As the AIDS pandemic continues, the emergence of HIV variants that are drug resistant is a therapeutic challenge. The nine FDA-approved HIV-1 protease inhibitors are currently the most potent of the anti-viral drugs in the treatment of HIV infected patients. All of these inhibitors were the results of structure based drug design. Yet variants of HIV protease have evolved which are resistant to one or more of these drugs. Even within a single patient an ensemble of different viruses and therefore proteases exist. The challenge for the community is to develop HIV-1 protease inhibitors that are robust and therefore less vulnerable to drug resistance. This is a multi-disciplinary challenge, as two key thrusts must be addressed - both the underlying mechanisms of resistance must be elucidated and new strategies for identifying robust inhibitors against resistance must be developed. This project aims to address this challenge by a comprehensive approach that integrates clinical data, structural biology and biophysical chemistry, medical informatics and biostatistics, biochemistry and molecular virology, computational chemistry and computer-aided design, and synthetic and medicinal chemistry. With this integrated program we plan to address two global research objectives: 1. Elucidate the role of compensatory mutations in HIV-1 protease in conferring drug resistance 2. Develop new HIV-1 protease inhibitors that are more robust against drug resistance. Through this integrated approach our goal is to attain a better understanding of inhibitor recognition and to develop new methodologies for designing inhibitors against quickly evolving targets that have a propensity for acquiring drug resistance.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZRG1-AARR-A (40))
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Sakalian, Michael
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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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

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