Dieter Scholz

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 (N3dTTP) 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 IDso 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 N3dTTP (IDso=31 μM) and by the other analogues (IDso=1–2.2 μM). FdTTP has proved as effective as N3dTTP (IDso=0.05 μM) in suppressing the HIV-RT activity. Kinetic analysis revealed for both dTTP analogues a competitive type of inhibition and the same K1 values (about 0.05 μM).

Synthesis and Anti-HIV Activity of Modified 2′,3′-Dideoxy-3′-Fluoro Pyrimidine Nucleosides

Abstract - Among the 2′, 3′ -dideoxy-3′-fluoro pyrimidine nucleosidea modified at C-4 and C-5 several congeners have been identified which show a selective inhibition of HIV-1 replication in vitro.