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Comparative Study | Journal Article | Research Support, U.S. Gov't, Non-P.H.S. | Research Support, U.S. Gov't, P.H.S.

Comparative kinetic analyses of interaction of inhibitors with Rauscher murine leukemia virus and human immunodeficiency virus reverse transcriptases.

J M Cherrington, M D Fuller, A S Mulato, S J Allen, S C Kunder, M A Ussery, Z Lesnikowski, R F Schinazi, J P Sommadossi, M S Chen
J M Cherrington
Gilead Sciences, Foster City, California 94404, USA.
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M D Fuller
Gilead Sciences, Foster City, California 94404, USA.
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A S Mulato
Gilead Sciences, Foster City, California 94404, USA.
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S J Allen
Gilead Sciences, Foster City, California 94404, USA.
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S C Kunder
Gilead Sciences, Foster City, California 94404, USA.
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M A Ussery
Gilead Sciences, Foster City, California 94404, USA.
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Z Lesnikowski
Gilead Sciences, Foster City, California 94404, USA.
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R F Schinazi
Gilead Sciences, Foster City, California 94404, USA.
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J P Sommadossi
Gilead Sciences, Foster City, California 94404, USA.
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M S Chen
Gilead Sciences, Foster City, California 94404, USA.
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DOI: 10.1128/AAC.40.5.1270
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ABSTRACT

The inhibitory effects of several nucleoside triphosphate analogs on Rauscher murine leukemia virus (RMuLV) and human immunodeficiency virus (HIV) type 1 reverse transcriptases (RTs) were studied. With RNA as the template, the apparent K(m) and apparent K(i) values of HIV RT toward its substrates and inhibitors are 12 to 500 times lower than the corresponding values for RMuLV RT. However, the k(i)/k(m) ratios (inhibition efficiencies) for HIV and RMuLV RTs'are similar for AZTTP (zidovudine triphosphate), d4TTP [3'-deoxythymidine-2'-ene-(3'-deoxy-2',3'-didehydrothymidine) triphosphate], PMEADP [9-(2-phosphonylmethoxyethyl)adenine diphosphate], FIAUTP [1-(2-fluoro-2-deoxy-beta-D-arabinofuranosyl)-5-iodouracil triphosphate], and HPMPCDP [(S)-1-(3-hydroxy-2-phosphylmethoxypropyl) cytosine diphosphate]. With DNA as the template, the K(m) values are similar for HIV and RMuLV RTs. However, the K(i)/K(m) values of HIV and RMuLV RTs are significantly different for ddCTP, ddATP, and 3TCTP (2',3'-dideoxy-3'-thiacytidine). The RTs of RMuLV and HIV are sufficiently different from one another that the kinetic inhibition constants for a particular antiviral compounds should be determined to indicate whether anti-RMuLV activity is likely to be predictive for the anti-HIV activity of the compound. This information, in conjunction with species-specific drug metabolism differences and tissue culture antiviral activity, is important in determining the suitability of a particular animal model.

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Comparative kinetic analyses of interaction of inhibitors with Rauscher murine leukemia virus and human immunodeficiency virus reverse transcriptases.
J M Cherrington, M D Fuller, A S Mulato, S J Allen, S C Kunder, M A Ussery, Z Lesnikowski, R F Schinazi, J P Sommadossi, M S Chen
Antimicrobial Agents and Chemotherapy May 1996, 40 (5) 1270-1273; DOI: 10.1128/AAC.40.5.1270

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Comparative kinetic analyses of interaction of inhibitors with Rauscher murine leukemia virus and human immunodeficiency virus reverse transcriptases.
J M Cherrington, M D Fuller, A S Mulato, S J Allen, S C Kunder, M A Ussery, Z Lesnikowski, R F Schinazi, J P Sommadossi, M S Chen
Antimicrobial Agents and Chemotherapy May 1996, 40 (5) 1270-1273; DOI: 10.1128/AAC.40.5.1270
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