Synthesis of Glycooligomers with Defined Sialyllactose Valency and Spacing for Multivalent Binding to Influenza Hemagglutinin

Influenza A virus is a medically important target. Hemagglutinin (HA), a trimeric glycoprotein on the viral surface, recognizes sialylated glycans through three receptor-binding sites. Glycoligands that interact with HA through multivalent binding can serve as viral inhibitors. To achieve efficient multivalent binding, precise control over glycoligand structures is essential. Here, we synthesized glycooligomers displaying sialyllactose units at defined intramolecular spacings and investigated how ligand structure affects binding to HA. Glycooligomers displaying one, two, or three sialyllactose units at regular intervals exhibited enhanced binding as carbohydrate valency increased. When the spacing between two sialyllactose units was varied, shorter spacing enhanced binding, likely because of a statistical rebinding effect. Interestingly, the presentation of an excessive number of sialyllactose units weakened the interaction with HA, presumably because of steric hindrance. These findings highlight the importance of precise carbohydrate arrangement in the design of effective multivalent ligands.