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

HIV-1蛋白因其在抗病毒治疗中的重要作用而成为抗病毒治疗的新靶点。 通过将病毒Gag和Gag-Pol多蛋白处理成结构和功能，在病毒生命周期中发挥作用 病毒成熟所必需的蛋白质。基于蛋白水解酶和逆转酶结合的化疗 转录酶抑制剂在降低艾滋病患者死亡率方面取得了显著的成功。 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 多药耐药(MDR)蛋白水解酶的变异对现有的蛋白水解酶抑制剂的疗效提出了巨大的挑战。 PPG团队一直在追求一种基于结构和信息学的战略来设计和评估新的 以HIV-1蛋白酶为靶标的蛋白酶抑制物库。麻省理工学院的计算小组(Tidor Lab)和CARB(Gilson Lab)使用市场上可获得的数据库设计了缓蚀剂库 化合物；这些文库分别被称为MIT和CARB文库。核心小组位于 UMASS(拉纳实验室)已经进行了设计的缓蚀剂库的化学合成，并测试了它们的 对野生型和三种多药耐药酶变异体的活性。此外，拉纳实验室还设计了， 抗野生型高效蛋白水解酶抑制剂的合成及活性评价 和多药耐药变种。作为PPG的核心组件，Rana实验室已经合成了数百种新的 并评估了它们对野生型和三种多药耐药蛋白酶变异体的活性。目前的PPG 小组，由艾滋病毒耐药性分析和数据库小组(Shafer Lab)、分子病毒学 小组(Swanstrom实验室)、结构生物学小组(Schiffer实验室)、计算小组(Tidor实验室)和 化学合成和筛选小组(核心A，拉纳实验室)，正在继续追求以下总体目标 靶向MDR全套的新型蛋白水解酶抑制物库的设计、合成和评价 蛋白酶。这些设计的抑制剂可能不太容易产生抗药性，从而改善 HIV-1蛋白酶抑制剂预防HIV-1感染进展的长期疗效。少校 核心设备的目标是合成和筛选通过计算设计的针对野生型的抑制物库 和精选的蛋白酶多药耐药变异体。核心设施由三名科学家组成，他们是 负责仪器的合成、筛选和维护。

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.