TTP and Hepatitis-B

Novel beta-L-2',3'-dideoxy-3'-fluoro nucleosides were synthesized and further converted to their 5'-triphosphates. Their inhibitory activities against hepatitis B virus (HBV) and duck hepatitis B virus (DHBV) DNA polymerases, human immunodeficiency virus (HIV) reverse transcriptase (RT), and the cellular DNA polymerases alpha, beta, gamma, delta, and epsilon were investigated and compared with those of the corresponding 3'-fluoro-modified beta-d-analogues. The 5'-triphosphates of 3'-deoxy-3'-fluoro-beta-L-thymidine (beta-L-FTTP), 2',3'-dideoxy-3'-fluoro-beta-L-cytidine (beta-L-FdCTP), and 2',3'-dideoxy-3'-fluoro-beta-l-5-methylcytidine (beta-L-FMetdCTP) emerged as effective inhibitors of HBV/DHBV DNA polymerases (IC50 = 0.25-10.4 microM). They were either equally (FTTP) or less (FMetdCTP, FdCTP) effective than their beta-d-counterparts. Also the 5'-triphosphate of beta-L-thymidine (beta-L-TTP) was shown to be a strong inhibitor of these two viral enzymes (IC50 = 0.46/1.0 microM). However, all beta-L-FdNTPs (also beta-L-TTP) were inactive against HIV-RT, a result which contrasts sharply with the high efficiency of the beta-D- FdNTPs against this polymerase. Between the cellular DNA polymerases only the beta and gamma enzymes displayed a critical susceptibility to beta-D-FdNTPs which is largely abolished by the beta-L-enantiomers. These results recommend beta-L-FTdR, beta-L-FCdR, and beta-L-FMetCdR for further evaluation as selective inhibitors of HBV replication at the cellular level.

Topics: Animals; Cattle; DNA Polymerase beta; DNA Polymerase gamma; DNA Polymerase I; DNA Polymerase II; DNA Polymerase III; DNA-Directed DNA Polymerase; Enzyme Inhibitors; HeLa Cells; Hepatitis B; Hepatitis B Virus, Duck; HIV Reverse Transcriptase; Humans; Kinetics; Nucleic Acid Synthesis Inhibitors; Organophosphates; Placenta; Pyrimidine Nucleosides; Reverse Transcriptase Inhibitors; Stereoisomerism; Structure-Activity Relationship