DRUG DESIGN CYCLE TARGETED TO RETROVIRAL PROTEASE

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。 该计划包括五个 集成部件：1.对接活性位点配体的计算方法 （抑制剂），以及抑制剂铅的详细说明和精细设计 化合物; 2.逆转录病毒蛋白酶的设计和化学合成 使用新的化学方法的抑制剂; 3. X射线晶体学研究 猫免疫缺陷病毒（FIV PR）和抑制剂复合物; 4. 使用全化学合成对FIV PR进行蛋白质化学研究; 5. FIV系统的分子生物学/病毒学。 基础研究 猫科动物逆转录病毒蛋白酶的结构生物学 免疫缺陷病毒将在发展的背景下进行， 用于靶向药物设计的新工具， 增加我们对这一重要类别的抑制剂设计的理解 逆转录病毒酶。 人类免疫缺陷病毒-1（HIV-1）PR是 对病毒的复制至关重要，因此是目标 主要药物设计项目。 基于我们过去的工作， 其他人的工作已经有迹象表明，独特的结构和 HIV-1 PR的机制特征与细胞编码的乙酰基相比 蛋白酶，可以作为一类设计的基础， 逆转录病毒选择性抑制剂，作为候选的艾滋病治疗剂。 的 该计划的目的是将这些研究扩展到更直接的领域 可测试模型系统FIV PR，并验证其真实性和通用性 这些特征。 从这些研究中获得的基础知识 FIV PR对于了解相关临床- 相关酶，如HIV-1和其他逆转录病毒蛋白酶，和 细胞编码的胰蛋白酶，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.