INHIBITORY EFFECT OF PENCICLOVIR-TRIPHOSPHATE ON DUCK HEPATITIS-B VIRUS REVERSE TRANSCRIPTION

The aim of this study was to investigate the mechanism of inhibition o f hepatitis B virus replication by penciclovir-triphosphate, the activ e metabolite of famciclovir. A recently developed in vitro translation assay For the expression of an enzymatically active duck hepatitis B virus (DHBV) reverse transcriptase was used to assess the inhibitory a ctivity of penciclovir-triphosphate (PCV-TP) in comparison with other guanosine analogue triphosphates. Acyclovir-triphosphate (ACV-TP), the chiral triphosphates of penciclovir (PCV), (R)-PCV-TP and (S)-PCV-TP, and carbocyclic 2'-deoxyguanosine-TP (CDG-TP) did inhibit reproducibl y minus strand DNA synthesis to different extents. CDG-TP was the most potent inhibitor of dGTP incorporation. The inhibitory effect of thes e compounds against the incorporation of the first nucleotide of minus strand DNA, dGMP, was similar to that observed with DNA chain elongat ion. 2',3'-dideoxyguanosine-TP (ddG-TP), ACV-TP and both (R) and (S)-P CV-TP inhibited the incorporation of the next nucleotides in the short DNA primer, whereas CDG-TP did not. These results demonstrate that PC V-TP inhibits hepadnavirus reverse transcription by inhibiting the syn thesis of the short DNA primer. The data obtained with the inhibition of the enzymatic activity of the DHBV polymerase provides a now insigh t into the mechanism of action of penciclovir-triphosphate on HBV repl ication.