江南大学尹健团队报道了含（S）-4,6-O-丙酮酮的痢疾志贺氏菌血清型10O-抗原四糖的化学合成及抗原性评价。相关研究成果于2022年11月10日发表在国际顶尖学术期刊《美国化学会杂志》。

志贺氏菌是引起儿童急性腹泻的第二大常见病原体。由于志贺氏菌的耐药性不断增加，抗志贺氏杆菌疫苗仍在等待中。志贺氏O抗原是一种很有前途的疫苗靶点。

为了鉴定聚糖的免疫表位，完成了含（S）-4,6-O-丙酮酸缩酮的痢疾杆菌血清型10O-抗原四糖的首次全合成。1,2-反式-β-糖基化和C2差向异构化以及构象锁定策略有助于构建两个1,2-双-β-糖苷键。通过添加给电子苄基，提高了糖基供体和受体的反应性，从而实现了四糖的有效组装。由于对糖基化立体特异性和效率的影响，在最后阶段引入了（S）-4,6-O-丙酮酸缩酮。

研究人员还合成了（R）-4,6-O-丙酮酸和非丙酮酸四糖以及另外三个片段。聚糖微阵列筛选显示，四糖重复单元是O抗原的关键抗原表位。此外，（S）-4,6-O-丙酮酸缩酮是该抗原的一个基本结构特征，用于设计针对痢疾链球菌血清型10的基于碳水化合物的疫苗。（S）-4，6-O-丙酮酸聚糖及其（R）-差向异构体的比较，将为含丙酮酸缩醛的其他细菌聚糖的生物学评价提供一个范例。

附：英文原文

Title: Chemical Synthesis and Antigenicity Evaluation of Shigella dysenteriae Serotype 10 O-Antigen Tetrasaccharide Containing a (S)-4,6-O-Pyruvyl Ketal

Author: Chunjun Qin, Lingxin Li, Guangzong Tian, Meiru Ding, Shengyong Zhu, Wuqiong Song, Jing Hu, Peter H. Seeberger, Jian Yin

Issue&Volume: November 10, 2022

Abstract: Shigella is the second most common etiologic pathogen responsible for childhood acute diarrhea. An anti-Shigella vaccine is still eagerly awaited due to the increasing drug resistance of this pathogen. The Shigella O-antigen is a promising vaccine target. To identify the immune epitopes of the glycan, the first total synthesis of Shigella dysenteriae serotype 10 O-antigen tetrasaccharide containing a (S)-4,6-O-pyruvyl ketal was completed. The 1,2-trans-β-glycosylation & C2 epimerization and conformational locking strategies facilitated the construction of two 1,2-cis-β-glycosidic linkages. The reactivities of both the glycosyl donor and acceptor were improved by adding electron-donating benzyl groups, enabling an efficient assembly of the tetrasaccharide. The (S)-4,6-O-pyruvyl ketal was introduced at the final stage due to its influence on the glycosylation stereospecificity and efficiency. In addition, (R)-4,6-O-pyruvylated and nonpyruvylated tetrasaccharides and three further fragments were synthesized. Glycan microarray screening revealed that the tetrasaccharide repeating unit is the key antigenic epitope of the O-antigen. Moreover, the (S)-4,6-O-pyruvyl ketal is an essential structural feature of this antigen for designing carbohydrate-based vaccines against S. dysenteriae serotype 10. The comparison of the (S)-4,6-O-pyruvylated glycan and its (R)-epimer will set an example for biological evaluation of other bacterial glycans containing pyruvyl ketals.

DOI: 10.1021/jacs.2c05953

Source: https://pubs.acs.org/doi/10.1021/jacs.2c05953