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

Abstract

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.

Highlights

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  SARS-CoV-2 spike protein interacts with heparan sulfate and ACE2 through the RBD

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  Heparan sulfate promotes Spike-ACE2 interaction

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  SARS-CoV-2 infection is co-dependent on heparan sulfate and ACE2

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  Heparin and non-anticoagulant derivatives block SARS-CoV-2 binding and infection

Abstract

Clausen et al. provide evidence that heparin sulfate is a necessary co-factor for SARS-CoV-2 infection. They show that heparin sulfate interacts with the Receptor Binding Domain of the SARS-CoV-2 spike glycoprotein, adjacent to ACE2, shifting the spike structure to an open conformation to facilitate ACE2 binding.