Although heparan sulfate modified by a 3-O-sulfate ester has been implicated in many physiological and disease processes, there is only a rudimentary understanding of ligand requirements of HS-binding proteins requiring this type of modification. We have developed a modular synthetic approach that provided a structurally diverse collection of HS hexasaccharides with and without 3-OS. The compounds were printed as a glycan microarray to determine ligand requirements of HS-binding proteins, which revealed specific HS-sequons for binding. It let to the discovery of new proteins requiring a 3-O-sulfate ester for binding. The HS-oligosaccharides were examined as inhibitors of cell entry by Herpes simplex virus type-1, which showed a lack of dependence of 3-O-sulfatiom, indicating that instead of glycoprotein D (gD), they competitively bind to gB and gC. The HS-oligosaccharides were also used to dissect substrate specificities of heparin lyases, which are enzymes used for depolymerization of HS/heparin for sequence determination and production of therapeutic heparins. It was found that cleavage by lyase-II is influenced by 3-OS, while digestion by lyase-I is only affected by 2-OS. Lyase-III exhibited sensitivity to both 3-OS and 2-OS.

Synthetic HS oligosaccharides to dissect the importance of 3-O-sulfation to modulates protein binding and lyase degradation

ACS Fall 2021

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