Synthetic and Biological Studies of Chondroitin Sulfate Oligosaccharides and Glycopeptides

该奖项由密歇根州立大学生命过程化学项目资助密歇根州立大学黄学飞博士研究硫酸软骨素(CS)和硫酸软骨素蛋白多糖(CSPG)的合成和功能。碳水化合物在许多生物过程中扮演着重要的角色。然而，由于自然界中复杂的碳水化合物结构缺乏一致性，彻底了解它们的功能一直是非常具有挑战性的。该项目将专注于一类特定的碳水化合物，称为硫酸软骨素(CS)和硫酸软骨素蛋白多糖(CSPG)，即与蛋白质结合的硫酸软骨素。将开发新的合成方法来生产这些复杂分子，这将极大地扩大通过化学合成可以获得的结构范围。有了这些材料，就有可能确定不同结构对CS和CSPG与淀粉样β蛋白相互作用的影响，例如，淀粉样β蛋白是阿尔茨海默病患者大脑中存在的聚集体和斑块的前体。此外，研究生、本科生和高中研究人员的参与将为他们提供在复杂碳水化合物合成这一重要和具有挑战性的领域接受培训的机会。所产生的结果将为合成化学的力量以及如何利用化学合成来解决重要的生物学问题提供一个亮点。硫酸软骨素(CS)和硫酸软骨素蛋白多糖(CSPG)参与了许多重要的生物学事件，包括神经发育、器官形态发生、炎症、感染和β淀粉样斑块的形成。CS和CSPG中O-硫酸盐的数量和位置对其生物学性质有显著影响。由于天然存在的CS和CSPG含有不同的硫酸盐化模式，利用从自然界中分离出来的CS和CSPG来破译详细的结构功能关系是非常具有挑战性的。在文献中已经报道了相互矛盾的结果。为了克服这一问题并促进生物学研究，将开发合成方法来生产具有明确硫化模式和结构的CS寡糖和CSPG糖肽。这些化合物的用途将在CS/CSPG与β-淀粉样肽相互作用的研究中得到证明，以探索淀粉样斑块形成的潜在机制，淀粉样斑块是阿尔茨海默病的病理标志。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Xuefei Huang from Michigan State University to study the synthesis and functions of chondroitin sulfate (CS) and chondroitin sulfate proteoglycans (CSPG). Carbohydrates play important roles in many biological processes. However, due to the lack of uniformity of complex carbohydrate structures in nature, it has been very challenging to thoroughly understand their function. This project will focus on one specific class of carbohydrates referred to as chondroitin sulfate (CS) and chondroitin sulfate proteoglycans (CSPG), chondroitin sulfate that is bonded to protein. New synthetic approaches will be developed to produce these complex molecules, which will greatly expand the range of structures that can be accessed through chemical synthesis. With these materials, it will be possible to establish the impact of different structures on the interactions of CS and CSPG with, for example, amyloid beta peptide, the precursor to the aggregates and plaques that are present in the brains of people with Alzheimer's disease. In addition, the engagement of graduate, undergraduate and high school researchers in this project will provide them with opportunities to be trained in the important and challenging field of complex carbohydrate synthesis. The results generated will provide a highlight for the power of synthetic chemistry, and how chemical synthesis can be utilized to address important biological problems. Chondroitin sulfate (CS) and chondroitin sulfate proteoglycans (CSPG) are involved in many important biological events including neural development, organ morphogenesis, inflammation, infection and beta amyloid plaque formation. The number and location of O-sulfates in CS and CSPG can significantly influence their biological properties. As naturally existing CS and CSPG contain heterogeneous sulfation patterns, it is highly challenging to decipher the detailed structure function relationship using CS and CSPG isolated from nature. Contradicting results have been reported in the literature. In order to overcome this problem and facilitate biological studies, synthetic methodologies will be developed to produce CS oligosaccharides and CSPG glycopeptides with well-defined sulfation patterns and structures. The utility of these compounds will be demonstrated in the study of CS/CSPG interactions with beta-amyloid peptide to investigate a potential mechanism for the formation of amyloid plaques, a pathological hallmark of Alzheimer's disease.