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Synthesis of a Systematic 64-Membered Heparan Sulfate Tetrasaccharide Library |
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| Authors: | Kedar N. Baryal Sherif Ramadan Guowei Su Changxin Huo Yuetao Zhao Jian Liu Linda C. Hsieh-Wilson Xuefei Huang |
| Affiliation: | 1. Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI 48824 USA These authors contributed equally to this work.;2. Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI 48824 USA Chemistry Department, Faculty of Science, Benha University, Benha, Qaliobiya, 13518 Egypt These authors contributed equally to this work.;3. Glycan Therapeutics, 617 Hutton Street, Raleigh, NC 27606 USA;4. Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI 48824 USA;5. School of Life Sciences, Central South University, Changsha, Hunan, 410013 China Department of Chemistry, Michigan State University, 578 S. Shaw Lane, East Lansing, MI 48824 USA;6. Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599 USA;7. Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 USA |
| Abstract: | Heparan sulfate (HS) has multifaceted biological activities. To date, no libraries of HS oligosaccharides bearing systematically varied sulfation structures are available owing to the challenges in synthesizing a large number of HS oligosaccharides. To overcome the obstacles and expedite the synthesis, a divergent approach was designed, where 64 HS tetrasaccharides covering all possible structures of 2-O-, 6-O- and N-sulfation with the glucosamine-glucuronic acid-glucosamine-iduronic acid backbone were successfully produced from a single strategically protected tetrasaccharide intermediate. This extensive library helped identify the structural requirements for HS sequences to have strong fibroblast growth factor-2 binding but a weak affinity for platelet factor-4. Such a strategy to separate out these two interactions could lead to new HS-based potential therapeutics without the dangerous adverse effect of heparin-induced thrombocytopenia. |
| Keywords: | biological activity carbohydrates heparan sulfate library synthesis oligosaccharides |