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

Thomas Mandel Clausen, Daniel R. Sandoval, Charlotte B. Spliid, Jessica Pihl, Hailee R. Perrett, Chelsea D. Painter, Anoop Narayanan, Sydney A. Majowicz, Elizabeth M. Kwong, Rachael N. McVicar, Bryan E. Thacker, Charles A. Glass, Zhang Yang, Jonathan L. Torres, Gregory J. Golden, Phillip L. Bartels, Ryan N. Porell, Aaron F. Garretson, Logan Laubach, Jared FeldmanXin Yin, Yuan Pu, Blake M. Hauser, Timothy M. Caradonna, Benjamin P. Kellman, Cameron Martino, Philip L.S.M. Gordts, Sumit K. Chanda, Aaron G. Schmidt, Kamil Godula, Sandra L. Leibel, Joyce Jose, Kevin D. Corbett, Andrew B. Ward, Aaron F. Carlin, Jeffrey D. Esko

Research output: Contribution to journalArticlepeer-review

359 Scopus citations


We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold. Electron micrographs of spike protein suggests that heparin enhances the open conformation of the RBD that binds ACE2. On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus. We suggest a model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities.

Original languageEnglish (US)
Pages (from-to)1043-1057.e15
Issue number4
StatePublished - Nov 12 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)


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