Synthesis of 3- O-sulfated oligosaccharides to understand the relationship between structures and functions of heparan sulfate

Abstract

The sulfation at the 3-OH position of glucosamine is an important modification in forming structural domains for heparan sulfate to enable its biological functions. Seven 3- O-sulfotransferase isoforms in the human genome are involved in the biosynthesis of 3- O-sulfated heparan sulfate. As a rare modification present in heparan sulfate, the availability of 3- O-sulfated oligosaccharides is very limited. Here, we report the use of a chemoenzymatic synthetic approach to synthesize six 3- O-sulfated oligosaccharides, including three hexasaccharides and three octasaccharides. The synthesis was achieved by rearranging the enzymatic modification sequence to accommodate the substrate specificity of 3- O-sulfotransferase 3. We studied the impact of 3- O-sulfation on the conformation of the pyranose ring of 2- O-sulfated iduronic acid using NMR, and on the correlation between ring conformation and anticoagulant activity. We identified a novel octasaccharide that interacts with antithrombin and displays anti factor Xa activity. Interestingly, the octasaccharide displays a faster clearance rate than fondaparinux, an FDA approved pentasaccharide drug, in a rat model, making this octasaccharide a potential short acting anticoagulant drug candidate that could reduce bleeding risk. Having access to a set of critically important 3- O-sulfated oligosaccharides offers the potential to develop new heparan sulfate-based therapeutics.

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