DESIGN, SYNTHESIS AND CHARACTERIZATION OF FLUORINATED HIV PROTEASE INHIBITOR

HIV蛋白酶是治疗艾滋病的重要化疗靶点；迄今为止，最成功的治疗方法是将蛋白酶抑制剂与抑制逆转录酶的核苷类似物联合使用。然而，该病毒的高突变率使得对迄今为止开发的大多数蛋白酶抑制剂进行选择成为可能。这个项目最近的工作包括几个目标：1。开发具有更大稳定性的HIV蛋白酶突变体，特别是允许对未络合酶进行核磁共振研究；2. 基于多种结合模式抑制剂的新抑制策略评估3. 一种新的核磁共振抑制剂设计方法的发展。后一种方法被称为配体间Overhauser效应，它允许研究弱结合配体之间的结构关系，以便它们可以结合起来产生单一的、更有效的抑制剂。- HIV蛋白酶；脯氨酸;核磁共振;核大修效应；抑制剂绑定

HIV protease is an important chemotherapeutic target for the treatment of AIDS; the most successful treatments developed to date involve combinations of protease inhibitors with nucleoside analogs which inhibit the reverse transcriptase. However, the high mutation rate of the virus makes it possible to select against most of the protease inhibitors which thus far have been developed. Recent work on this project has included several goals: 1. Development of HIV protease mutants with greater stability, particularly to allow NMR studies of the uncomplexed enzyme; 2. Evaluation of a new inhibition strategy based on the use of inhibitors with multiple binding modes; 3. Development of a new NMR approach for inhibitor design. The latter method, called the inter-ligand Overhauser effect, allows the investigation of structural relationships between weakly bound ligands so that they can be combined to yield a single, more potent inhibitor. - HIV protease; proline; NMR; nuclear Overhauser effect; inhibitor binding