DNA-POLYMERASE-ACTIVITY OF HEPATITIS-B VIRUS-PARTICLES - DIFFERENTIALINHIBITION BY L-ENANTIOMERS OF NUCLEOTIDE ANALOGS

DNA polymerase activity was assayed in hepatitis B virus (HBV) and cor e particles isolated from chronic producer lines. The particle-associa ted DNA polymerase activity, which was found to be limited to incorpor ation of only a few nucleotides, was inhibited by the 5'-triphosphates of nucleoside analogs. The 1-beta-L (1S,4R) and 1-beta-D (1R,4S) enan tiomers of antiviral nucleoside analogs were compared for the ability to inhibit incorporation of natural nucleoside triphosphates into the viral DNA. Previously, both enantiomers of several analogs were found to be substrates for human immunodeficiency virus type 1 reverse trans criptase (HIV RT); the 1-beta-D enantiomers of some pairs were preferr ed as substrates. In contrast, the 1-beta-L enantiomers of all pairs t ested were the more potent inhibitors of labeled substrate incorporati on into hepatitis B virus DNA; the concentration required to inhibit t he incorporation of the natural substrate by 50% was 6-fold to several hundred-fold lower than the concentration of the 1-beta-D enantiomer required for the same inhibitory effect. This preference for the 1-bet a-L enantiomers was observed for both RNA-directed synthesis in core p articles and DNA-directed synthesis in viral particles. The observed a ntiviral effect of the nucleoside analogs in cell culture seemed to be limited chiefly by their phosphorylation in cells.