HIV-1 reverse transcriptase (RT) is a central target for antiviral treatment of AIDS and detailed knowledge of its structure and function has important clinical and biological consequences. Both nucleoside and non-nucleoside RT inhibitors are used as effective drugs for treating AIDS, but success can be limited by the emergence of drug-resistant viral variants. Novel non-nucleoside RT inhibitors have been developed through structure-based methods, including the recently approved drug etravirine/TMC125/Intelence, and we propose to carry out crystallographic studies that could enable structure-guided improvement of additional classes of RT inhibitors. The proposed work will involve structure determination of wild-type and drug-resistant HIV-1 RT in the presence and absence of nucleic acid substrates and inhibitors. Structural studies of inhibitor will explore binding sites for known drugs (NRTIs and NNRTIs) as well as other potential drug targeting sites including the RNase H active site. Use of strategically modified protein and nucleic acids will enhance the efficiency and quality of the structural studies. The structures determined will enhance our understanding of mechanisms of polymerase and RNase H catalysis, inhibition, and of drug resistance.

Public Health Relevance

HIV-1 reverse transcriptase (RT) is a central target for antiviral treatment of AIDS and detailed knowledge of its structure and function has important clinical and biological consequences. Both nucleoside and non-nucleoside RT inhibitors are used as effective drugs for treating AIDS, but success can be limited by the emergence of drug-resistant viral variants. The proposed studies will enhance opportunities for targeting known and new sites on RT including RNase H, the only HIV enzyme not yet blocked by anti-AIDS drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI027690-25
Application #
8416384
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Gupta, Kailash C
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
25
Fiscal Year
2013
Total Cost
$676,603
Indirect Cost
$238,672
Name
Rutgers University
Department
Type
Schools of Medicine
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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Lee, Won-Gil; Frey, Kathleen M; Gallardo-Macias, Ricardo et al. (2015) Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase. Bioorg Med Chem Lett 25:4824-7
Goswami, Devrishi; Tuske, Steve; Pascal, Bruce D et al. (2015) Differential isotopic enrichment to facilitate characterization of asymmetric multimeric proteins using hydrogen/deuterium exchange mass spectrometry. Anal Chem 87:4015-22

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