Synthesis of 3-O-Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate

Abstract

<p class="first" id="P1">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- <i>O</i>-sulfotransferase isoforms in the human genome are involved in the biosynthesis of 3- <i>O</i>-sulfated heparan sulfate. As a rare modification present in heparan sulfate, the availability of 3- <i>O</i>-sulfated oligosaccharides is very limited. Here, we report the use of a chemoenzymatic synthetic approach to synthesize six 3- <i>O</i>-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- <i>O</i>-sulfotransferase 3. We studied the impact of 3- <i>O</i>-sulfation on the conformation of the pyranose ring of 2- <i>O</i>-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- <i>O</i>-sulfated oligosaccharides offers the potential to develop new heparan sulfate-based therapeutics. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/6e80e757-f52b-4185-abd4-af61874be210/PubMedCentral/image/nihms864307u1.jpg"/> </div> </p>