identifier.doihttps://doi.org/10.1039/D1SC01494C
dc.identifier.urihttps://hdl.handle.net/1911/111596
dc.language.isoeng
dc.publisherRoyal Society of Chemistry
dc.rightsThis Open Access Article is licensed under a Creative Commons Attribution-Non Commercial 3.0 Unported Licence
dc.rights.urihttps://creativecommons.org/licenses/by-nc/3.0/
dc.titleSynergistic inhibition of SARS-CoV-2 cell entry by otamixaban and covalent protease inhibitors: pre-clinical assessment of pharmacological and molecular properties
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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