STRUCTURE BASED DRUG DESIGN FOR TREATMENT OF PARASITIC AND VIRAL DISEASES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们这个项目的目标是设计和合成新的多肽和类似肽的抑制剂，特别针对疟疾、血吸虫病、锥虫病和甲型肝炎发病机制中的关键蛋白酶。晶体结构和在某些情况下基于同源的靶蛋白结构模型被用于基于计算机图形的配基结合的建模、用于潜在抑制剂的数据库筛选以及潜在的结合模式的分析。优化这些化合物的目的是提高特异性、半衰期和降低毒性。利用药物化学方法，我们设计和合成了多种化合物，包括杂芳烃抑制剂、多肽类和模拟多肽类抑制剂。在该项目的最初几年，质谱学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来靶向特定功能亚类的蛋白酶活性。

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.