Synergistic inhibition of SARS-CoV-2 cell entry by otamixaban and covalent protease inhibitors: pre-clinical assessment of pharmacological and molecular properties. Issue 38 (26th August 2021)

• Record Type: Journal Article
• Authors: Hempel, Tim; Elez, Katarina; Krüger, Nadine; Raich, Lluís; Shrimp, Jonathan H.; Danov, Olga; Jonigk, Danny; Braun, Armin; Shen, Min; Hall, Matthew D.; Pöhlmann, Stefan; Hoffmann, Markus; Noé, Frank
• Is Part Of: Chemical science. Volume 12:Issue 38(2021)
• Page Start: 12600
• Page End: 12609
• Publication Date: 2021-08-26
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d1sc01494c
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : SARS-CoV-2, the cause of the COVID-19 pandemic, exploits host proteins for viral entry into human lung cells and is blocked by otamixaban in combination with a covalent protease inhibitor. Abstract : SARS-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.