合成生物学在多糖结合疫苗研发中的应用

doi:10.12211/2096-8280.2023-054

摘要/Abstract

摘要：

由于合成生物学的快速发展，目前已经实现了人工设计DNA和蛋白质的合成，对具有重要生物学功能、结构也更为复杂的糖类物质进行精准设计合成，也将是合成生物学未来发展的重要方向。近年来，一种基于细菌寡糖转移酶体系的蛋白多糖偶联技术发展迅速，已被广泛应用于病原细菌多糖结合疫苗的生物合成制备。本文综述了该技术体系中的寡糖转移酶元件、载体蛋白元件、异源多糖抗原合成线路以及工程菌株改造等核心关键模块的最新研究进展。使用生物活体系统，发酵生产多糖结合疫苗，具有产物均一性好、步骤简便、绿色环保等优势，是一种亟待发展的新兴技术，同时也存在一些技术细节需要完善。未来，寡糖转移酶的定向进化、纳米颗粒型蛋白载体的应用、多糖合成基因的组合重排、工程菌株的代谢途径优化，将有望进一步促进多糖结合疫苗的生物合成研究。

关键词: 糖合成生物学, 多糖结合疫苗, 蛋白多糖偶联技术, 寡糖转移酶

Abstract:

The precise design and synthesis of carbohydrates with important biological functions and more complex structures is a frontier in synthetic biology. Recently, a novel strategy named Protein Glycan Coupling Technology (PGCT) based on bacterial oligosaccharyltransferases has been developed and widely used in the biosynthesis of bacterial glycoconjugate vaccines, which are one of achievements in modern medicine due to their effectiveness in fighting against infectious diseases. Herein, progress in developing key components for manufacturing glycoconjugate vaccines, such as oligosaccharyltransferases (PglL, PglS, PglB, and TfmP), carrier proteins (CRM197, diphtheria toxoid, recombinant Pseudomonas aeruginosa exotoxin A, and nanoparticles), polysaccharide biosynthesis gene circuits, and glyco-engineered strains is reviewed. Meanwhile, producing glycoconjugate vaccines through fermentation presents advantages in good product quality control for safety and efficacy, low production cost, and environmental-friendly manufacturing. PGCT has potentials to overcome some limitations of chemical conjugation production processes, such as complex purification and high cost, for competitiveness with existing chemical conjugates. As an emerging technology, more technological innovations are needed for PGCT. In the future, the directed evolution of oligosaccharyltransferases, the application of protein nanoparticle carriers, the combination rearrangement of glycosyltransferases, and the optimization of engineered bacterial strains with better metabolic pathways are expected to further promote the biosynthesis of conjugate vaccines. The next few years will be an important and exciting time for PGCT, as recent technological advances are being applied to the development of novel glycoconjugates, and ongoing large-scale clinic trials on the efficacy of glycoconjugate vaccines will also demonstrate the feasibility of this technology, making the future of PGCT vaccinology promising. {L-End}

Key words: synthetic glycobiology, conjugate vaccine, protein glycan coupling technology (PGCT), oligosaccharyltransferases

中图分类号:

叶精勤, 黄文华, 潘超, 朱力, 王恒樑. 合成生物学在多糖结合疫苗研发中的应用[J]. 合成生物学, 2024, 5(2): 338-352.

Jingqin YE, Wenhua HUANG, Chao PAN, Li ZHU, Hengliang WANG. Applications of synthetic biology in developing polysaccharide conjugate vaccines[J]. Synthetic Biology Journal, 2024, 5(2): 338-352.

图/表 2

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菌株	抗原	载体蛋白	偶联技术	研究阶段
B型流感嗜血杆菌	天然多糖	TT	化学偶联	已授权
B型流感嗜血杆菌	寡糖	CRM₁₉₇	化学偶联	已授权
C型脑膜炎奈瑟氏菌	天然多糖	TT	化学偶联	已授权
C型脑膜炎奈瑟氏菌	寡糖	CRM₁₉₇	化学偶联	已授权
ACWY型脑膜炎奈瑟氏菌	寡糖	CRM₁₉₇	化学偶联	已授权
肺炎链球菌	天然多糖	PD, DT, TT	化学偶联	已授权
肺炎链球菌	天然多糖	链霉亲和素融合蛋白	生物偶联	临床Ⅱ期
肠外致病大肠杆菌	寡糖	EPA	生物偶联	临床Ⅲ期
志贺氏菌2a	寡糖	EPA	生物偶联	临床Ⅰ期
志贺氏菌2a	寡糖	TT	化学反应	临床Ⅰ期
肺炎克雷伯氏菌	O-抗原寡糖	EPA	生物偶联	临床Ⅰ期

菌株	抗原	载体蛋白	偶联技术	研究阶段
B型流感嗜血杆菌	天然多糖	TT	化学偶联	已授权
B型流感嗜血杆菌	寡糖	CRM₁₉₇	化学偶联	已授权
C型脑膜炎奈瑟氏菌	天然多糖	TT	化学偶联	已授权
C型脑膜炎奈瑟氏菌	寡糖	CRM₁₉₇	化学偶联	已授权
ACWY型脑膜炎奈瑟氏菌	寡糖	CRM₁₉₇	化学偶联	已授权
肺炎链球菌	天然多糖	PD, DT, TT	化学偶联	已授权
肺炎链球菌	天然多糖	链霉亲和素融合蛋白	生物偶联	临床Ⅱ期
肠外致病大肠杆菌	寡糖	EPA	生物偶联	临床Ⅲ期
志贺氏菌2a	寡糖	EPA	生物偶联	临床Ⅰ期
志贺氏菌2a	寡糖	TT	化学反应	临床Ⅰ期
肺炎克雷伯氏菌	O-抗原寡糖	EPA	生物偶联	临床Ⅰ期

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