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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
United States
Zip Code
Zhou, Hao; Li, Shangyang; Badger, John et al. (2015) Modulation of HIV protease flexibility by the T80N mutation. Proteins 83:1929-39
Mittal, Seema; Bandaranayake, Rajinthna M; King, Nancy M et al. (2013) Structural and thermodynamic basis of amprenavir/darunavir and atazanavir resistance in HIV-1 protease with mutations at residue 50. J Virol 87:4176-84
Lee, Sook-Kyung; Cheng, Nancy; Hull-Ryde, Emily et al. (2013) A sensitive assay using a native protein substrate for screening HIV-1 maturation inhibitors targeting the protease cleavage site between the matrix and capsid. Biochemistry 52:4929-40
Foulkes-Murzycki, Jennifer E; Rosi, Christina; Kurt Yilmaz, Nese et al. (2013) Cooperative effects of drug-resistance mutations in the flap region of HIV-1 protease. ACS Chem Biol 8:513-8
Shen, Yang; Altman, Michael D; Ali, Akbar et al. (2013) Testing the substrate-envelope hypothesis with designed pairs of compounds. ACS Chem Biol 8:2433-41
Silver, Nathaniel W; King, Bracken M; Nalam, Madhavi N L et al. (2013) Efficient Computation of Small-Molecule Configurational Binding Entropy and Free Energy Changes by Ensemble Enumeration. J Chem Theory Comput 9:5098-5115
Schiffer, Celia (2013) Interview with Celia Schiffer. Future Med Chem 5:1193-7
Nalam, Madhavi N L; Ali, Akbar; Reddy, G S Kiran Kumar et al. (2013) Substrate envelope-designed potent HIV-1 protease inhibitors to avoid drug resistance. Chem Biol 20:1116-24
Alvizo, Oscar; Mittal, Seema; Mayo, Stephen L et al. (2012) Structural, kinetic, and thermodynamic studies of specificity designed HIV-1 protease. Protein Sci 21:1029-41
Lee, Sook-Kyung; Potempa, Marc; Kolli, Madhavi et al. (2012) Context surrounding processing sites is crucial in determining cleavage rate of a subset of processing sites in HIV-1 Gag and Gag-Pro-Pol polyprotein precursors by viral protease. J Biol Chem 287:13279-90

Showing the most recent 10 out of 73 publications