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 #
5R37AI027690-24
Application #
8213421
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Bridges, Sandra H
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
24
Fiscal Year
2012
Total Cost
$724,064
Indirect Cost
$255,414
Name
Rutgers University
Department
None
Type
Schools of Medicine
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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Sagong, Hye Yeon; Bauman, Joseph D; Patel, Disha et al. (2014) Phenyl substituted 4-hydroxypyridazin-3(2H)-ones and 5-hydroxypyrimidin-4(3H)-ones: inhibitors of influenza A endonuclease. J Med Chem 57:8086-98
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Das, Kalyan; Martinez, Sergio E; Bandwar, Rajiv P et al. (2014) Structures of HIV-1 RT-RNA/DNA ternary complexes with dATP and nevirapine reveal conformational flexibility of RNA/DNA: insights into requirements for RNase H cleavage. Nucleic Acids Res 42:8125-37
Vijayan, R S K; Arnold, Eddy; Das, Kalyan (2014) Molecular dynamics study of HIV-1 RT-DNA-nevirapine complexes explains NNRTI inhibition and resistance by connection mutations. Proteins 82:815-29
Bauman, Joseph D; Patel, Disha; Dharia, Chhaya et al. (2013) Detecting allosteric sites of HIV-1 reverse transcriptase by X-ray crystallographic fragment screening. J Med Chem 56:2738-46
Bollini, Mariela; Frey, Kathleen M; Cisneros, Jose A et al. (2013) Extension into the entrance channel of HIV-1 reverse transcriptase--crystallography and enhanced solubility. Bioorg Med Chem Lett 23:5209-12
Das, Kalyan; Arnold, Eddy (2013) HIV-1 reverse transcriptase and antiviral drug resistance. Part 1. Curr Opin Virol 3:111-8
Das, Kalyan; Arnold, Eddy (2013) HIV-1 reverse transcriptase and antiviral drug resistance. Part 2. Curr Opin Virol 3:119-28

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