Effects of β-l-3′-azido-3′-deoxythymidine 5′-triphosphate on host and viral DNA polymerases

Add time:09/07/2019    Source:sciencedirect.com

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 Ki 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 Ki 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.

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