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.