SYNTHESIS OF STRUCTURALLY DIVERSE C-OLIGOSACCHARIDES

结构多样的低聚糖的合成

• 批准号: 2189382
• 负责人: ROBERT W ARMSTRONG
• 金额: $ 21.58万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2189382
• 关键词: Actinomyces; Helicobacter; Orthomyxoviridae; bacterial antigens; bacterial polysaccharides; binding proteins; carbohydrate receptor; carbohydrate structure; cell adhesion; chemical synthesis; genetic library; intermolecular interaction; oligosaccharides; receptor binding; surface antigens; virus receptors

The purpose of this study is to provide a survey of spatial requirements of cell-surface carbohydrates antigens in order to identify soluble receptor analogs which could competitively inhibit pathogenic bacteria/viral attachment. Three targets are addressed: 1) Influenza virus - inhibition of viral attachment to sialic acid residues by designing inhibitors with C2 or C3 symmetry which are capable of multidentate (intra- or intermolecular) binding to the viral hemagglutinin coat proteins. 2) Helicobacter pylori - inhibition of bacterial attachment to human gastric mucosa mediated by the fucose-containing Lewis (b) blood group antigen. This bacteria is the causative agent in chronic active gastritis, gastric and duodenal ulcers, and gastric adenocarcinoma, one of the most common forms of cancer in humans. The tetrasaccharide Lewis (b), as well as a Lewis (b)-albumin conjugate (32 copies of Lewis (b) on surface of albumin have recently been shown in vitro to be inhibitors for adhesion of H. pylori to human gastric surface mucosal cells. The synthesis of C- analogs of Lewis (b) (O-analogs are incompatible with the gastric environment) including a combinatorial library of C-oligosaccharides will be targeted. 3) Actinomyces viscosus and Actinomyces naeslundii - Inhibition of attachment to oral endothelial cells mediated by a beta-galactose residue. A systematic clustering survey using readily available C-beta-galactose analogs is designed to map out the as yet unknown receptor geometry using an Ugi four-component condensation as a highly efficient strategy for the generation of high-density oligosaccharide clusters. The synthetic efforts in the proposal are divided into two sections. The first involves the synthesis of the carbon-linked analogs of the three relevant cell surface antigens: a) C-N-acetylneuraminic acid, b) C-and/or O-linked Lewis (b) tetrasaccharide derivatives, and, c) C-galactose. The second section involves the synthesis of appropriate scaffolding for the first systematic study of polydentate inhibitors where antigen analogs are positioned over large distances (up to 100 A apart). This involves the incorporation of C-acetylenic oligosaccharides (already synthesized by us) into symmetry-related oligomers and dendromers. This proposal outlines a plan for synthesizing large libraries of unique soluble receptor analogs for each target and the methods for assaying these inhibitors. Our intent is to systematically survey spatial relationships of potential ligands on oligosaccharide scaffoldings as an empirical approach to the design of inhibitors. The successful accomplishment of these goals will provide a research tool for the systematic study of molecular interactions involving macromolecular structures. In addition, it will provide some insight into the design, synthesis, and conformational analysis of carbohydrate oligomers capable of interfering in binding processes involving surface antigens.

这项研究的目的是提供有关空间要求的调查 细胞表面碳水化合物抗原，以识别可溶受体 可以竞争抑制致病细菌/病毒的类似物 依恋。 解决了三个目标： 1）流感病毒 - 抑制病毒附着在唾液酸上 通过使用C2或C3对称性设计抑制剂的残留物，该抑制剂能够 与病毒结合的多培养基（分子间或分子间） 血凝素涂层蛋白。 2）幽门螺杆菌 - 对人类的细菌附着的抑制 由含岩藻糖的刘易斯（B）血型介导的胃粘膜 抗原。 该细菌是慢性活性胃炎的致病剂， 胃溃疡和十二指肠溃疡，以及胃腺癌，最多的腺癌之一 人类癌症的常见形式。 四糖刘易斯（b）也 作为刘易斯（b） - α-雌激素结合物（在表面上的32份刘易斯（b）副本 最近已经显示白蛋白在体外显示为粘附的抑制剂 幽门螺杆菌到人类胃表面粘膜细胞。 c-的合成 刘易斯的类似物（b）（o-analogs与胃不兼容 环境）包括C-寡糖组合的组合库 是针对性的。 3）放线肌粘膜和放线菌Naeslundii-抑制 通过β-半乳糖残基介导的口服内皮细胞的附着。 使用随时可用的C-beta-galactose进行系统的聚类调查 类似物旨在使用未知的受体几何形状绘制 UGI四组分凝结是一种高效的策略 高密度寡糖簇的产生。 该提案中的合成工作分为两个部分。 这 首先涉及三个碳连接类似物的合成 相关细胞表面抗原：a）c-n-乙酰神经酰胺酸，b）c- and/o O连接的Lewis（B）四糖衍生物和C）C-半乳糖。 这 第二部分涉及合成适当的脚手架的 首次系统研究抗原类似物的聚乙酸抑制剂 位于大距离（最多100个距离）上。 这涉及 C-乙酰基寡糖的掺入（我们已经合成） 进入与对称相关的低聚物和树突。 该提案概述了合成独特的大型库的计划 每个目标的可溶性受体类似物以及分析这些目标的方法 抑制剂。 我们的目的是系统地调查空间关系 寡糖支架上的潜在配体作为经验 设计抑制剂的方法。 成功的成就 这些目标将为系统研究提供研究工具 涉及大分子结构的分子相互作用。 此外， 它将提供一些有关设计，合成和构象的见解 分析能够干扰结合的碳水化合物寡聚物 涉及表面抗原的过程。