Studies on the Synthesis and Biochemistry of Complex Glycans

碳水化合物(也称为多糖)在许多生物过程中起着关键作用。在过去的20年里，我的实验室一直专注于合成基于多糖的探针，以在分子水平上建立对这些作用的理解。我们对覆盖在细菌、真菌、寄生虫和病毒表面的多糖特别感兴趣。我们的工作产生了双重影响，提供了合成多糖的新方法，并产生了新的分子，用于我的团队和合作者的基础结构-功能研究。在这次探索资助金续期中，我们将工作扩展到三个新项目。选择用于研究的系统将结构上有趣的分子与尚未见过实质性研究的系统和分子结合在一起。这里提出的开创性研究将影响合成碳水化合物化学和微生物糖生物学领域。这笔赠款支持的三个项目是：*1.合成含有寄生虫和病毒中发现的高支链单糖残基的葡聚糖。这些多糖还没有成为合成研究的对象。除了揭示组装这些复杂结构的“规则”外，这项工作还将为我实验室的免疫化学研究和生物合成的合作研究提供探针。这项工作的长期应用包括针对病毒和寄生虫感染的新型疫苗或诊断，以及用于治疗病毒疾病的化合物。*2.从引起结核病的有机体、结核分枝杆菌合成多糖及其作为阿拉伯聚糖酶底物的评价。这些酶参与降解被称为阿拉伯糖的关键分枝杆菌碳水化合物。这项工作将为这些酶带来新的底物和检测方法，这些酶是新型抗分枝杆菌药物的潜在靶点。*3.与猪链球菌中发现的多糖有关的多糖的合成，猪链球菌是养猪业的一种昂贵的病原体，也是一种日益导致人类感染的有机体。这些以前没有得到合成化学家注意的猪链球菌多糖，将与合作者一起用于基础免疫学研究。一个长期目标是为这些感染设计有效的疫苗和诊断测试，无论是对动物还是对人类。*计划项目每年将培养6名研究生和1名本科生。所有受训人员将获得有机分子的合成化学和表征方面的技能。在一些项目中，他们将获得分析开发或免疫学方面的专门技能(在我的团队中或与合作者一起)。他们将在这样一个环境中工作，通过将研究培训与为每个人的职业目标量身定做的专业发展机会相结合，在为自然科学和工程领域的职业生涯培训个人方面取得了极大的成功。

Carbohydrates (also called glycans) play pivotal roles in many biological processes. Over the past 20 years my lab has focused on synthesizing glycan-based probes to build understanding of these roles at the molecular level. We have been particularly interested in glycans that coat the surfaces of microbes: bacteria, fungi, parasites and viruses. Our work has had double impact, providing new methods to synthesize glycans and generating novel molecules that are used in fundamental structure–function studies both by my group and with collaborators. In this Discovery Grant renewal, we extend our work to three new projects. The systems chosen for study combine structurally intriguing molecules with systems and molecules that have not yet seen substantial investigation. The groundbreaking studies proposed here will impact the fields of synthetic carbohydrate chemistry and microbial glycobiology. The three projects to be supported by this grant are: ******1. Synthesis of glycans containing highly-branched monosaccharide residues that are found in parasites and viruses. These glycans have not yet been the subject of synthetic investigations. In addition to uncovering the ‘rules' for assembling these complex structures, this work will provide probes for immunochemical studies in my lab and collaborative studies on biosynthesis. Long-term applications of this work include novel vaccines or diagnostics for viral and parasitic infections, and compounds for treating viral diseases. ******2. Synthesis of glycans from the organism that causes tuberculosis, Mycobacterium tuberculosis, and their evaluation as substrates for arabinanases. These enzymes are involved in degrading key mycobacterial carbohydrates called arabinans. This work will lead to novel substrates and assays for these enzymes, which are potential targets for new classes of anti-mycobacterial agents. ******3. Synthesis of glycans related to polysaccharides found in Streptococcus suis, a costly pathogen for the pig industry and an organism that increasingly leads to human infections. These S. suis glycans, which have not previously received the attention of synthetic chemists, will be used in fundamental immunological studies with collaborators. A long-term goal is to design effective vaccines and diagnostic tests for these infections, both for animals and humans. ******The planned projects will train six graduate students and one undergraduate each year. All trainees will gain skills in synthetic chemistry and characterization of organic molecules. In some projects, they will gain specialized skills in assay development or immunology (in my group or with collaborators). They will work in an environment that has been highly successful in training individuals for careers in the natural sciences and engineering, by combining research training with professional development opportunities tailored to each individual's career objectives.