STRUCTURE AND FUNCTION OF SYNTHETIC GLYCOSAMINOGLYCANS

肝素样糖胺聚糖（HLGAGs）是最酸的天然生物聚合物。这些在细胞外基质中发现的复杂多糖，在调节凝血级联中几种蛋白质的生物活性以及许多其他生物医学重要过程中发挥关键作用，包括生长因子相互作用、病毒进入和血管生成。由于这些聚合物的复杂性和非均质性，人们对其结构和活性之间的关系仍然知之甚少。越来越多的证据表明，特定长度和序列的HLGAGs负责与特定蛋白质结合并调节其生物活性。确定HLGAGs的结构-功能关系为发现针对各种疾病状态的新型治疗干预措施创造了机会。所提出的研究的总体目标是开发一种模块化的、通用的合成策略，用于在溶液和固体载体上制备肝素样糖胺聚糖和非天然类似物。作为整个程序的一部分，将被合成的定义结构将被用作分子工具来阐明3-0-硫转移酶的底物特异性，它负责创建肝素的精细结构。了解这些和其他生物合成酶的底物特异性也可能为化学-酶联合方法的发展奠定基础，以合成定义的HLGAGs。本研究结果将为深入研究HLGAGs的结构-功能关系提供结构、生化和生物物理基础。受体结合的特定序列的确定为分子工具的发展带来了巨大的希望，这将使我们能够调节病毒进入、血管生成、肾脏疾病和中枢神经系统疾病的潜在过程。

Heparin-like glycosaminoglycans (HLGAGs) are the most acid naturally occurring biopolymers. These complex polysaccharides, found in the extracellular matrix, play a key role in regulating the biological activity of several proteins in the coagulation cascade along with many other processes of biomedical importance including growth factor interactions, virus entry, and angiogenesis. 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 evidence that defined lengths and sequences of HLGAGs are responsible for binding to a particular protein and modulating its biological activity. Determining of structure-function relationships of HLGAGs creates an opportunity for the discovery of novel therapeutic interventions for a variety of disease states. The overall thrust of the proposed research is the development of a modular, general synthetic strategy for the preparation of heparin-like glycosaminoglycans and non-natural analogs in solution and on a solid support. The defined structures that will be synthesized as part of the overall program will be used as molecular tools to elucidate the substrate specificity of 3-0-sulfotransferases, which are responsible for creating the fine structure of heparin. An understanding of the substrate specificity of these and other biosynthetic enzymes may also lay the foundation for the development of a combined chemo-enzymatic approach to the synthesis of defined HLGAGs. The results of the proposed research are expected t provide the basis for structural, biochemical, and biophysical studies into the structure-function relationship of HLGAGs. The determination of specific sequences involved in receptor binding holds great promise for the development of molecular tools which will allow us to modulate processes underlying viral entry, angiogenesis, kidney diseases and diseases of the central nervous system.