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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.

项目摘要耐药微生物菌株的出现对全球构成了巨大威胁，人体健康预防细菌感染，减少对抗生素的依赖治疗，开发替代有效的方法是极其紧迫的。侵入性细菌通常产生独特和复杂的细胞表面聚糖，例如荚膜多糖。多糖（CPS），其结构与人类糖组显著不同。这些微生物聚糖是病原体入侵的基本毒力因子，有希望的目标，为发展有效的疫苗，以防止细菌感染.基于聚糖的抗微生物疫苗通常通过缀合将荚膜多糖与蛋白质载体结合。目前，聚糖抗原主要是从细菌发酵中获得。因此，难以控制质量和长度的聚糖。为了制备均质的全合成糖缀合物疫苗，化学合成仍然是获得足够数量的可靠方法，细菌碳水化合物分子的良好纯度。在结构上，微生物聚糖通常由不寻常和高度复杂的单糖组成，糖苷键。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。在本申请中，将开发糖基化方法，包括：1）阳离子金（I）催化的糖基化方法，涉及糖基N-1，1-二烷基炔丙基氨基甲酸酯供体的糖基化，和2）a 铯催化异头O-烷基化立体选择性合成β-甘露糖苷类型链接。由合成代表性抗原性寡糖重复单元有害细菌，如沙门氏菌菌株、炭疽杆菌和芽孢杆菌将使用这些新开发的糖基化方法.