Many of the most deadly diseases that plague our society evolve quickly, challenging most of our therapeutic strategies. The pressures of evolution will likely result in a variety of pathways for resistance to evolve. Drug resistance can be caused by a change in the balance of molecular recognition events that selectively weakens inhibitor binding but maintains the biological function of the therapeutic target. To reduce the likelihood of drug resistance, the interdependency of the target's function within the context of the biological system in which it exists must be elucidated. Disrupting the therapeutic target's activity is necessary but not sufficient for avoiding resistance. In this collaborative proposal we hypothesize that key pathways and coupled mechanisms confer drug resistance to therapeutic targets. We seek to define the sequence, structural and dynamic, and temporal evolutionary constraints of the interdependency of drug resistance: 1) to recognize the pathways by which resistance occurs and 2) to devise drug design strategies for developing a drug that is robust against resistance. HIV-1 Protease is the perfect case study! HIV evolves very quickly with on average a point mutation introduced in every third genome replicated. HIV protease inhibitors have the potential of being both very potent and robust to resistance. Protease inhibitors are the only HIV inhibitor class that are transition state analogs and can be evolutionarily constrained within the substrate envelope. Inhibitors that leverage both of these characteristics, such as Darunavir (DRV) and similar analogs, have the potential of being robust, nearly resistance proof inhibitors, to drug- na?ve HIV infected patients. If HIV achieves resistance to these inhibitors it is only through complex pathways and combinations of mutations. Further elucidating these complex pathways will bring us closer to resistance-proof inhibitors. In this project our team will use and develop cutting-edge technology to follow the pathways of drug resistance selection, to elucidate the molecular basis for their interdependent patterns and incorporate these mechanisms into drug design strategies. Together we will make inroads into tackling drug resistance that would be impossible for any of us to individually achieve

Public Health Relevance

Many of the most deadly diseases that plague our society evolve quickly, challenging most of our therapeutic strategies. The pressures of evolution will likely result in a variety of pathways for resistance to evolve. HIV evolves very quickly with on average a point mutation introduced in every third genome replicated. HIV protease inhibitors have the potential of being both very potent and robust to resistance. If HIV achieves resistance to these potent drugs it is only through complex pathways and combinations of mutations. In this project our team will use and develop cutting-edge technology to follow the pathways of drug resistance selection, to elucidate the molecular basis for their interdependent patterns and incorporate these mechanisms into drug design strategies

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
1P01GM109767-01A1
Application #
8789525
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sakalian, Michael
Project Start
2014-09-01
Project End
2019-07-31
Budget Start
2014-09-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Worcester
State
MA
Country
United States
Zip Code
01655
Kurt Yilmaz, Nese; Swanstrom, Ronald; Schiffer, Celia A (2016) Improving Viral Protease Inhibitors to Counter Drug Resistance. Trends Microbiol 24:547-57
Özer, Nevra; Özen, Ayşegül; Schiffer, Celia A et al. (2015) Drug-resistant HIV-1 protease regains functional dynamics through cleavage site coevolution. Evol Appl 8:185-98
Potempa, Marc; Nalivaika, Ellen; Ragland, Debra et al. (2015) A Direct Interaction with RNA Dramatically Enhances the Catalytic Activity of the HIV-1 Protease In Vitro. J Mol Biol 427:2360-78
Zhou, Hao; Li, Shangyang; Badger, John et al. (2015) Modulation of HIV protease flexibility by the T80N mutation. Proteins 83:1929-39
Ishima, Rieko (2015) Effects of radiation damping for biomolecular NMR experiments in solution: a hemisphere concept for water suppression. Concepts Magn Reson Part A Bridg Educ Res 44A:252-262
Cai, Yufeng; Myint, Wazo; Paulsen, Janet L et al. (2014) Drug Resistance Mutations Alter Dynamics of Inhibitor-Bound HIV-1 Protease. J Chem Theory Comput 10:3438-3448
Ragland, Debra A; Nalivaika, Ellen A; Nalam, Madhavi N L et al. (2014) Drug resistance conferred by mutations outside the active site through alterations in the dynamic and structural ensemble of HIV-1 protease. J Am Chem Soc 136:11956-63
Kolli, Madhavi; Ozen, Ayşegül; Kurt-Yilmaz, Nese et al. (2014) HIV-1 protease-substrate coevolution in nelfinavir resistance. J Virol 88:7145-54
Özen, Ayşegül; Lin, Kuan-Hung; Kurt Yilmaz, Nese et al. (2014) Structural basis and distal effects of Gag substrate coevolution in drug resistance to HIV-1 protease. Proc Natl Acad Sci U S A 111:15993-8