STRUCTURE BASED DRUG DESIGN FOR TREATMENT OF PARASITIC AND VIRAL DISEASES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 本项目的目标是设计和合成新型肽和肽模拟物抑制剂，特异性靶向于疟疾、血吸虫病、锥虫病和甲型肝炎发病机制的核心蛋白酶。 晶体结构和在某些情况下，基于同源性的结构模型的目标蛋白酶用于计算机图形的配体结合的建模，潜在的抑制剂的数据库筛选，以及潜在的结合模式的分析。 这些化合物的优化旨在改善特异性、半衰期和降低毒性。 利用药物化学的方法，我们已经设计并合成了各种各样的化合物，包括杂芳族抑制剂，肽基和拟肽抑制剂。 在该项目的早期，质谱分析在这些先导化合物的化学表征中发挥了重要作用。 蛋白质组学分析在靶标鉴定的早期阶段也很重要，使用基于亲和力的探针靶向蛋白酶活性的特定功能亚类。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.