Besides the cellular attachment receptor ACE2, SARS-CoV-2 also requires host proteases, such as TMPRSS2, for entry. These proteases cleave spike, thereby activating it. In a screen to identify entry inhibitors, Kastenhuber et al. noticed that some anticoagulants reduced spike-pseudotyped virus entry, leading the authors to speculate that coagulation factors might also process spike. Indeed, thrombin and factor Xa cleaved SARS-CoV-2 spike similarly to TMPRSS2 and increased infection of cell lines with spike-pseudotyped virus as well as of lung organoids with authentic SARS-CoV-2. Finally, the authors tested a range of protease inhibitors and anticoagulants and found variable reduction of spike cleavage, with nafamostat, a serine protease inhibitor in clinical use as an anticoagulant, having the broadest inhibitory effect. The authors speculate that activation of coagulation during infection might further increase SARS-CoV-2 entry and that early treatment with anticoagulants might prevent this feedback loop.
Kastenhuber, E. R. et al. Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry. eLife 11, e77444 (2022)
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Hofer, U. Clotting and SARS-CoV-2 entry. Nat Rev Microbiol 20, 317 (2022). https://doi.org/10.1038/s41579-022-00729-6