Stable Carbohydrate Libraries in Infectious Disease

由细菌和病毒病原体引起的传染病对预防工作提出了重要挑战， 保护和治疗。微生物的碳水化合物与哺乳动物的碳水化合物共同进化 宿主并为病原体提供伪装，这是一种与宿主相互作用的手段，并利用相对 静态结构虽然微生物碳水化合物提供了潜在的治疗靶点，但它们与人类碳水化合物的相似性， 碳水化合物的选择性应用需要创新的方法。最常见的方法， 对抗传染病依赖于免疫、防止感染和感染后治疗。 分解代谢稳定的碳水化合物，在控制传染病中重要但尚未开发的目标， 是这项提案的重点。唾液酸是一种常见的乌洛糖酸，存在于唾液酸的非还原末端。 糖萼中的聚糖，一种围绕动物细胞的碳水化合物外壳，以及粘蛋白中的高度带电的 保护某些组织的糖蛋白屏障。由于糖复合物既被重塑又被分解代谢， 从非还原性末端通过逐步酶促除去它们的糖单元， 它们的乌洛糖酸组分代表了阻断这种转化的靶点。可能的 稳定的乌洛糖酸C-糖苷的应用包括：主动和被动疫苗， 靶向或提供病原体屏障的纳米材料或涂层，以及作为神经氨酸酶和 血凝素该提案描述了图书馆的设计，综合和初步评估， 用于抗病原体的含有乌洛糖酸C-糖苷的糖缀合物。这些分子也将 对生物材料的应用有影响。具体目标是三个指标的准备和评价 图书馆：1.用于制备脑膜炎球菌疫苗的α-2，8 C-连接的唾液酸寡聚体; 2. 粘蛋白C-连接的类似物作为抗感染剂/针对2型和3型病原体和流感的屏障;和3.唾液酸 酸性C-糖苷作为神经氨酸酶/血凝素抑制剂和抗病毒剂。

Infectious disease caused by bacterial and viral pathogens pose important challenges in prevention, protection and therapy. Microbial carbohydrates co-evolved with the carbohydrates of their mammalian hosts and provide camouflage to pathogens, a means of interacting with their hosts and utilize a relatively static structure. While microbial carbohydrates offer a potential therapeutic target, their similarity to human carbohydrates require innovative methods for their selective application. The most common approaches to counter infectious disease rely on immunization, protection from infection, and post-infection therapy. Catabolically stable carbohydrates, important yet under exploited targets in controlling infectious disease, are the focus of this proposal. Sialic acid is a common ulosonic acid found at the non-reducing terminus of glycans in the glycocalyx, a carbohydrate shell surrounding animal cells, and in mucins, a highly charged glycoprotein barrier that protects certain tissues. Since glycoconjugates are both remodeled and catabolized from the non-reducing terminus by stepwise enzymatic removal of their saccharide units, the modification of their ulosonic acid component represents a target for blocking such transformation. The possible applications of stable ulosonic acid C-glycosides include: active and passive vaccines, the preparation of nanomaterials or coatings to target or provide a pathogen barrier, and as inhibitors of neuraminidases and hemagglutinins. This proposal describes the design, synthesis and preliminary evaluation of libraries of glycoconjugates containing ulosonic acid C-glycosides for use against pathogens. These molecules will also have impact on biomaterial applications. The specific aims are the preparation and evaluation of three target libraries: 1. alpha-2,8 C-linked sialic acid oligomers for use in the preparation of meningococcal vaccines; 2. mucin C-linked analogs as anti-infectives/barriers against type 2&3 pathogens and influenza; and 3.sialic acid C-glycosides as neuraminidase/hemagglutinin inhibitors & antiviral agents.