INHIBITION OF HEPATITIS-B VIRUS BY A NOVEL L-NUCLEOSIDE, 2'-FLUORO-5-METHYL-BETA-L-ARABINOFURANOSYL URACIL

2'-Fluoro-5-methyl-beta-L-arabinofuranosyl uracil (L-FMAU) was discove red to have potent antiviral activity against hepatitis B virus (HBV), L-FMAU was more potent than its D-enantiomer and produced dose-depend ent inhibition of the viral DNA replication in 2.2.15 cells (human Hep G2 cells with the HBV genome), with a 50% inhibitory concentration of 0.1 mu M. There was no inhibitory effect on HBV transcription or prote in synthesis, In the 2.2.15 cell system, L-FMAU did not show any toxic ity up to 200 mu M, whereas the D-enantiomer was toxic, with a 50% inh ibitory concentration of 50 mu M. Repeated treatments of HepG2 cells w ith L-FMAU at a 1 mu M concentration for 9 days did not result in any decrease in the total mitochondrial DNA content, suggesting that a mod e of toxicity similar to that produced by 2',3'-dideoxycytidine is unl ikely, Also at concentrations as high as 200 mu M, L-FMAU did not adve rsely affect mitochondrial function as determined by lactic acid produ ction by L-FMAU-treated hepatoma cells, L-FMAU was metabolized in the cells to its mono-, di-, and triphosphates. A dose-dependent inhibitio n of HBV DNA synthesis by L-FMAU triphosphate was observed in the DNA polymerase assays with isolated HBV particles, suggesting that the mod e of action of this compound could involve viral polymerase. However, L-FMAU was not incorporated into the cellular DNA, Considering the pot ent inhibition of the viral DNA synthesis and the nontoxicity of L-FMA U towards the host DNA synthetic machinery, this compound should be fu rther explored for development as an anti-HBV drug.