Enzymatic properties and sensitivity to inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase with Glu-138-->Arg and Tyr-188-->His mutations.
Two mutants of HIV-1 reverse transcriptase (RT), Tyr-188-->His and Glu-138-->Arg have been prepared and their catalytic properties and sensitivities to inhibitors studied. As compared to wild type RT, a reduction in catalytic efficiency and turn over number was observed, especially for the Tyr-188-->His mutant. The non-nucleoside inhibitors nevirapine, L-697,661 and 9-Cl-TIBO caused a mixed type of inhibition of RT (Arg-138) with respect to substrate, and with the exception of a non-competitive inhibition by nevirapine, also a mixed type of inhibition of RT (His-188). Foscarnet (PFA) caused a non-competitive type of inhibition of RT (Arg-138) and a mixed inhibition of RT (His-188). The inhibition by ddG-TP was competitive with both mutant RTs. Inhibition by nevirapine gave IC50 values of 0.15, 0.23 and 0.72 microM; by 9-Cl-TIBO of 0.20, 2.50 and 10.3 microM; by L-697,661 of 0.064, 0.28 and 0.60 microM; by ddGTP of 0.13, 0.14 and 0.02 microM; by PFA of 17.0, 48.0 and 15.0 microM for RT wt, RT (Arg-138) and RT (His-188), respectively.
Zhang
H
H
Medivir AB, Huddinge, Sweden.
Vrang
L
L
Bäckbro
K
K
Unge
T
T
Noréen
R
R
Oberg
B
B
D000596:Amino Acids / Q000235:genetics*; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D001569:Benzodiazepines / Q000494:pharmacology; D001583:Benzoxazoles / Q000494:pharmacology; D001667:Binding, Competitive; D003848:Deoxyguanine Nucleotides / Q000494:pharmacology; D054306:Dideoxynucleotides; D017245:Foscarnet / Q000494:pharmacology; D054303:HIV Reverse Transcriptase; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D008969:Molecular Sequence Data; D009154:Mutation; D019829:Nevirapine; D011725:Pyridines / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors; D012680:Sensitivity and Specificity
D000596:Amino Acids; D000998:Antiviral Agents; D001583:Benzoxazoles; D003848:Deoxyguanine Nucleotides; D054306:Dideoxynucleotides; D007093:Imidazoles; D011725:Pyridines; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D001569:Benzodiazepines; D017245:Foscarnet; C076516:L-697661; C067413:R-82913; C031709:2',3'-dideoxyguanosine 5'-triphosphate; D019829:Nevirapine; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase