FXa cleaves the SARS-CoV-2 spike protein and blocks cell entry to protect against infection with inferior effects in B.1.1.7 variant

Yu, J.; Dong, W.; Wang, J.; Tian, L.; Zhang, J.; Mead, H. L.; Jaramillo, S.; Li, A.; Zumwalt, R.; Whelan, S. P. J.; Settles, E.; Keim, P.; Barker, B. M.; Caligiuri, M.

doi:10.1101/2021.06.07.447437

bioRxiv · 10.1101/2021.06.07.447437

FXa cleaves the SARS-CoV-2 spike protein and blocks cell entry to protect against infection with inferior effects in B.1.1.7 variant

Yu, J.·Dong, W.·Wang, J.·Tian, L.·Zhang, J.·Mead, H. L.·Jaramillo, S.·Li, A.·Zumwalt, R.·Whelan, S. P. J.·Settles, E.·Keim, P.·Barker, B. M.·Caligiuri, M.

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Abstract

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human natural defense mechanisms against SARS-CoV-2 are largely unknown. Serine proteases (SPs) including furin and TMPRSS2 cleave SARS-CoV-2 spike protein, facilitating viral entry. Here, we show that FXa, a SP for blood coagulation, is upregulated in COVID-19 patients compared to non-COVID-19 donors and exerts anti-viral activity. Mechanistically, FXa cleaves the SARS-CoV-2 spike protein, which prevents its binding to ACE2, and thus blocks viral entry. Furthermore, the variant B.1.1.7 with several mutations is dramatically resistant to the anti-viral effect of FXa compared to wild-type SARA-CoV-2 in vivo and in vitro. The anti-coagulant rivaroxaban directly inhibits FXa and facilitates viral entry, whereas the indirect inhibitor fondaparinux does not. In a lethal humanized hACE2 mouse model of SARS-CoV-2, FXa prolonged survival while combination with rivaroxaban but not fondaparinux abrogated this protection. These preclinical results identify a previously unknown SP function and associated anti-viral host defense mechanism and suggest caution in considering direct inhibitors for prevention or treatment of thrombotic complications in COVID-19 patients.

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Yu, J., Dong, W., Wang, J., Tian, L., Zhang, J., Mead, H. L., Jaramillo, S., Li, A., Zumwalt, R., Whelan, S. P. J., Settles, E., Keim, P., Barker, B. M., Caligiuri, M.. 2021-06-08. FXa cleaves the SARS-CoV-2 spike protein and blocks cell entry to protect against infection with inferior effects in B.1.1.7 variant. https://doi.org/10.1101/2021.06.07.447437

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