Synthesis of complex carbohydrate antigens of pathogenic bacteria

在过去的几十年里，糖生物学的研究不断增加，导致了对碳水化合物的识别，这些碳水化合物在细胞信号和免疫学中发挥着重要的关键作用。荚膜多糖(CPS)和/或脂多糖(LPS)是细菌表面的主要成分。从细菌的CPS或LPS中已经分离出几种较高级的单糖(含有8到11个连续碳原子的单糖)，这些碳水化合物的合成可以获得有价值的潜在抗原分子。医学上相关的2-酮基-磺酸家族具有多种生物学功能，是细菌CPS和/或内毒素的组成部分。尽管多年来进行了广泛的努力，但目前还没有一种通用和实用的方法来合成这些碳水化合物。 我们研究计划的统一主题是通过合作研究开发复杂的碳水化合物作为新的杀菌分子或半乳糖凝集素抑制剂。为了达到这一目标，我们建议对更高级单糖的新合成进行绿色化学评估。为此，一种新的从头合成方法将通过级联反应获得功能化的二氢吡喃。然后，将唾液酸聚合并连接到一种新的载体蛋白(PaPMV包膜蛋白)上，以获得基于碳水化合物的抗菌疫苗。糖结合疫苗中新的蛋白载体的发现引起了科学界的极大兴趣。同样，新型水杨酸类半乳糖凝集素抑制剂的合成将在分子水平上更好地了解碳水化合物与蛋白质的相互作用，从而产生潜在的新药设计。 这些项目将有助于培训高素质的科学家，他们的技能将使私营和公共研究实验室受益。拟议的研究计划将教育和培训本科生和研究生在碳水化合物化学中的化学合成艺术和科学方面。

During the last few decades, increasing research in glycobiology has led to the identification of carbohydrates that play important key roles in cell signaling and immunology. Capsular polysaccharides (CPS) and/or lipopolysaccharides (LPS) are the major components on the surface of bacteria. Several higher monosaccharides (monosaccharides containing between 8 and 11 consecutive carbon atoms) have been isolated from bacterial CPS or LPS, and the synthesis of these carbohydrates could allow access to valuable potential antigenic molecules. The medically relevant 2-keto-ulosonic acid family have various biological functions and are constituents of bacterial CPS and/or LPS. Despite extensive efforts over the years, there is no general and practical route to the synthesis of these carbohydrates. The unifying theme of our research program is to exploit, through collaborative research, complex carbohydrates as new bactericidal molecules or galectin inhibitors. To reach this goal, we propose the evaluation of green chemistry towards a new synthesis of higher monosaccharides. To this end, a new de novo approach will give access to functionalized dihydropyrans via cascade reactions. Then, sialic acid will be polymerized and conjugated onto a new carrier protein (PaPMV coated protein) to achieve carbohydrate-based antibacterial vaccines. The discovery of new protein carriers in glycoconjugate vaccines is of great interest to the scientific community. Similarly, the synthesis of novel salic acid-based galectin inhibitors will allow a better understanding of the carbohydrates-protein interactions at the molecular level, leading to potential new drug design. These projects will contribute to the training of highly qualified scientists whose skills will benefit private and public research laboratories. The research program proposed will educate and train undergraduate and graduate students in the art and science of chemical synthesis in carbohydrate chemistry.