New Glycosylation Methods for Microbial Glycan Synthesis

微生物聚糖合成的新糖基化方法

基本信息

批准号：
10515058
负责人：
Jianglong Zhu
金额：
$ 45.15万
依托单位：
UNIVERSITY OF TOLEDO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

项目摘要

Project Summary The emergence of drug resistant microbial strains has posed a great threat to the global human health. To prevent bacterial infections and reduce our reliance on antibiotic treatment, development of alternative effective approaches is extremely urgent. Invasive bacteria often produce unique and complex cell surface glycans, e.g. capsular polysaccharides (CPS), whose structures are significantly different from human glycome. These microbial glycans are essential virulence factors for pathogen invasion and promising targets for the development of effective vaccines for preventing bacterial infections. Glycan-based antimicrobial vaccines are often prepared by conjugation of capsular polysaccharides to a protein carrier. Currently, glycan antigens are mainly obtained from bacterial fermentation. Hence, it is difficult to control the quality and length of glycans. In order to prepare homogeneous fully synthetic glycoconjugate vaccines, chemical synthesis remains as a reliable approach to access sufficient quantities and good purity of bacterial carbohydrate molecules. Structurally, microbial glycans often consists of unusual and highly complex monosaccharides as well as challenging glycosidic linkages. Therefore, their chemical synthesis demands the development of new efficient glycosylation methods and strategies. In this application, two new catalytic glycosylation methodologies will be developed including: 1) a cationic gold(I)-catalyzed glycosylation involving glycosyl N-1,1-dialkylpropargyl carbamate donors, and 2) a cesium-catalyzed anomeric O-alkylation for stereoselective construction of β-mannoside type linkages. Synthesis of representative antigenic oligosaccharide repeating units from harmful bacteria, such as Salmonella strains, Bacillus anthracis and Bacillus stearothermophilus will be carried out employing these newly developed glycosylation methods.

项目概要耐药微生物菌株的出现对全球造成了巨大威胁预防细菌感染并减少我们对抗生素的依赖。治疗，开发替代有效的侵入性方法迫在眉睫。细菌通常产生独特且复杂的细胞表面聚糖，例如荚膜多糖（CPS），其结构与人类糖组显着不同。这些微生物聚糖是病原体入侵和入侵的重要毒力因子。开发有效预防细菌疫苗的有希望的目标基于聚糖的抗菌疫苗通常通过结合来制备。目前，以荚膜多糖为蛋白质载体。由于是通过细菌发酵获得的，因此很难控制质量和长度。为了制备均质的全合成糖复合物疫苗，化学合成仍然是获取足够数量的可靠方法从结构上看，微生物聚糖通常具有良好的纯度。由不寻常且高度复杂的单糖组成，并且具有挑战性因此，它们的化学合成需要开发新的高效糖基化方法和策略在此应用中，有两种新的催化。将开发的糖基化方法包括：1）阳离子金（I）催化糖基化糖基N-1,1-二烷基炔丙基氨基甲酸酯供体，和2)a 铯催化异头O-烷基化立体选择性构建β-甘露糖苷类型连接的代表性抗原寡糖重复单元的合成。有害细菌，如沙门氏菌、炭疽杆菌和芽孢杆菌嗜热脂肪菌将利用这些新开发的糖基化进行方法。