SYNTHETIC VACCINE AGAINST SHIGELLOSIS

由1型志贺氏菌引起的志贺氏菌病仍然是主要的 全球范围内的肠道疾病，大多数菌株现在对抗生素具有抗药性。 尽管控制这种疾病的疫苗的需求一直是 根据世卫组织的记录，目前还没有针对志贺氏菌病的许可疫苗。 在罗宾斯和他的同事发现血清抗体 抗宋内氏志贺菌O型特异性多糖(OSP) 对于这种病原体在人类身上引起的疾病，我们假设 OSP的延伸片段也可能适合于诱导 保护性抗体与免疫原性蛋白偶联时，前提是 这种糖类的构象组合接近于 天然多糖的构象决定因素。对.的使用 确定结构的合成糖而不是天然糖 复杂结构的多糖可能会提供优势 包括增强共轭化合物的均匀性和消除 与已建立的多糖相关的分析困难- 蛋白质疫苗。基于这一假设，我们正在开发合成的 基于寡糖和多糖的免疫原的明确定义 特点。我们设计了一种策略来准备OSP的片段 沙门氏菌1型。OSP由四糖组成 由D-半乳糖、N-乙酰-D-氨基葡萄糖、 和L-鼠李糖。从携带单糖的积木开始 正交保护和活化基团，一种四糖 组装了供体/受体分子。这一点的迭代组合 积木提供重复单元的二、三和四异构体 对应于八、十二和十六糖。十二岁--以及 十六糖具有高度的构象。 核磁共振谱显示与天然O-SP相似。四元环的第一个共轭化合物- 合成了重复单元。体外实验表明， 合成的糖抑制OSP与同系物的结合 单克隆抗体。

Shigellosis caused by Shiqella dysenteriae type 1 continues to be a major enteric disease worldwide and most strains are now antibiotic resistant. Although the need for vaccines to control this disease has been documented by the WHO, there is no licenced vaccine against shigellosis. Following the discovery by Robbins and coworkers that serum antibodies against the O-specific polysaccharide (OSP) of Shigella sonnei immunity to disease caused by this pathogen in humans, we hypothesized that extended fragments of the OSP may also be suitable for the induction of protective antibodies when coupled to immunogenic proteins, provided that the conformational ensemble of such saccharides approaches that of the conformational determinant of the native polysaccharide. The use of synthetic saccharides of defined structure instead of native polysaccharides of complex architecture is likely to offer advantages including enhanced uniformity of conjugates and elimination of the analytical difficulties associated with the established, polysaccharide- protein vaccines. Based on this hypothesis we are developing synthetic oligo- and poly-saccharide-based immunogens of well -defined characteristics. We designed a strategy to prepare fragments of the OSP of S. dysenteriae type 1. The OSP consists of a tetrasaccharide repeating unit that is composed of D-galactose, N-acetyl-D-glucosamine, and L-rhamnose. Starting from monosaccharide building blocks that carry orthogonal protecting and activating groups, a tetrasaccharide donor/acceptor molecule was assembled. Iterative combination of this building block afforded di-, tri- and tetramers of the repeating unit corresponding to octa-, dodeca- and hexadeca-saccharides. The dodeca- and the hexadeca-saccharides exhibit a high degree of conformational similarity to the native O-SP by NMR. The first conjugate of a tetra- repeating unit has been synthesized. In vitro experiments showed that the synthetic saccharides inhibit the binding of the OSP to homologous monoclonal antibodies.