Stable Carbohydrate Libraries in Infectious Disease

描述（由申请人提供）：由细菌和病毒病原体引起的传染病对预防、保护和治疗提出了重要挑战。微生物碳水化合物与其哺乳动物宿主的碳水化合物共同进化，并为病原体提供伪装，这是与其宿主相互作用的一种手段，并利用相对静态的结构。虽然微生物碳水化合物提供了一个潜在的治疗靶点，但它们与人类碳水化合物的相似性需要创新的方法来选择性应用。对抗传染病的最常见方法依赖于免疫接种、预防感染和感染后治疗。分解代谢稳定的碳水化合物是控制传染病的重要但尚未开发的目标，是该提案的重点。唾液酸是一种常见的乌洛糖酸，存在于糖萼（一种围绕动物细胞的碳水化合物外壳）和粘蛋白（一种保护某些组织的高电荷糖蛋白屏障）中聚糖的非还原末端。由于糖缀合物通过逐步酶促去除其糖单元而从非还原末端被重塑和分解代谢，因此其酮糖酸组分的修饰代表了阻断这种转化的靶标。稳定的乌洛糖酸C-糖苷的可能应用包括：主动和被动疫苗，制备纳米材料或涂层以靶向或提供病原体屏障，以及作为神经氨酸酶和血凝素的抑制剂。该提案描述了用于对抗病原体的含有阿洛糖酸C-糖苷的糖缀合物库的设计、合成和初步评价。这些分子也将对生物材料应用产生影响。具体目标是准备和评估三个目标库：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C-糖苷作为神经氨酸酶/血凝素抑制剂和抗病毒剂。

DESCRIPTION (provided by applicant): Infectious diseases 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.