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.
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.
|Boyer, Paul L; Smith, Steven J; Zhao, Xue Zhi et al. (2018) Developing and Evaluating Inhibitors against the RNase H Active Site of HIV-1 Reverse Transcriptase. J Virol 92:|
|Das, Kalyan; Martinez, Sergio E; Arnold, Eddy (2017) Structural Insights into HIV Reverse Transcriptase Mutations Q151M and Q151M Complex That Confer Multinucleoside Drug Resistance. Antimicrob Agents Chemother 61:|
|Balzarini, Jan; Menni, Michael; Das, Kalyan et al. (2017) Guanine ?-carboxy nucleoside phosphonate (G-?-CNP) shows a different inhibitory kinetic profile against the DNA polymerases of human immunodeficiency virus (HIV) and herpes viruses. Biochem Pharmacol 136:51-61|
|Neogi, Ujjwal; Häggblom, Amanda; Singh, Kamalendra et al. (2016) Factors influencing the efficacy of rilpivirine in HIV-1 subtype C in low- and middle-income countries. J Antimicrob Chemother 71:367-71|
|Bauman, Joseph D; Harrison, Jerry Joe E K; Arnold, Eddy (2016) Rapid experimental SAD phasing and hot-spot identification with halogenated fragments. IUCrJ 3:51-60|
|Miller, Matthew T; Tuske, Steve; Das, Kalyan et al. (2016) Structure of HIV-1 reverse transcriptase bound to a novel 38-mer hairpin template-primer DNA aptamer. Protein Sci 25:46-55|
|Mullins, Nicholas D; Maguire, Nuala M; Ford, Alan et al. (2016) Exploring the role of the ?-carboxyphosphonate moiety in the HIV-RT activity of ?-carboxy nucleoside phosphonates. Org Biomol Chem 14:2454-65|
|Das, Kalyan; Balzarini, Jan; Miller, Matthew T et al. (2016) Conformational States of HIV-1 Reverse Transcriptase for Nucleotide Incorporation vs Pyrophosphorolysis-Binding of Foscarnet. ACS Chem Biol 11:2158-64|
|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|
|Boyer, Paul L; Das, Kalyan; Arnold, Eddy et al. (2015) Analysis of the Zidovudine Resistance Mutations T215Y, M41L, and L210W in HIV-1 Reverse Transcriptase. Antimicrob Agents Chemother 59:7184-96|
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