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Relationship between 3'-azido-3'-deoxythymidine resistance and primer unblocking activity in foscarnet-resistant mutants of human immunodeficiency virus type 1 reverse transcriptase 下载免费PDF全文
Meyer PR Matsuura SE Zonarich D Chopra RR Pendarvis E Bazmi HZ Mellors JW Scott WA 《Journal of virology》2003,77(11):6127-6137
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Deval J Alvarez K Selmi B Bermond M Boretto J Guerreiro C Mulard L Canard B 《The Journal of biological chemistry》2005,280(5):3838-3846
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Kim J Wang L Li Y Becnel KD Frey KM Garforth SJ Prasad VR Schinazi RF Liotta DC Anderson KS 《Bioorganic & medicinal chemistry letters》2012,22(12):4064-4067
Pre-steady state kinetic analysis was utilized for biochemical evaluation of a series of cyclobutyl adenosine nucleotide analogs with HIV-1 RT(WT). The phosphonyl-diphosphate form of the cyclobutyl nucleotide, 5, was the most efficiently incorporated of the series. Nucleotide 5 was fourfold more efficiently incorporated than the FDA approved TFV-DP by RT(WT). The kinetics of incorporation for 5 using the drug resistant mutant enzyme K65R was also determined. Compound 5 was threefold more efficiently incorporated compared to TFV-DP with RT(K65R). These results demonstrate cyclobutyl adenosine analogs can act as substrates for incorporation by HIV-1 RT and be a potential scaffold for HIV inhibitors. 相似文献
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Operario DJ Balakrishnan M Bambara RA Kim B 《The Journal of biological chemistry》2006,281(43):32113-32121
We have recently demonstrated that HIV-1 RT mutants characterized by low dNTP binding affinity display significantly reduced dNTP incorporation kinetics in comparison to wild-type RT. This defect is particularly emphasized at low dNTP concentrations where WT RT remains capable of efficient synthesis. Kinetic interference in DNA synthesis can induce RT pausing and slow down the synthesis rate. RT stalling and slow synthesis rate can enhance RNA template cleavage by RT-RNase H, facilitating transfer of the primer to a homologous template. We therefore hypothesized that reduced dNTP binding RT mutants can promote template switching during minus strand synthesis more efficiently than WT HIV-1 RT at low dNTP concentrations. To test this hypothesis, we employed two dNTP binding HIV-1 RT mutants, Q151N and V148I. Indeed, as the dNTP concentration was decreased, the template switching frequency progressively increased for both WT and mutant RTs. However, as predicted, the RT mutants promoted more transfers compared with WT RT. The WT and mutant RTs were similar in their intrinsic RNase H activity, supporting that the elevated template switching efficiency of the mutants was not the result of the mutations enhancing RNase H activity. Rather, kinetic interference leading to stalled DNA synthesis likely enhanced transfers. These results suggest that the RT-dNTP substrate interaction mechanistically influences strand transfer and recombination of HIV-1 RT. 相似文献
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Deval J Navarro JM Selmi B Courcambeck J Boretto J Halfon P Garrido-Urbani S Sire J Canard B 《The Journal of biological chemistry》2004,279(24):25489-25496
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Selection of mutations in the connection and RNase H domains of human immunodeficiency virus type 1 reverse transcriptase that increase resistance to 3'-azido-3'-dideoxythymidine 总被引:1,自引:0,他引:1 下载免费PDF全文
Brehm JH Koontz D Meteer JD Pathak V Sluis-Cremer N Mellors JW 《Journal of virology》2007,81(15):7852-7859