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

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.