Inhibition of HIV-associated reverse transcriptase by sugar-modified derivatives of thymidine 5′-triphosphate in comparison to cellular DNA polymerases α and β

Abstract The sugar-modified dTTP analogues 2′,3′-didehydro-2′,3′-dideoxythymidine 5′-triphosphate (ddeTTP), 2′,3′-dideoxythymidine 5′-triphosphate (ddTTP), 3′-fluorothymidine 5′-triphosphate (FdTTP), and 3′-azidothymidine 5′-triphosphate (N 3 dTTP) are demonstrated to be very effective and selective inhibitors of the HIV-associated reverse transcriptase (HIV-RT). This conclusion is based on a comparison of the ID so values of the compounds for the HIV-RT (ranging from 0.03 μM for ddeTTP to 0.1 μM for ddTTP) and the cellular DNA polymerase α (> 200 μM). DNA polymerase β is partially affected by N 3 dTTP (ID so =31 μM) and by the other analogues (ID so =1–2.2 μM). FdTTP has proved as effective as N 3 dTTP (ID so =0.05 μM) in suppressing the HIV-RT activity. Kinetic analysis revealed for both dTTP analogues a competitive type of inhibition and the same K 1 values (about 0.05 μM).