STRUCTURE BASED DRUG DESIGN FOR TREATMENT OF PARASITIC AND VIRAL DISEASES

用于治疗寄生虫和病毒性疾病的基于结构的药物设计

• 批准号: 8169745
• 负责人: James H. McKerrow
• 金额: $ 0.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-12 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169745
• 关键词: Affinity; Binding; Chemicals; Computer Graphics; Computer Retrieval of Information on Scientific Projects Database; Databases; Drug Design; Funding; Goals; Grant; Half-Life; Hepatitis A; Institution; Lead; Ligand Binding; Malaria; Mass Spectrum Analysis; Modeling; Pathogenesis; Peptide Hydrolases; Peptides; Pharmaceutical Chemistry; Play; Proteomics; Research; Research Personnel; Resources; Role; Schistosomiasis; Screening procedure; Source; Specificity; Staging; Structural Models; Structure; Toxic effect; Trypanosomiasis; United States National Institutes of Health; Virus Diseases; base; design; improved; inhibitor/antagonist; mimetics; novel; peptidomimetics

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our goal for this project is to design and synthesize novel peptide and peptido-mimetic inhibitors, specifically targeted against proteases central to the pathogenesis of malaria, schistosomiasis, trypanosomiasis, and hepatitis A. Crystal structures and in some cases homology-based structural models for target proteases are used for computer-graphics based modeling of ligand binding, for database screening of potential inhibitors as well as for analysis of potential binding modes. Optimization of these compounds is aimed at improving specificity, half-life, and diminishing toxicity. Using medicinal chemistry approaches, we have designed and synthesized a wide variety of chemical compounds which include heteroaromatic inhibitors, peptide-based and peptidomimetic inhibitors. In the early years of this project, mass spectrometry has played an important role in chemical characterization of these lead compounds. Proteomic analysis is also important at early stages of target identification, using affinity based probes that target specific functional subclasses of protease activities.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们该项目的目标是设计和合成新型肽和拟肽抑制剂，专门针对对疟疾、血吸虫病、锥虫病和甲型肝炎发病机制至关重要的蛋白酶。晶体结构，以及在某些情况下基于同源性的靶标结构模型蛋白酶用于基于计算机图形学的配体结合建模、潜在抑制剂的数据库筛选以及潜在结合模式的分析。 这些化合物的优化旨在提高特异性、半衰期和降低毒性。 利用药物化学方法，我们设计并合成了多种化合物，包括杂芳族抑制剂、肽基抑制剂和拟肽抑制剂。 在该项目的早期，质谱法在这些先导化合物的化学表征中发挥了重要作用。 蛋白质组分析在目标鉴定的早期阶段也很重要，使用基于亲和力的探针来靶向蛋白酶活性的特定功能亚类。