<br>使用药物化学方法发现针对细菌感染的半合成和全合成碳水化合物疫苗,Chemical Reviews

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使用药物化学方法发现针对细菌感染的半合成和全合成碳水化合物疫苗
Chemical Reviews ( IF 51.4 ) Pub Date : 2021-04-01 , DOI: 10.1021/acs.chemrev.0c01210
Peter H Seeberger _{1,

2}

Affiliation

糖萼是一层厚厚的碳水化合物，包围着大多数细菌和寄生病原体的细胞壁。人类免疫系统对这些独特的聚糖的识别会导致入侵者被消灭。为了引发保护性免疫反应，需要施用从细菌细胞表面分离的多糖或与载体蛋白缀合的多糖，以帮助 T 细胞。基于分离碳水化合物的结合疫苗目前可以保护数百万人免受肺炎链球菌、b 型流感嗜血杆菌和脑膜炎奈瑟菌感染。活性药物成分 (API) 越来越多地通过药物化学发现和合成，而不是从天然来源中分离出来。将疫苗从生物制品转变为药物需要对人类免疫系统如何识别碳水化合物有基本的了解，现在可以实现。为了说明基于化学的疫苗发现方法，我总结了专注于基于合成聚糖的药物化学的努力，以了解哺乳动物抗聚糖免疫反应并定义针对肺炎链球菌、艰难梭菌、肺炎克雷伯菌等的新型合成糖复合物疫苗的聚糖表位细菌。这里描述的化学工具帮助我们深入了解人体系统如何识别碳水化合物并推动碳水化合物疫苗的发现。

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Discovery of Semi- and Fully-Synthetic Carbohydrate Vaccines Against Bacterial Infections Using a Medicinal Chemistry Approach

The glycocalyx, a thick layer of carbohydrates, surrounds the cell wall of most bacterial and parasitic pathogens. Recognition of these unique glycans by the human immune system results in destruction of the invaders. To elicit a protective immune response, polysaccharides either isolated from the bacterial cell surface or conjugated with a carrier protein, for T-cell help, are administered. Conjugate vaccines based on isolated carbohydrates currently protect millions of people against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitides infections. Active pharmaceutical ingredients (APIs) are increasingly discovered by medicinal chemistry and synthetic in origin, rather than isolated from natural sources. Converting vaccines from biologicals to pharmaceuticals requires a fundamental understanding of how the human immune system recognizes carbohydrates and could now be realized. To illustrate the chemistry-based approach to vaccine discovery, I summarize efforts focusing on synthetic glycan-based medicinal chemistry to understand the mammalian antiglycan immune response and define glycan epitopes for novel synthetic glycoconjugate vaccines against Streptococcus pneumoniae, Clostridium difficile, Klebsiella pneumoniae, and other bacteria. The chemical tools described here help us gain fundamental insights into how the human system recognizes carbohydrates and drive the discovery of carbohydrate vaccines.

更新日期：2021-04-14

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