Synthesis of 3-O-Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate.
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.
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599, United States.|National Glycoengineering Research Center, Shandong University , Jinan 250100, China.
Zhangjie
Z
Wang
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599, United States.
Po-Hung
PH
Hsieh
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599, United States.
Yongmei
Y
Xu
Complex Carbohydrate Research Center, University of Georgia , Athens, Georgia 30602, United States.
David
D
Thieker
School of Pharmacy, University College London , 29-39 Brunswick Square, London WC1N 1AX, United Kingdom.
Evangeline Juan En
http://orcid.org/0000-0002-0753-2427
EJE
Chai
National Glycoengineering Research Center, Shandong University , Jinan 250100, China.
Shaoshuai
S
Xie
Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina , Chapel Hill, North Carolina 27599, United States.
Brian
B
Cooley
Complex Carbohydrate Research Center, University of Georgia , Athens, Georgia 30602, United States.
Robert J
RJ
Woods
National Glycoengineering Research Center, Shandong University , Jinan 250100, China.
Lianli
L
Chi
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599, United States.
Jian
http://orcid.org/0000-0001-8552-1400
J
Liu