Design, Synthesis and Biological Evaluation of HIV-1 Protease Inhibitor Libraries

HIV-1蛋白酶是艾滋病患者抗病毒治疗的一个有前途的治疗靶点，因为它在艾滋病的治疗中起着关键的作用。 通过将病毒Gag和Gag-Pol多聚蛋白加工成结构和功能蛋白， 病毒成熟所必需的蛋白质。基于蛋白酶和逆转录酶联合的化疗 转录酶抑制剂在降低艾滋病患者的死亡率方面取得了显着成功。 然而，在药物治疗的选择性压力下，出现了许多可行的多药耐药 (MDR)蛋白酶变体对目前可用的蛋白酶抑制剂的功效提出了巨大的挑战。 PPG团队一直在追求基于结构和信息的战略，以设计和评估新的 靶向HIV-1蛋白酶系的蛋白酶抑制剂文库。麻省理工学院的计算小组（Tidor 实验室）和CARB（Gilson实验室）已经使用市售的 这些库分别被称为MIT和CARB库。核心小组在 UMASS（Rana实验室）已经进行了设计的抑制剂文库的化学合成，并测试了它们的活性。 对野生型和三种MDR蛋白酶变体的活性。此外，拉纳实验室还设计了， 合成并评价了2个新的蛋白酶抑制剂系列，它们对野生型具有高效活性 和MDR变体。作为PPG的核心组成部分，Rana实验室已经合成了数百种新的 抑制剂，并评估其对野生型和三种MDR蛋白酶变体的活性。当前PPG 小组，包括艾滋病毒耐药性分析和数据库组（谢弗实验室），分子病毒学 一组（Swanstrom实验室），一个结构生物学组（Schiffer实验室），一个计算组（Tidor实验室），和一个 化学合成和筛选组（核心A，拉纳实验室），正在继续追求的总体目标， 设计、合成和评估靶向MDR集合的新蛋白酶抑制剂文库 蛋白酶这些设计的抑制剂将可能对耐药性不太敏感，从而改善药物的耐药性。 HIV-1蛋白酶抑制剂预防HIV-1感染进展的长期疗效。主要 核心设施的目标是合成和筛选针对野生型的计算机设计的抑制剂文库 和选择的蛋白酶MDR变体。核心设施由三名科学家组成， 负责合成、筛选和维护仪器。

HIV-1 protease is a promising therapeutic target for antiviral therapy in AIDS patients since it plays a critical role in the virus life cycle by processing the viral Gag and Gag-Pol polyproteins into structural and functional proteins essential for viral maturation. Chemotherapy based on the combination of protease and reverse transcriptase inhibitors has been remarkably successful in reducing the mortality rates in AIDS patients. However, under the selective pressure of drug therapy, the emergence of many viable multidrug-resistant (MDR) protease variants is posing a great challenge to the efficacy of currently available protease inhibitors. The PPG team has been pursuing a structure- and informatics-based strategy to design and evaluate new protease inhibitor libraries targeting ensembles of HIV-1 proteases. The computational groups at MIT (Tidor lab) and CARB (Gilson lab) have designed inhibitor libraries using databases of commercially available compounds; these libraries are referred to as the MIT and CARB libraries, respectively. The core group at UMASS (Rana lab) has carried out the chemical synthesis of designed inhibitor libraries and tested their activities against wild-type and three MDR protease variants. In addition, the Rana lab has designed, synthesized and evaluated 2 novel series of protease inhibitors with highly potent activities against wild-type and MDR variants. As a core component of the PPG, the Rana lab has synthesized hundreds of new inhibitors and evaluated their activities against wild-type and three MDR protease variants. The current PPG team, comprising a HIV drug-resistance analysis and database group (Shafer lab), a molecular virology group (Swanstrom lab), a structural biology group (Schiffer lab), a computational group (Tidor lab), and a chemical synthesis and screening group (Core A, Rana lab), is continuing to pursue the overall goals of designing, synthesizing and evaluating new protease inhibitor libraries targeting ensembles of MDR proteases. These designed inhibitors will likely be less susceptible to drug resistance, thus improving the long-term efficacy of HIV-1 protease inhibitors in preventing the progression of HIV-1 infections. The major goal of the core facility is to synthesize and screen computationally designed inhibitor libraries against wildtype and selected MDR variants of protease. The core facility consists of three scientists who are responsible for synthesizing, screening and maintaining instruments.