Inhibition of hepatitis B virus by a novel L-nucleoside, 2'-fluoro-5-methyl-beta-L-arabinofuranosyl uracil
Inhibition of hepatitis B virus by a novel L-nucleoside, 2'-fluoro-5-methyl-beta-L-arabinofuranosyl uracil
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DOI：
10.1128/aac.40.2.380
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发表时间：
1996-02-01
影响因子：
4.9
通讯作者：
Cheng, YC
中科院分区：
文献类型：
--
作者：
Pai, SB;Liu, SH;Cheng, YC
发现2 '-氟-5-甲基-β-L-阿拉伯呋喃糖基尿嘧啶（L-FMAU）对B肝炎病毒（HBV）具有强效抗病毒活性，L-FMAU比其D-对映体更有效，并对2.2.15细胞（具有HBV基因组的人HepG 2细胞）中的病毒DNA复制产生剂量依赖性抑制，50%抑制浓度为0.1 μ M。对HBV转录或蛋白质合成没有抑制作用。在2.2.15细胞系统中，L-FMAU在高达200 μ M时没有显示出任何毒性，而D-对映体是有毒的，50%抑制浓度为50 μ M。用浓度为1 μ M的L-FMAU重复处理HepG 2细胞9天，未导致总线粒体DNA含量的任何降低，表明不可能产生类似于2 ′，3 ′-双脱氧胞苷产生的毒性模式。L-FMAU没有不利地影响线粒体功能，如通过L-FMAU处理的肝癌细胞的乳酸产生所确定的，L-FMAU在细胞中代谢成其单磷酸、二磷酸和三磷酸。在使用分离的HBV颗粒的DNA聚合酶试验中观察到L-FMAU三磷酸盐对HBV DNA合成的剂量依赖性抑制，表明该化合物的作用模式可能涉及病毒聚合酶。然而，L-FMAU并不掺入细胞DNA中，考虑到L-FMAU对病毒DNA合成的有效抑制和对宿主DNA合成机制的无毒性，该化合物应进一步开发为抗HBV药物。
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 mu M. 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 mu M, whereas the D-enantiomer was toxic, with a 50% inhibitory concentration of 50 mu M. Repeated treatments of HepG2 cells with 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 mode of toxicity similar to that produced by 2',3'-dideoxycytidine is unlikely, Also at concentrations as high as 200 mu M, 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 an anti-HBV drug.