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

碳水化合物是无处不在的，并与所有细胞间的通讯有关。我们的研究兴趣是开发新的方法学，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：第一个目标是制备能够刺激宿主产生持久免疫反应的碳水化合物-蛋白质结合物(疫苗)；第二个目标是设计和合成基于碳水化合物的配体，作为能够与酶、毒素、凝集素等蛋白质竞争性结合的抑制剂，以阻止不受欢迎的识别。在我们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，或者产生有可能选择性地消除恶性肿瘤细胞的治疗性抗体。在第二个目标的背景下，如果不良相互作用是由于酶对底物的识别，我们的研究可以产生能够与酶的活性部位结合的高亲和力配体，导致酶的效率下调以产生不良分子；如果不良相互作用直接与病原体的附着有关，这样的毒素与宿主细胞表面存在的碳水化合物有关，我们的研究可能导致产生能够防止病原体附着的高亲和力碳水化合物疗法。基于以上概述的概念和过去三年的研究结果，我们建议在以下三个方面开展研究：第一，与α(2，8)连接的寡糖苷的化学及其免疫化学有关；第二，与KDO糖苷的合成方法学的发展有关；第三，研究利用多取代环糊精作为构建单元来生成能够远距离结合蛋白质结合位点的新型环糊精超分子体系的可能性。

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.