Effects of β-L-3'-azido-3'-deoxythymidine 5'-triphosphate on host and viral DNA polymerases

Academic Article

Abstract

  • We have previously reported that several β-L-thymidine analogues including β-L-3'-azido-3'-deoxythymidine (β-L-AZT), β-L-3'-fluoro-2',3'- dideoxythymidine (β-L-FLT) and β-L-2',3'-didehydro-2',3'-dideoxythymidine (β-L-D4T) did not inhibit HIV replication in human peripheral blood mononuclear (PBM) cells whereas their corresponding β-D-counterparts are known as potent and selective anti-HIV agents [Faraj et al., 1997. Nucleosides and Nucleotides 16, 1287-1290]. In order to gain insight on the lack of antiviral activities of these β-L-derivatives, in vitro enzymatic steady state studies were conducted in the present study with β-L-AZT. β-L- AZT 5'-triphosphate (L-AZTTP) was chemically synthesized and found to moderately inhibit wild-type HIV reverse transcriptase (HIV-1 RT) with a K(i) value of 2 μM; while lacking any inhibitory effect towards human DNA polymerase α, β or γ. However, the inhibitory effect of L-AZTTP towards HIV-1 RT was very modest (266-fold less potent) when compared to its isomer β-D-AZT 5'-triphosphate (D-AZTTP) which exhibits a K(i) value of 0.0075 μM and this finding was further confirmed by DNA chain termination assay. These data suggest that the absence of antiviral activity of the parent β-L-AZT may in part be explained by the poor inhibition of the targeted viral enzyme by L-AZTTP, the active metabolite. Finally, L-AZTTP was found to lack affinity for the mutant RT at position 184 (M184V) demonstrating that this mutation confers resistance not only to β-L-2',3'-dideoxycytidine analogs as previously reported by our group [Faraj et al., 1994. Antimicrob. Agents Chemother. 38, 2300-2305] but as well as to β-L-2',3'-dideoxythymidine analogs. (C) 2000 Elsevier Science B.V.
  • Published In

  • Antiviral Research  Journal
  • Digital Object Identifier (doi)

    Author List

  • Faraj A; El Alaoui AM; Gosselin G; Imbach JL; Morrow C; Sommadossi JP
  • Start Page

  • 97
  • End Page

  • 102
  • Volume

  • 47
  • Issue

  • 2