SYNTHETIC VACCINE AGAINST SHIGELLOSIS I--SHIGELLA DYSENTERIAE TYPE 1

抗志贺氏菌 I-1 型志贺氏菌痢疾的合成疫苗

• 批准号: 6162486
• 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/6162486
• 关键词: Shigella vaccines; drug design /synthesis /production; gastrointestinal infection; immunoconjugates; nuclear magnetic resonance spectroscopy; synthetic vaccines; vaccine development

Shigellosis is a major enteric disease worldwide causing diarrhea and dysentery, an acute invasive disease of the lower intestines in many parts of the world with a very low infectious dose (approximately 100 bacteria). Because of the multiple-antibiotic resistance of many strains of Shigellae, the treatment of shigellosis is difficult and prevention by vaccination should be an alternative to control this disease. We hypothesized that extended fragments of the O-specific polysaccharide (O-SP) components of the lipopolysaccharides of Shigellae may be suitable for the induction of protective antibodies when covalently coupled to immunogenic proteins. The use of synthetic saccharides of defined structure instead of polysaccharides of highly complex architecture offers numerous advantages including enhanced uniformity of conjugates, the possibility of using saccharides with pre-determined termini on the saccharide chain, and elimination of much of the analytical difficulties associated with the polysaccharide-protein vaccines. In addition, the possible dangers inherent with materials of biological origin are also minimized. Based on this hypothesis we are developing synthetic oligosaccharide-based immunogens of well-defined molecular characteristics. We designed a synthetic strategy to prepare oligosaccharide fragments of the O-SP of S. dysenteriae type 1. The O-SP consists of a tetrasaccharide repeating unit that is composed of D-galactose, N-acetyl-D-glucosamine, and L-rhamnose. Starting from monosaccharides that carry orthogonal protecting and activating groups, a tetrasaccharide donor/acceptor molecule was assembled. Iterative combination of the building blocks afforded di-, tri- and tetramers of the repeating unit corresponding to octa-, dodeca- and hexadeca-saccharide portions of the native O-SP. These oligo/polysaccharides are equipped with an w-hydrazinocarbonylpentyl aglycon that can be used to anchor the saccharides to proteins and other macromolecules. A new heterobifunctional linker molecule was developed and used to attach the saccharides to proteins under mild conditions.

志贺氏菌病是世界范围内引起腹泻的主要肠道疾病， 痢疾是一种急性侵入性疾病， 感染剂量非常低的世界部分地区（约100 细菌）。 由于许多菌株对多种抗生素具有耐药性， 志贺氏菌感染后，志贺氏菌病的治疗很困难，通过 接种疫苗应该是控制这种疾病的一种替代办法。 我们 假设O-特异性多糖的延伸片段 志贺氏菌脂多糖的（O-SP）组分可能是合适的 用于在共价偶联至 免疫原性蛋白质。 使用定义的合成氨 而不是高度复杂结构的多糖 提供了许多优点包括增强的缀合物均匀性， 使用具有预定末端的双链烷烃的可能性， 糖链，并消除了许多分析困难 与多糖蛋白疫苗有关。 此外该 生物来源材料固有的可能危险也 最小化基于这一假设，我们正在开发合成 基于寡糖的明确分子的免疫原 特色 我们设计了一种合成策略 S.紫茎泽兰1型 O-SP 由四糖重复单元组成，所述四糖重复单元由 D-半乳糖、N-乙酰基-D-葡糖胺和L-鼠李糖。日起 带有正交保护和活化基团的单糖， 组装四糖供体/受体分子。 迭代 结构单元的组合提供了以下物质的二聚体、三聚体和四聚体 重复单元对应于八-、十二-和 天然O-SP的十六糖部分。 寡糖/多糖配备有N-肼基羰基戊基， 可用于锚蛋白质和其他蛋白质的糖苷配基 大分子 开发了一种新的异双功能连接分子 并用于在温和条件下将酶连接到蛋白质上。