The structural &dynamic basis for the interdependence of drug resistance Project 1 - Schiffer, UMASS Medical School In many drug resistance variants variants, multiple site mutations co-evolve to both decrease the affinity of a particular inhibitor and increase the viability and fitness of the enzyme. We hypothesize that the impact of particular mutations on conferring drug resistance is not simply additive, but that these mutations have a complex interdependent effect leading to viable variants that are highly resistant to existing drugs. As a project team we will test this hypothesis through a systematic and quantitative evaluation of the interdependency in drug resistance at the molecular level in HIV protease, through changes in the protease structure, thermodynamics, enzyme kinetics and dynamics by state-of-the-art experimental and computational techniques and apply this knowledge to develop inhibitors with high barrier to resistance. This data will identify residues and combinations of mutations that are pivotal signature sites in conferring drug resistance. Such a strategy is critical to revealing the complex molecular mechanisms of drug resistance, and both avoid resistance from the start and target highly resistant variants seen in clinic. This strategy will be directly applicable to other quickly evolving diseases where drug resistance thwarts effective therapy.

Public Health Relevance

The structural &dynamic basis for the interdependence of drug resistance Project 1 - Schiffer, UMASS Medical School Drug resistance involves complex changes in the structure and dynamics of the therapeutic target. Studying HIV protease and using biophysical and structural biology techniques we are elucidating the molecular mechanisms of drug resistance should lead to strategies of avoiding drug resistance.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
1P01GM109767-01A1
Application #
8789530
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
City
Worcester
State
MA
Country
United States
Zip Code
01655
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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