SYNTHETIC VACCINE AGAINST SHIGELLOSIS

志贺氏菌合成疫苗

• 批准号: 2575686
• 负责人: V POZSGAY
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2575686
• 关键词: Shigella vaccines; drug design /synthesis /production; immunoconjugates; nuclear magnetic resonance spectroscopy; synthetic vaccines; vaccine development

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.

由志贺氏菌1型引起的志贺氏菌病仍然是主要的 肠道疾病在世界范围内，大多数菌株现在都具有抗生素抗性。 虽然需要疫苗来控制这种疾病， 根据世界卫生组织的记录，目前还没有针对志贺氏菌病的许可疫苗。 在罗宾斯和同事发现血清抗体 抗宋内志贺菌O-特异性多糖（OSP）的免疫 这种病原体在人类中引起的疾病，我们假设 OSP的延伸片段也可能适合于诱导 当与免疫原性蛋白偶联时，保护性抗体，条件是 这种双链构象的集合接近于 天然多糖的构象决定簇。 使用 定义结构而非天然结构的合成酶 具有复杂结构的多糖可能提供优势， 包括增强缀合物的均匀性和消除 分析困难与建立，多糖- 蛋白质疫苗 基于这一假设，我们正在开发合成 基于寡糖和多糖的免疫原， 特色 我们设计了一种策略来制备OSP的片段 色葡萄紫茎泽兰1型 OSP由四糖组成， 由D-半乳糖、N-乙酰基-D-葡糖胺、 和L-鼠李糖。 从单糖开始， 正交保护和活化基团，四糖 组装供体/受体分子。这种迭代组合 构建块提供重复单元的二聚体、三聚体和四聚体 对应于八碳、十二碳和十六碳。十二生肖-和 十六碳纳米管表现出高度构象 与天然O-SP相似。 第一个共轭的四- 重复单元的合成。 体外实验表明， 所述合成的寡核苷酸抑制OSP与同源寡核苷酸的结合， 克隆抗体