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.
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