Stable Carbohydrate Libraries in Infectious Disease

传染病中的稳定碳水化合物库

• 批准号: 7748958
• 负责人: ROBERT J LINHARDT
• 金额: $ 38.08万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7748958
• 关键词: Acids; Adhesions; Animals; Anti-Infective Agents; Antibodies; Antigens; Antiviral Agents; Binding Proteins; Biocompatible Materials; Bioterrorism; Brain; C-glycoside; Carbohydrates; Carbon; Catabolism; Cell surface; Cells; Charge; Combinatorial Synthesis; Communicable Diseases; Disease; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Evaluation; Excision; Exposure to; Glycocalyx; Glycoconjugates; Glycolipids; Glycoproteins; Hemagglutinin; Human; Hydrolase; Immunization; Immunologics; Infection; Infectious Agent; Influenza; Laboratories; Libraries; Link; Lipids; Masks; Meningococcal Infections; Meningococcal vaccine; Methods; Modification; Molecular; Monosaccharides; Mucins; Mutate; Natural Immunity; Neuraminidase; Neuraminidase inhibitor; Passive Immunization; Phase; Polysaccharides; Polysialic Acid; Preparation; Prevention; Proteins; Resistance; Scheme; Screening procedure; Sialic Acids; Solid; Structure; Surface; Takeda brand of pioglitazone hydrochloride; Therapeutic Intervention; Therapeutic Uses; Tissues; Vaccines; Viral; Virus Diseases; analog; base; combinatorial; design; direct application; disorder prevention; ear infection; in vivo; inhibitor/antagonist; innovation; microbial; mimetics; nanomaterials; pathogen; prevent; receptor; response; sugar; therapeutic target

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.

由细菌和病毒病原体引起的传染病在预防方面构成了重大挑战， 保护和治疗。微生物碳水化合物与哺乳动物的碳水化合物共同进化 寄主并为病原体提供伪装，一种与寄主互动的方式，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。最常见的方法是 对抗传染病依赖于免疫、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未被开发的目标， 是这项提案的重点。唾液酸是一种常见的磺酸，存在于非还原末端 糖萼中的葡聚糖，动物细胞周围的碳水化合物外壳，以及粘蛋白中的高度带电的 保护某些组织的糖蛋白屏障。因为糖共轭化合物既被改造又被分解代谢 从非还原末端通过逐步酶法去除它们的糖单元，修饰 它们的磺酸成分是阻止这种转化的靶标。可能的 稳定的乌糖酸C-糖苷的应用包括：主动和被动疫苗，制备 纳米材料或涂层，用于靶向或提供病原体屏障，并作为神经氨酸酶和 血凝素。该方案描述了文库的设计、合成和初步评估 含有磺酸C-糖苷的糖偶联物，用于对抗病原体。这些分子也会 对生物材料应用产生影响。具体目标是三个指标的准备和评价 文库：1.用于制备脑膜炎双球菌疫苗的α-2，8-C-连接唾液酸低聚物； 粘蛋白C连接的类似物，作为抗感染/对抗2型和3型病原体和流感的屏障；以及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药物。