Rxivist logo

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

By Jianhua Yu, Wenjuan Dong, Jing Wang, Lei Tian, Jianying Zhang, Heather L Mead, Sierra Jaramillo, Aimin Li, Ross Zumwalt, Sean P. J. Whelan, Erik Settles, Paul Keim, Bridget M Barker, Michael Caligiuri

Posted 08 Jun 2021
bioRxiv DOI: 10.1101/2021.06.07.447437

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.

Download data

  • Downloaded 436 times
  • Download rankings, all-time:
    • Site-wide: 88,355
    • In microbiology: 5,875
  • Year to date:
    • Site-wide: 23,372
  • Since beginning of last month:
    • Site-wide: 53,671

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

News