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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM066524-09
Application #
8144310
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
9
Fiscal Year
2010
Total Cost
$356,415
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Zhou, Hao; Li, Shangyang; Badger, John et al. (2015) Modulation of HIV protease flexibility by the T80N mutation. Proteins 83:1929-39
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
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
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
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
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
Mittal, Seema; Cai, Yufeng; Nalam, Madhavi N L et al. (2012) Hydrophobic core flexibility modulates enzyme activity in HIV-1 protease. J Am Chem Soc 134:4163-8
Ozen, Ay?egül; Halilo?lu, Türkan; Schiffer, Celia A (2012) HIV-1 Protease and Substrate Coevolution Validates the Substrate Envelope As the Substrate Recognition Pattern. J Chem Theory Comput 8:

Showing the most recent 10 out of 73 publications