Exploring Phosphate Substitution in Heparan Sulfate Mimetics: Synthesis and Antiviral Evaluation

Heparan sulfate (HS) is a ubiquitously expressed glycosaminoglycan (GAG) found on most mammalian cells. Its heterogeneous structure and dense negative charge allow HS to interact with a wide range of proteins, regulating their stability, localization, and engagement with cell-surface receptors. Given the role of disrupted HS-protein interactions in numerous diseases, HS mimetics represent a promising avenue for therapeutic intervention. These mimetics are designed to reproduce the functional properties of native HS while offering improved stability, scalability, and selectivity. Whereas most HS mimetics exploit naturally occurring sulfate groups to provide anionic character, this study explores phosphates as a sulfate bioisostere. Using a dendrimer-based scaffold, a focused library of phosphorylated maltose constructs was synthesized, comprising four (dimer), six (trimer), or eight (tetramer) units, with lipid-modified variants prepared for the dimer and trimer series. In vitro screening against four clinically relevant DNA viruses reveal that these phosphorylated HS mimetics display antiviral activity, albeit with reduced potency relative to their sulfated analogs.