Stable Carbohydrate Libraries in Infectious Disease

传染病中的稳定碳水化合物库

基本信息

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
项目类别：
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

项目摘要

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要挑战，保护和治疗。与哺乳动物的碳水化合物共同进化的微生物碳水化合物宿主并为病原体提供伪装，一种与宿主互动并使用相对较高的方法静态结构。虽然微生物碳水化合物提供了潜在的治疗靶标，但它们与人类的相似性碳水化合物需要创新的方法来进行选择性应用。最常见的方法反感染疾病依赖于免疫，免受感染和感染后治疗。分解代谢稳定的碳水化合物，在控制传染病方面很重要但受剥削的靶标。是该提议的重点。唾液酸是在非还原末端发现的一种常见溃疡酸糖卵果中的聚糖，围绕动物细胞的碳水化合物壳和粘蛋白，高度带电的保护某些组织的糖蛋白屏障。由于糖缀合物均已重塑和分解代谢从非还原末端通过逐步酶促去除糖单元，修改它们的溃疡酸成分代表了阻止这种转化的目标。可能稳定磺酸C-糖苷的应用包括：主动和被动疫苗，制备纳米材料或涂层以靶向或提供病原体屏障，以及神经氨酸酶和血凝素素。该建议描述了对图书馆的设计，综合和初步评估含有溃疡酸C-糖苷用于病原体的糖缀合物。这些分子也将对生物材料应用有影响。具体目的是对三个目标的准备和评估图书馆：1。Alpha-2,8 C连接的唾液酸寡聚物用于制备脑膜炎球菌疫苗； 2。粘蛋白C连接类似物作为针对2型和3型病原体和流感的抗感染/屏障；和3.Sialic 酸C-糖苷作为神经氨酸酶/血凝素抑制剂和抗病毒剂。