SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2

Clausen, T. M.; Sandoval, D. R.; Spliid, C. B.; Pihl, J.; Painter, C. D.; Thacker, B. E.; Glass, C. A.; Narayanan, A.; Majowicz, S. A.; Zhang, Y.; Torres, J. L.; Golden, G. J.; Porell, R.; Garretson, A. F.; Laubach, L.; Feldman, J.; Yin, X.; Pu, Y.; Hauser, B.; Caradonna, T. M.; Kellman, B. P.; Martino, C.; Gordts, P. L. S. M.; Leibel, S. L.; Chanda, S. K.; Schmidt, A. G.; Godula, K.; Jose, J.; Corbett, K. D.; Ward, A. B.; Carlin, A. F.; Esko, J. D.

doi:10.1101/2020.07.14.201616

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bioRxiv · 10.1101/2020.07.14.201616

SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2

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Abstract

We show that SARS-CoV-2 spike protein interacts with cell surface heparan sulfate and angiotensin converting enzyme 2 (ACE2) through its Receptor Binding Domain. Docking studies suggest a putative heparin/heparan sulfate-binding site adjacent to the domain that binds to ACE2. In vitro, binding of ACE2 and heparin to spike protein ectodomains occurs independently and a ternary complex can be generated using heparin as a template. Contrary to studies with purified components, spike protein binding to heparan sulfate and ACE2 on cells occurs codependently. Unfractionated heparin, non-anticoagulant heparin, treatment with heparin lyases, and purified lung heparan sulfate potently block spike protein binding and infection by spike protein-pseudotyped virus and SARS-CoV-2 virus. These findings support a model for SARS-CoV-2 infection in which viral attachment and infection involves formation of a complex between heparan sulfate and ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin may represent new therapeutic opportunities.

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Clausen, T. M., Sandoval, D. R., Spliid, C. B., Pihl, J., Painter, C. D., Thacker, B. E., Glass, C. A., Narayanan, A., Majowicz, S. A., Zhang, Y., Torres, J. L., Golden, G. J., Porell, R., Garretson, A. F., Laubach, L., Feldman, J., Yin, X., Pu, Y., Hauser, B., Caradonna, T. M., Kellman, B. P., Martino, C., Gordts, P. L. S. M., Leibel, S. L., Chanda, S. K., Schmidt, A. G., Godula, K., Jose, J., Corbett, K. D., Ward, A. B., Carlin, A. F., Esko, J. D.. 2020-07-14. SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2. https://doi.org/10.1101/2020.07.14.201616

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