Synthesis of complex carbohydrate antigens of pathogenic bacteria

病原菌复合糖抗原的合成

• 批准号: RGPIN-2015-05756
• 负责人: Giguere, Denis
• 金额: $ 1.46万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613730
• 关键词: Synthesis; complex; carbohydrate; antigens; pathogenic

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.

在过去的几十年里，越来越多的糖生物学研究已经导致碳水化合物的鉴定，在细胞信号传导和免疫学中发挥重要的关键作用。荚膜多糖（CPS）和/或脂多糖（LPS）是细菌表面的主要成分。已经从细菌CPS或LPS中分离出几种高级单糖（含有8至11个连续碳原子的单糖），这些碳水化合物的合成可以允许获得有价值的潜在抗原分子。医学相关的2-酮基-酮糖酸家族具有多种生物学功能，并且是细菌CPS和/或LPS的成分。尽管多年来进行了广泛的努力，但没有合成这些碳水化合物的通用和实用的路线。 我们的研究计划的统一主题是通过合作研究，利用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，我们提出了一个新的合成高级单糖的绿色化学评价。为此，一种新的从头方法将通过级联反应获得官能化的二氢吡喃。然后，将唾液酸聚合并缀合到新的载体蛋白（PaPMV包被蛋白）上，以实现基于碳水化合物的抗菌疫苗。在糖缀合物疫苗中发现新的蛋白质载体是科学界的极大兴趣。类似地，新型水杨酸基半乳糖凝集素抑制剂的合成将允许在分子水平上更好地理解碳水化合物-蛋白质相互作用，从而导致潜在的新药设计。 这些项目将有助于培训高素质的科学家，他们的技能将有益于私人和公共研究实验室。该研究计划将教育和培养本科生和研究生在艺术和科学的化学合成碳水化合物化学。