Heparin is administered intravenously as an anticoagulant to COVID-19 patients and via aerosol to treat other lung diseases. It has recently been found to have antiviral activity against SARS-CoV-2 as it hinders attachment of the virus to the host cell by binding to the virus spike glycoprotein . Here, we describe molecular dynamics simulations and experiments to investigate how heparin binds to the spike and the mechanism by which it exerts its antiviral activity. The simulations show that heparin polyanionic chains can bind at long, mostly positively charged patches on the spike, and thereby mask the basic residues of the receptor binding domain and the basic S1/S2 site , which is unique specific to SAR-CoV-2 and is important for furin-mediated spike cleavage and the subsequent formation of its post-fusion conformation . Experiments corroborated the simulation results by showing that heparin binds the basic S1/S2 site of spike, inhibiting cleavage by furin. The simulations show that heparin can act on the hinge region responsible for the motion of the RBD between inactive closed and active open conformations of the spike. In simulations of the closed spike, heparin binds the RBD and the N-terminal domain of two adjacent spike subunits and hinders the opening. In simulations of the open spike, heparin binds similarly but induces stabilization of the hinge region and a change in RBD motion. Our results indicate that heparin is able to inhibit SARS-CoV-2 infection by allosterically hindering binding to the host cell receptor, by directly competing with binding to the host heparan sulfate proteoglycan co-receptors, and by preventing spike cleavage by furin . Furthermore, the simulations provide insights into how heparan sulphate proteoglycans on the host cell can facilitate viral infection. Our results will aid the rational optimization of heparin derivatives for SARS-CoV-2 antiviral therapy.
Heparin has been found to have antiviral activity against SARS-CoV-2 . Here, by means of sliding window docking, molecular dynamics simulations and biochemical assays, we investigate the binding mode of heparin to the virus spike glycoprotein and the molecular basis for its antiviral activity. The simulations show that heparin binds at long, mostly positively charged patches on the spike, thereby masking the basic residues of the receptor binding domain and of the S1/S2 site . Experiments corroborated the simulation results by showing that heparin inhibits the cleavage of spike by furin by binding to the basic S1/S2 site . Our results indicate that heparin exerts its antiviral activity by both direct and allosteric mechanisms . Furthermore, the simulations provide insights into how heparan sulfate proteoglycans on the host cell can facilitate viral infection. Our results will aid the rational optimization of heparin derivatives for SARS-CoV-2 antiviral therapy.
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