Antiviral Activity of Dendritic Heparan Sulfate Mimetics against Respiratory Syncytial Virus and Herpes Simplex Virus‑1.

Heparan sulfate (HS) can act as an attachment receptor for many different animal viruses. Virus binding to HS occurs through electrostatic interactions between the negatively charged sulfate and carboxyl groups of HS and positively charged amino acids present in viral proteins. Soluble heparin, a glycosaminoglycan related to HS, can inhibit infection by many viruses, but the clinical use of heparin is limited by its anticoagulant activity. Synthetic HS mimetics that lack anticoagulant activity have been developed and can inhibit virus infection in vitro and in vivo. Building on this precedent, we investigated inhibition of respiratory syncytial virus (RSV) and herpes simplex virus type-1 (HSV-1) by a set of tri- and tetrameric dendritic HS mimetics. Several of these compounds exhibited submicromolar inhibition of both viruses when used as receptor decoys in assays of virus entry, and a lead compound inhibited the cell-to-cell spread of RSV in vitro and RSV-mediated membrane fusion. Additionally, we observed synergistic effects when an HS mimetic was used in combination with clinical antiviral remdesivir. The solubility, lack of anticoagulant activity, and antiviral potency of these dendritic HS mimetics make them a promising new class of broad-spectrum antiviral therapeutics.