Chemical Synthesis of All Phosphatidylinositol Mannoside (PIM) Glycans from Mycobacterium tuberculosis
Chemical Synthesis of All Phosphatidylinositol Mannoside (PIM) Glycans from Mycobacterium tuberculosis
复制标题
DOI：
10.1021/ja806283e
复制
发表时间：
2008-12-10
影响因子：
15
通讯作者：
Seeberger, Peter H.
中科院分区：
文献类型：
--
作者：
Boonyarattanakalin, Siwarutt;Liu, Xinyu;Seeberger, Peter H.
耐多药结核病（TB）的出现和BCG结核病疫苗保护人类免受结核病的问题促使人们通过探索新的细菌药物靶标和疫苗来研究对抗这种疾病的替代方法。磷脂酰肌醇甘露糖苷（PIM）是生物学上重要的糖缀合物，并且代表更复杂的分枝杆菌细胞壁糖脂的常见必需前体;包括脂甘露聚糖（LM）、脂阿拉伯甘露聚糖（LAM）和甘露聚糖封端的脂阿拉伯甘露聚糖（ManLAM）。合成的PUS构成了重要的生物化学工具，以阐明这类分子的生物合成，揭示PIM与宿主细胞的相互作用，并研究PIM作为疫苗开发的潜在抗原和/或佐剂的功能。在这里，我们报告了所有PIM的有效合成，包括磷脂酰肌醇（PI）和磷脂酰肌醇单到六甘露糖苷（PIM 1到PIM 6）。开发了稳健的合成方案用于利用双环和三环原酸酯以及甘露糖基磷酸盐作为糖基化剂。每个合成的PIM配备有用于固定在表面上的巯基连接体和用于生物学和免疫学研究的载体蛋白。将合成的PUS固定在微阵列载玻片上，以阐明与树突状细胞特异性细胞间粘附分子抓取非整合素（DC-SIGN）受体结合的差异。在C57 BL/6小鼠的免疫实验中，当与模型抗原钥孔-血蓝蛋白（KLH）偶联时，合成的PUS充当免疫刺激剂。
The emergence of multidrug-resistant tuberculosis (TB) and problems with the BCG tuberculosis vaccine to protect humans against TB have prompted investigations into alternative approaches to combat this disease by exploring novel bacterial drug targets and vaccines. Phosphatidylinositol mannosides (PIMs) are biologically important glycoconjugates and represent common essential precursors of more complex mycobacterial cell wall glycolipids; including lipomannan (LM), lipoarabinomannan (LAM), and mannan capped lipoarabinomannan (ManLAM). Synthetic PUS constitute important biochemical tools to elucidate the biosynthesis of this class of molecules, to reveal PIM interactions with host cells, and to investigate the function of PIMs as potential antigens and/or adjuvants for vaccine development. Here, we report the efficient synthesis of all PIMs including phosphatidylinositol (PI) and phosphatidylinositol mono- to hexa-mannoside (PIM1 to PIM6). Robust synthetic protocols were developed for utilizing bicyclic and tricyclic orthoesters as well as mannosyl phosphates as glycosylating agents. Each synthetic PIM was equipped with a thiol-linker for immobilization on surfaces and carrier proteins for biological and immunological studies. The synthetic PUS were immobilized on microarray slides to elucidate differences in binding to the dendritic cell specific intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN) receptor. Synthetic PUS served as immune stimulators during immunization experiments in C57BL/6 mice when coupled to the model antigen keyhole-limpet hemocyanin (KLH).