Structural Determinants of HIV-1 Reverse Transcriptase Stereoselectivity Towards (β)-L-Deoxy- and Dideoxy-Pyrimidine Nucleoside Triphosphates: Molecular Basis for the Combination of L-Dideoxynucleoside Analogs with Non-nucleoside Inhibitors in Anti HIV Chemotherapy
- 1 April 1999
- journal article
- research article
- Published by Taylor & Francis in Nucleosides and Nucleotides
- Vol. 18 (4) , 795-805
- https://doi.org/10.1080/15257779908041566
Abstract
We have compared the HIV-11 RT mutants containing the single substitutions L100I, K103N, V106A, V179D, Y181I and Y188L, known to confere NNI-resistance in treated patients, to HIV-1 RT wt for their sensitivity towards inhibition by D- and L-deoxy- and dideoxy-nucleoside tiphosphates. The results showed a differential effect of the substitutions on the affinity for both D- and L-enantiomers of deoxy- and dideoxy-nucleoside triphosphates and provide a rationale for the utilization of L-dideoxynucleoside analogs with NNI in combination chemotherapy.Keywords
This publication has 12 references indexed in Scilit:
- Resistance to nevirapine of HIV-1 reverse transcriptase mutants: loss of stabilizing interactions and thermodynamic or steric barriers are induced by different single amino acid substitutionsJournal of Molecular Biology, 1997
- Stereoisomers of Deoxynucleoside 5′-Triphosphates as Substrates for Template-dependent and -independent DNA PolymerasesJournal of Biological Chemistry, 1997
- [25] Analysis of inhibition of retroviral reverse transcriptasePublished by Elsevier ,1996
- Potential Mechanism for Sustained Antiretroviral Efficacy of AZT-3TC Combination TherapyScience, 1995
- HIV Population Dynamics in Vivo: Implications for Genetic Variation, Pathogenesis, and TherapyScience, 1995
- Stereospecificity of human DNA polymerases α,β,γ,§ and ɛ, HIV-reverse transcriptase, HSV- DNA polymerase, calf thymus terminal transferase andEscherichia coliDNA polymerase I in recognizing D- and L-thymidine 5′-triphosphate as substrateNucleic Acids Research, 1995
- Inhibition of human immunodeficiency virus type 1 reverse transcriptase by the 5'-triphosphate beta enantiomers of cytidine analogsAntimicrobial Agents and Chemotherapy, 1994
- Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitroAntimicrobial Agents and Chemotherapy, 1994
- Interactions Between Drug Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse TranscriptaseJournal of General Virology, 1994
- Chiral Discrimination of Enantiomeric 2′-Deoxythymidine 5′-Triphosphate by HIV-1 Reverse Transcriptase and Eukaryotic DNA PolymerasesBiochemical and Biophysical Research Communications, 1994