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

View ORCID ProfileEdward R. Kastenhuber, Jared L. Johnson, Tomer M. Yaron, Marisa Mercadante, Lewis C. Cantley
doi: https://doi.org/10.1101/2022.06.16.496428
Edward R. Kastenhuber
1Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY, USA
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  • ORCID record for Edward R. Kastenhuber
Jared L. Johnson
1Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY, USA
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Tomer M. Yaron
1Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY, USA
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Marisa Mercadante
1Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY, USA
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Lewis C. Cantley
1Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY, USA
2Dana Farber Cancer Institute, Boston, MA, USA
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  • For correspondence: lcantley@med.cornell.edu
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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.

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. T.M.Y. is a stockholder and on the board of directors of DESTROKE, Inc., an early-stage start-up developing mobile technology for automated clinical stroke detection.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 16, 2022.
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Evolution of host protease interactions among SARS-CoV-2 variants of concern and related coronaviruses
Edward R. Kastenhuber, Jared L. Johnson, Tomer M. Yaron, Marisa Mercadante, Lewis C. Cantley
bioRxiv 2022.06.16.496428; doi: https://doi.org/10.1101/2022.06.16.496428
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Evolution of host protease interactions among SARS-CoV-2 variants of concern and related coronaviruses
Edward R. Kastenhuber, Jared L. Johnson, Tomer M. Yaron, Marisa Mercadante, Lewis C. Cantley
bioRxiv 2022.06.16.496428; doi: https://doi.org/10.1101/2022.06.16.496428

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