Heparin, a heterogeneously sulfated glycosaminoglycan (GAG), consists of -1,4-linked glucosamine (GlcN) and uronic acid [either D-glucuronic acid (GlcA) or L-iduronic acid (IdoA)] disaccharide repeating units. It has been used as an anticoagulant drug for over 80 years. In addition, it plays significant roles in various biological processes such as inflammation, growth factor regulation, bacterial and viral infection, cell adhesion, cell growth, tumor metastasis, lipid metabolism and diseases of the nervous system. However, the complex heterogeneity of natural heparin polysaccharides has hindered efforts to understand the relationship between their diverse structures and biological functions. While chemical and enzymatic syntheses of heparin oligosaccharides have seen tremendous advances in recent years, it is still challenging to prepare heparin analogs approaching the length of polysaccharides with distinct backbone structures and sulfation patterns. In this project, we have developed a new strategy, where (GlcN-IdoA) disaccharide modules with defined sulfation pattern are synthesized and conjugated through amide bond formation. Novel "head-to-tail" multimers are accessed to mimic the linear connections in natural GAG polysaccharides. The ligand requirements of fibroblast growth factor 2 (FGF-2) are studied using bio-layer interferometry (BLI) and surface plasmon resonance (SPR), and the results show the synthetic multimers could mimic the natural heparin mimetics. Heparanase inhibitory activities have also been examined through the colorimetric assay.
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