DRUG DESIGN CYCLE TARGETED TO RETROVIRAL PROTEASES

该计划的目标是开发成熟的工具来帮助药物 抗逆转录病毒药物的设计周期。该计划由五个部分组成 集成部分：1.活性中心配基对接的计算方法 (缓蚀剂)，以及缓蚀剂铅的精细化设计 化合物；2.逆转录病毒蛋白水解酶的设计和化学合成 使用新的化学方法的缓蚀剂；3.X射线结晶学研究 猫免疫缺陷病毒(FIV PR)及其抑制物复合体的研究； 利用全化学合成法对FIV PR进行蛋白质化学研究； FIV系统的分子生物学/病毒学。的基础研究。 猫逆转录病毒蛋白水解酶的结构生物学 免疫缺陷病毒将在开发的背景下进行 用于靶向药物设计的新工具，最终目标是 增加我们对这一重要类别的缓蚀剂设计的理解 逆转录病毒的酶。人类免疫缺陷病毒-1(HIV-1)PR是 对病毒的复制是必不可少的，因此是目标 世界各地的主要药物设计项目。基于我们过去的工作和 其他人的工作已经有迹象表明，独特的结构和 HIV-1 PR与细胞编码天冬氨酸的机制比较 蛋白水解酶可以作为设计一类 逆转录病毒选择性抑制剂，作为艾滋病治疗的候选药物。这个 本计划的目的是将这些研究扩展到更直接的 可测试的模型系统，FIV PR，并确认了真实性和通用性 这些功能中。从这些研究中获得的基本知识 FIV PR对临床相关疾病的认识具有重要意义 相关酶，如艾滋病毒-1和其他逆转录病毒蛋白酶，以及 细胞编码的天冬氨酸蛋白酶，如肾素。

The goal of this Program is to develop mature tools to aid in the drug design cycle for anti-retroviral agents. The program consists of five integrated parts: 1. Computational methods for docking active-site ligands (inhibitors), and for elaboration and refined design of inhibitor lead compounds; 2. design and chemical synthesis of retroviral protease inhibitors using new chemical approaches; 3. Xray crystallographic studies of the feline immunodeficiency virus (FIV PR) and inhibitor complexes; 4. Protein chemical studies of the FIV PR using total chemical synthesis; 5. Molecular biology/virology of the FIV system. Fundamental studies of the structural biology of the retroviral protease of the feline immunodeficiency virus will be undertaken in the context of developing novel tools for targeted drug design and with the ultimate goal of increasing our understanding of inhibitor design for this important class of retroviral enzyme. The human immunodeficiency virus-1 (HIV-1) PR is essential to the replication of the virus, and consequently is the target of major drug design programs worldwide. Based on our own past work and the work of others there are already indications of unique structural and mechanistic features of HIV-1 PR compared with cell-encoded aspartyl proteinases that could serve as a basis for the design of a class of retroviral-selective inhibitors, as candidate AIDS therapeutics. The purpose of this Program is to extend these studies to a more directly testable model system, the FIV PR, and confirm the reality and generality of these features. the fundamental knowledge resulting from these studies of FIV PR will be important for the understanding of related clinically- relevant enzymes, such as the HIV-1 and other retroviral proteases, and cell-encoded aspartyl proteinases such as renin.