Klaus Gaertner

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).

Strong and Selective Inhibitors of Hepatitis B Virus Replication among Novel N4-Hydroxy- and 5-Methyl-β-l-Deoxycytidine Analogues

ABSTRACT Novel N4-hydroxy- and 5-methyl-modified β-l-deoxycytidine analogues were synthesized and evaluated as anti-hepatitis B virus (HBV) agents. Their in vitro efficiencies were investigated in HepG2.2.15 cells stably transfected with HBV. β-l-2′,3′-Didehydro-2′,3′-dideoxy-N4-hydroxycytidine (β-l-Hyd4C) was most effective in reducing secreted HBV DNA (50% effective concentration [EC50], 0.03 μM), followed by β-l-2′,3′-dideoxy-3′-thia-N4-hydroxycytidine (EC50, 0.51 μM), β-l-2′,3′-dideoxy-N4-hydroxycytidine (EC50, 0.55 μM), and β-l-5-methyl-2′-deoxycytidine (EC50, 0.9 μM). The inhibition of the presumed target, the HBV DNA polymerase, by the triphosphates of some of the β-l-cytidine derivatives was also assessed. In accordance with the cell culture data, β-l-Hyd4C triphosphate was the most active inhibitor, with a 50% inhibitory concentration of 0.21 μM. The cytotoxicities of some of the 4-NHOH-modified β-l-nucleosides were dramatically lower than those of the corresponding cytidine analogues with the unmodified 4-NH2 group. The 50% cytotoxic concentrations for β-l-Hyd4C in HepG2 and HL-60 cells were 2,500 μM and 3,500 μM, respectively. In summary, our results demonstrate that at least β-l-Hyd4C can be recommended as a highly efficient and extremely selective inhibitor of HBV replication for further investigations.

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.