Heparin-like glycosaminoglycans (HLGAGs) are the most acidic naturally occurring biopolymers, found in the extracellular matrices. These complex polysaccharides play a key role in regulating the biological activity of several proteins in the coagulation cascade and in hemostasis. The relationship between structure and activity of HLGAGs is still very poorly understood due to the complexity and heterogeneity of these polymers. It has become increasingly evident that defined lengths and sequences of HLGAGs are responsible for binding to a particular protein and modulating its biological activity. Detailed structure-activity studies on HLGAG oligosaccharides have suffered from the lack of pure material. Due to the complexity and heterogeneity of these polysaccharides there are, at the present time, no feasible approaches for the preparation of defined HLGAG oligosaccharides. Determination of structure-activity relationships of HLGAGs creates an opportunity for the discovery of novel therapeutic interventions for a variety of disease states. The principal investigator's present an entirely novel approach to the generation of defined HLGAG oligosaccharides by combining the enzymatic degradation of natural heparin with chemical synthesis. The program will draw from extensive expertise in enzymatic degradation of HLGAGs using heparinases, chemical synthesis of complex oligosaccharides and an understanding of the biological activities of HLGAGs. This relatively simple synthetic strategy would particularly lend itself to the solid support synthesis of defined HLGAG sequences, much like peptides and oligonucleotides are currently assembled. This novel and interdisciplinary program initially will be aimed at providing a proof-of-principle for the strategy to assemble HLGAG sequences involved in coagulation and hemostasis processes. However, areas of clinical opportunities of HLGAGs go beyond hemostasis, and can include angiogenesis and growth factor mediated signal transduction.
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