Inhibitors of HIV Protease (PIs) have proven to be powerful additionsto the armamentariurn for treating HIV infection,but their efficacy has been limited by the emergence of mutantforms of the protease that resist inhibitionby current HPIs. The overall goal of this project is to developand apply new strategies and structure-based computational methods for discovering PIs that will resist existingand, potentially,future mutations. A central element of our approach will be to design compounds based notupon a single protease structure but upon multiple structures. In order to increase the chances of success, combinatorial libraries, rather than singlecompounds, willbe designed and tested. The methodsto be developed will be applicable to other therapeutic targets as well.
The specificaims are as follows: 1. Develop one or more scoringfunctionstuned for HIV protease. 2. Use structuralinformationto design combinatoriallibraries of compounds designed to bind and inhibit HIV-1 protease and to evade key current,and potentiallyfuture, resistancemutations. 3. Use detailed, interactivecomputationalmethods to optimizecompounds identified by initialscreening.

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
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
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
Cai, Yufeng; Schiffer, Celia (2012) Decomposing the energetic impact of drug-resistant mutations: the example of HIV-1 protease-DRV binding. Methods Mol Biol 819:551-60

Showing the most recent 10 out of 73 publications