A modular approach for the synthesis of heparan sulfate oligosaccharides
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Heparan sulfate (HS) is a linear, polyanionic heavily O- and N- sulfated polysaccharide comprising a repeating disaccharide unit of 1→4 linked uronic acid (either α-L-iduronic acid or β-D-glucuronic acid) and α-D-glucosamine unit. HS interacts with a number of proteins such as growth factors, morphogens, enzymes and chemokines. HS-protein complexes mediate several biological processes such as homeostasis, growth-factor activity, anticoagulation, and cell adhesion and enzyme regulation. Recently, HS was shown to inhibit Alzheimer's β-secretase (BACE-1, β-site amyloid precursor protein cleaving enzyme-1). BACE-1 cleaves the amyloid precursor protein (APP) resulting in the formation of aggregates of amyloid β-peptide, which have been implicated in the pathogenesis of Alzheimer's disease. Although more than a hundred HS-binding proteins have been identified, the HS ligand requirements for binding and mediating biological activities by these proteins are mostly unknown. The structural complexity of natural heparan sulfate (HS) and difficulties of preparing well-defined HS oligosaccharides hampers efforts to understand structure-activity relationships. To address this deficiency, we developed a modular approach for the parallel combinatorial synthesis of HS oligosaccharides. The modular approach utilizes a relatively small number of selectively protected disaccharide building blocks which can be converted into glycosyl donors and acceptors. The utility of the modular building blocks has been demonstrated by the preparation of a library of 12 oligosaccharides, which has been employed to probe the structural features of HS for inhibiting the protease, BACE-1. The complex variations in activity with subtle changes in HS sequence and sulfation pattern support the view that important functional information is embedded in HS sequences. Furthermore, the most active derivative provides an attractive lead compound for the preparation of more potent compounds, which may find use as a therapeutic agent for Alzheimer’s disease.