Synthesis of glycoconjugates to elicit carbohydrate-specific immune responses and enhance molecular recognitions

碳水化合物无处不在，并涉及所有细胞间的通信。我们的研究兴趣是开发新的方法，并将碳水化合物化学，分子生物学和超分子化学的最新进展应用于设计和合成与生物活性碳水化合物相关的新型类似物以及了解相关的生物识别机制。有两个目标：第一个目的是制备能够刺激宿主产生持久免疫应答的碳水化合物-蛋白质缀合物（疫苗）;第二个目的是设计和合成用作抑制剂的基于碳水化合物的配体，所述抑制剂能够竞争性结合蛋白质如酶、毒素、凝集素，以阻断不希望的免疫反应。在我们的第一个目标的背景下，我们的研究可以导致针对细菌感染的预防性疫苗的生产，或产生具有选择性消除恶性肿瘤细胞的潜力的治疗性抗体。在第二个目标的上下文中，如果不期望的相互作用来自酶对底物的解离，则我们的研究可以产生能够结合到酶的活性位点的高亲和力配体，导致酶产生不期望的分子的效率下调;如果不希望的相互作用与病原体的附着直接相关，这种毒素与宿主细胞表面上存在的碳水化合物的附着，我们的研究可能导致产生能够防止致病性附着的基于高亲和力碳水化合物的治疗剂。基于上述概念和过去三年中获得的结果，我们建议在以下三个领域进行研究：第一个是与α（2，8）-连接的寡聚唾液酸糖苷的化学及其免疫化学有关;第二个是与KDO糖苷的合成方法学的发展有关，第三个是研究利用多个取代的环糊精作为结构单元，以产生新的基于环糊精的超分子系统，该系统能够跨越大距离接合蛋白质结合位点。

Carbohydrates are ubiquitous and implicated in all cell-cell communications. Our research interests are to develop new methodologies and apply recent advances in carbohydrate chemistry, molecular biology and supramolecular chemistry to the design and synthesis of novel analogs related to bioactive carbohydrates as well as to the understanding of relevant biorecognition mechanisms. Two objectives are pursued: the first is to prepare carbohydrate-protein conjugates (vaccines) capable of stimulating hosts to generate long-lasting immune responses; the second objective is to design and synthesize carbohydrate based ligands for use as inhibitors capable of competitively binding to proteins such as enzymes, toxins, lectins, in order to block undesired recognitions. In the context of our first objective, our research can lead to the production of preventive vaccines against bacterial infections, or to the generation of therapeutic antibodies with potential to selectively eliminate malignant tumour cells. In the context of the second objective, if the undesired interaction is from an enzyme's recognitions of a substrate, our research can generate high affinity ligands capable of binding to the enzyme's active site, leading to a downregulation of enzyme's efficiency to produce undesired molecules; if the undesired interaction is directly linked to the attachment of pathogens, such toxins to carbohydrates present on the surface of host cells, our research could lead to the generation of high affinity carbohydrates based therapeutics capable of preventing the pathogenic attachment. Based on the concepts outlined above and on results obtained during past three years, we propose to conduct research in the following three areas: the first is related to the chemistry of alpha(2,8)-linked oligosialosides and their immunochemistry; the second is related to the development of synthetic methodology for KDO glycosides and the third is to investigate the potential of utilizing multi-substituted cyclodextrins as building blocks to generate novel cyclodextrin-based supramolecular systems capable of engaging protein binding sites across large distances.