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Evolution of host protease interactions among SARS-CoV-2 variants of concern and related coronaviruses

Kastenhuber, E. R.; Mercadante, M.; Johnson, J. L.; Yaron, T. M.; Cantley, L. C.

2022-06-16 microbiology
10.1101/2022.06.16.496428 bioRxiv
Show abstract

Previously, we showed that coagulation factors directly cleave SARS-CoV-2 spike and promote viral entry (Kastenhuber et al., 2022). Here, we show that substitutions in the S1/S2 cleavage site observed in SARS-CoV-2 variants of concern (VOCs) exhibit divergent interactions with host proteases, including factor Xa and furin. Nafamostat remains effective to block coagulation factor-mediated cleavage of variant spike sequences. Furthermore, host protease usage has likely been a selection pressure throughout coronavirus evolution, and we observe convergence of distantly related coronaviruses to attain common host protease interactions, including coagulation factors. Interpretation of genomic surveillance of emerging SARS-CoV-2 variants and future zoonotic spillover is supported by functional characterization of recurrent emerging features.

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