New Glycosylation Methods for Microbial Glycan Synthesis

微生物聚糖合成的新糖基化方法

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10515058
• 关键词: Alkylation; Antibiotic Therapy; Antigens; Bacillus anthracis; Bacillus stearothermophilus; Bacteria; Bacterial Infections; Carbamates; Carbohydrates; Carrier Proteins; Catalysis; Cations; Cell Wall; Cell surface; Cesium; Complex; Development; Fermentation; Glycoconjugates; Glycosides; Gold; Health; Human; Length; Mannosides; Methodology; Methods; Microbial Drug Resistance; Monosaccharides; Oligosaccharides; Polysaccharides; Quality Control; Research; Salmonella; Structure; Vaccines; Virulence Factors; antimicrobial; base; catalyst; chemical synthesis; cost effectiveness; glycosylation; microbial; pathogen; prevent; success; therapeutic vaccine; vaccine development

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 抗药性微生物菌株的出现对全球构成了巨大威胁 人类健康。防止细菌感染并减少我们对抗生素的保留率 治疗，开发替代有效方法非常紧急。 细菌通常会产生独特而复杂的细胞表面糖，例如囊状 多糖（CPS），其结构与人类的结构显着不同。 这些微生物糖是病原体侵袭的必要病毒因素， 有望开发有效疫苗的有希望的靶标 感染。基于聚糖的抗菌疫苗通常是通过结合来制备的 蛋白质载体的囊囊多糖。目前，聚糖抗原主要是 从细菌发酵获得。因此，很难控制质量和长度 糖。为了制备同质完全合成糖缀合物的疫苗， 化学合成仍然是一种可靠的方法，可以获取足够数量的方法 细菌碳水化合物分子的纯度。在结构上，微生物糖经常 由异常且高度复杂的单糖和挑战组成 糖苷连接。因此，它们的化学合成需要 新的有效糖基化方法和策略。在此应用中，两个新的催化 将开发糖基化方法，包括：1）阳离子黄金（i）催化 糖基化涉及糖基N-1,1-二烷基丙烷碳酸盐供体，2）A 剖宫产的动漫O-烷基化以立体选择性结构β-甘露糖苷 类型链接。代表性抗原寡糖重复单位的合成 有害细菌，例如沙门氏菌菌株，炭疽芽孢杆菌和芽孢杆菌 将使用这些新开发的糖基化进行硬化菌 方法。

项目成果

Cationic gold(I)-catalyzed glycosylation with glycosyl N-1,1-dimethylpropargyl carbamate donors.

• DOI: 10.1039/d2ob01436j
• 发表时间: 2022-09-14
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2