Glycosaminoglycans (GAGs) are a family of structurally complex, highly sulfated, polydisperse, linear polysaccharides. Heparin, heparan sulfate, chondroitin sulfates, dermatan sulfate, and hyaluronic acid are all members of this family. Heparin, the most widely studied GAG, is a major activator of serine protease inhibitors and more recently heparin and other GAGs have been shown to be important in the regulation of cell growth and cell-cell interaction. Nearly 300 metric tons of heparin are produced worldwide each year from animal tissue and used as an anticoagulant. This activity results from heparin binding to antithrombin III making it a potent inhibitor of thrombin and other important serine proteases. The pentasaccharide sequence binding to antithrombin, has been chemically synthesized in greater than 60 synthetic steps and in less than 0.25 percent yield. Despite this challenging synthesis, this pentasaccharide is being used therapeutically throughout Europe. The chemical synthesis of heparin has not been attempted because of its large size and complex structure. There have been few reports of the synthesis of the oligosaccharide comprising the other GAGs. The synthesis of GAG oligosaccharides is proposed in which the GAG is first depolymerized into disaccharides using polysaccharide lyases. Five target structures have been chosen for synthesis: (1) a heparan sulfate tetrasaccharide with a variety of sulfation patterns; (2) a heparan sulfate octasaccharide; (3) the heparin tetrasaccharide and octasaccharide that bind basic fibroblast growth factor (FGF); (4) analogs of the FGF binding heparin tetrasaccharide containing modified functional groups will be synthesized using a novel sulfate imprinting method and used in structure activity relationship studies; (5) hybrid glycosaminoglycan oligosaccharides synthesized using lyase derived disaccharide building blocks from heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate and hyaluronic acid. The interaction of these synthetic oligosaccharides to a number of GAG-binding proteins will be evaluated. Lyases will be applied to modified GAGs to prepare tetrasaccharides that will extend the chemistry developed in this proposal to larger oligosaccharide targets.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Medicinal Chemistry Study Section (MCHA)
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Link, Rebecca P
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University of Iowa
Schools of Arts and Sciences
Iowa City
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