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。由于多重抗生素耐药性 在许多志贺氏菌株中，志贺氏菌病的治疗是困难的。 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1型痢疾链霉菌O型特异性多糖(OSP) 在人类中授予保护性免疫，我们假设延长了 OSP的片段也可能适合于诱导保护性 当抗体与免疫原蛋白偶联时，如果 这种糖的构象集成接近于 天然多糖的构象决定因素。对.的使用 用结构确定的合成糖类代替黄精多糖 复杂的体系结构可能会提供以下优势： 共轭化合物的均匀性和分析困难的消除 与已建立的多糖蛋白疫苗相关。基座 在这一假设的基础上，我们正在开发合成寡聚和 基于多糖的免疫原，具有明确的特征。我们 设计了一种制备痢疾杆菌OSP片段的策略 类型1。OSP由四糖重复单位组成，该单位是 由D-半乳糖、N-乙酰-D-氨基葡萄糖和L-鼠李糖组成。 从携带正交的单糖构建块开始 保护和激活基团，四糖供体/受体 分子被组装起来。此构建块的迭代组合 提供对应于以下的重复单元的二、三和四异构体 八糖、十二糖和十六糖。核磁共振 光谱分析表明，十二糖和十六糖 表现出与原生O-SP高度构象相似 我们认为这是保护性抗体诱导的先决条件。 体外实验表明，合成的糖抑制了 OSP与同源单抗的结合。

Shigellosis caused by Shigella dysenteriae type 1 continues to be a major enteric disease worldwide. Because of the multiple-antibiotic resistance of many strains of Shigellae, the treatment of shigellosis is difficult. 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 S. dysenteriae type 1 confer protective immunity 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 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. Nuclear magnetic resonance spectroscopy indicated that the dodeca- and the hexadeca-saccharides exhibit a high degree of conformational similarity to the native O-SP which we believe is a prerequisite for protective antibody induction. In vitro experiments showed that the synthetic saccharides inhibit the binding of the OSP to homologous monoclonal antibodies.