title: Inhibition of hepatitis B virus by a novel L-nucleoside, 2'-fluoro-5-methyl-beta-L-arabinofuranosyl uracil.
abstract: 2'-Fluoro-5-methyl-beta-L-arabinofuranosyl uracil (L-FMAU) was discovered to have potent antiviral activity against hepatitis B virus (HBV). L-FMAU was more potent than its D-enantiomer and produced dose-dependent inhibition of the viral DNA replication in 2.2.15 cells (human HepG2 cells with the HBV genome), with a 50% inhibitory concentration of 0.1 microM. There was no inhibitory effect on HBV transcription or protein synthesis. In the 2.2.15 cell system, L-FMAU did not show any toxicity up to 200 microM, whereas the D-enantiomer was toxic, with a 50% inhibitory concentration of 50 microM. Repeated treatments of HepG2 cells with L-FMAU at a 1 microM concentration for 9 days did not result in any decrease in the total mitochondrial DNA content, suggesting that a mode of toxicity similar to that produced by 2',3'-dideoxycytidine is unlikely. Also at concentrations as high as 200 microM, L-FMAU did not adversely affect mitochondrial function as determined by lactic acid production by L-FMAU-treated hepatoma cells. L-FMAU was metabolized in the cells to its mono-, di-, and triphosphates, A dose-dependent inhibition of HBV DNA synthesis by L-FMAU triphosphate was observed in the DNA polymerase assays with isolated HBV particles, suggesting that the mode of action of this compound could involve viral polymerase. However, L-FMAU was not incorporated into the cellular DNA. Considering the potent inhibition of the viral DNA synthesis and the nontoxicity of L-FMAU towards the host DNA synthetic machinery, this compound should be further explored for development as asn anti-HBV drug.
authors.affiliation: Department of Pharmacology, Yale University, New Haven, Connecticut 06510, USA.
authors.forename: S
authors.initials: S
authors.lastname: Balakrishna Pai
authors.forename: S H
authors.initials: SH
authors.lastname: Liu
authors.forename: Y L
authors.initials: YL
authors.lastname: Zhu
authors.forename: C K
authors.initials: CK
authors.lastname: Chu
authors.forename: Y C
authors.initials: YC
authors.lastname: Cheng
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D004279:DNA, Viral / Q000378:metabolism*; D006512:Hepatitis B Core Antigens / Q000032:analysis; D006514:Hepatitis B Surface Antigens / Q000032:analysis; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D019344:Lactic Acid / Q000096:biosynthesis; D019384:Nucleic Acid Synthesis Inhibitors; D013237:Stereoisomerism; D014158:Transcription, Genetic / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D019384:Nucleic Acid Synthesis Inhibitors; D001086:Arabinofuranosyluracil; D019344:Lactic Acid; C034935:clevudine