Controlling the Sulfation Density of Glycosaminoglycan Glycopolymer Mimetics Enables High Antiviral Activity against SARS-CoV-2 and Reduces Anticoagulant Activity

Sulfated glycosaminoglycans (sGAGs) make up a class of cell-surface glycans known to mediate pathogen engagement. Glycopolymers mimicking sGAGs can reduce or prevent pathogen attachment. However, their high anticoagulant activity limits their biomedical applications. Here, we report the synthesis and evaluation of synthetic glycopolymers mimicking sGAGs with high antiviral activity but low anticoagulant activity. The key lies in the control of the density of carbohydrates presented along the polymeric backbone. This was accomplished via copolymerization of carbohydrate with noncarbohydrate monomers. We reveal that the polymer chain length affects inhibition of SARS-CoV-2 pseudovirus (PsV) and authentic virus infections, and that above a critical chain length, density of carbohydrate and sulfate groups can be reduced, maintaining high antiviral activity while minimizing anticoagulant activity. This demonstrates, for the first time, how specific structural parameters of glycopolymers can be used to maximize inhibition while minimizing anticoagulative properties unlocking the full potential of sGAG mimetics in fighting infections.