STRUCTURE AND FUNCTION OF SYNTHETIC GLYCOSAMINOGLYCANS

合成糖胺聚糖的结构和功能

• 批准号: 6793481
• 负责人: PETER H SEEBERGER
• 金额: $ 20.6万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6793481
• 关键词: carbohydrate analog; chemical structure function; chemical synthesis; combinatorial chemistry; enzyme structure; enzyme substrate; heparin; high performance liquid chromatography; mucopolysaccharides; receptor binding; sulfotransferase

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.

肝素样糖胺聚糖（HLGAGs）是最酸性的天然存在的生物聚合物。这些在细胞外基质中发现的复合多糖在调节凝血级联中的几种蛋白质的生物活性以及许多其他生物医学重要性过程（包括生长因子相互作用、病毒进入和血管生成）中起关键作用，所述凝血级联沿着。由于这些聚合物的复杂性和异质性，人们对HLGAG的结构与活性之间的关系仍然知之甚少。越来越多的证据表明，HLGAGs的确定长度和序列负责与特定蛋白质结合并调节其生物活性。确定HLGAGs的结构-功能关系为发现用于各种疾病状态的新型治疗干预创造了机会。提出的研究的总体目标是开发一种模块化的通用合成策略，用于在溶液和固体支持物中制备肝素样糖胺聚糖和非天然类似物。将作为整体计划的一部分合成的定义结构将用作分子工具，以阐明3-0-磺基转移酶的底物特异性，该酶负责创建肝素的精细结构。对这些和其他生物合成酶的底物特异性的理解也可以为开发用于合成定义的HLGAGs的组合化学-酶促方法奠定基础。预计拟议研究的结果将为HLGAGs结构与功能关系的结构、生化和生物物理研究提供基础。参与受体结合的特异性序列的确定为分子工具的开发带来了巨大的希望，这些分子工具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。