Structural determinants of HIV-1 reverse transcriptase stereoselectivity towards (beta)-L-deoxy- and dideoxy-pyrimidine nucleoside triphosphates: molecular basis for the combination of L-dideoxynucleoside analogs with non-nucleoside inhibitors in anti HIV chemotherapy.
We have compared the HIV-1 RT mutants containing the single substitutions L100I, K103N, V106A, V179D, Y181I and Y188L, known to confer 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.
Maga
G
G
Istituto di Genetica Biochimica el Evoluzionistica, Consiglio Nazionale delle Ricerche, Pavia, Italy.
Amacker
M
M
Hübscher
U
U
Gosselin
G
G
Imbach
J L
JL
Mathé
C
C
Faraj
A
A
Sommadossi
J P
JP
Spadari
S
S
D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D001665:Binding Sites; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009154:Mutation; D017433:Protein Structure, Secondary; D011742:Pyrimidine Nucleotides / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D013237:Stereoisomerism
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D011742:Pyrimidine Nucleotides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase