Coagulation factors directly cleave SARS-CoV-2 spike, enhance viral entry

  

View ORCID ProfileEdward R Kastenhuber, Javier A. Jaimes, Jared L. Johnson, Marisa Mercadante, Frauke Muecksch, Yiska Weisblum, Yaron Bram, Robert E. Schwartz, Gary R. Whittaker, Lewis C. Cantley

doi: https://doi.org/10.1101/2021.03.31.437960

This article is a preprint and has not been certified by peer review [what does this mean?].

PDF:  https://www.biorxiv.org/content/10.1101/2021.03.31.437960v1.full.pdf

Abstract

Coagulopathy is recognized as a significant aspect of morbidity in COVID-19 patients. The clotting cascade is propagated by a series of proteases, including factor Xa and thrombin. Other host proteases, including TMPRSS2, are recognized to be important for cleavage activation of SARS-CoV-2 spike to promote viral entry. Using biochemical and cell-based assays, we demonstrate that factor Xa and thrombin can also directly cleave SARS-CoV-2 spike, enhancing viral entry. A drug-repurposing screen identified a subset of protease inhibitors that promiscuously inhibited spike cleavage by both transmembrane serine proteases as well as coagulation factors. The mechanism of the protease inhibitors nafamostat and camostat extend beyond inhibition of TMPRSS2 to coagulation-induced spike cleavage. Anticoagulation is critical in the management of COVID-19, and early intervention could provide collateral benefit by suppressing SARS-CoV-2 viral entry. We propose a model of positive feedback whereby infection-induced hypercoagulation exacerbates SARS-CoV-2 infectivity.

Competing Interest Statement

LCC is a founder and member of the SAB of Agios Pharmaceuticals and a founder and former member of the SAB of Ravenna Pharmaceuticals (previously Petra Pharmaceuticals). These companies are developing novel therapies for cancer. LCC holds equity in Agios. LCC laboratory also received some financial support from Ravenna Pharmaceuticals. RES is on the scientific advisory board for Miromatrix Inc and is a consultant and speaker for Alnylam Inc.

https://www.biorxiv.org/content/10.1101/2021.03.31.437960v1