Potent and selective inhibition of hepatitis C virus replication by novel phenanthridinone derivatives
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- 作者：Mohammed T.A. ; Salim<sup>asup> ; Hiroshi ; Aoyama<sup>bsup><sup> ; ; sup><sup>1sup> ; Kazuyuki ; Sugita<sup>bsup> ; Kouichi ; Watashi<sup>csup> ; Takaji ; Wakita<sup>csup> ; Takayuki ; Hamasaki<sup>asup> ; Mika ; Okamoto<sup>asup> ; Yasuo ; Urata<sup>dsup> ; Yuichi ; Hashimoto<sup>bsup> ; Masanori ; Baba<sup>asup><sup> ; ; sup><sup>m-baba@m2.kufm.kagoshima-u.ac.jpsup>
- 关键词：Flavivirus ; HCV ; Phenanthridinone ; Replicon cell ; JFH1
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：2011
- 出版时间：2 December 2011
- 年：2011
- 卷：415
- 期：4
- 页码：714-719
- 全文大小：307 K
文摘
A number of novel phenanthridinone derivatives were examined for their inhibitory effect on hepatitis C virus (HCV) replication in Huh-7 cells harboring self-replicating subgenomic viral RNA replicons with a luciferase reporter (LucNeo#2). The activity of compounds was further confirmed by inhibition of viral RNA copy number in different subgenomic and full-genomic replicon cells using real-time reverse transcription polymerase chain reaction. Among the compounds, 4-butyl-11-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-7-methoxy-[1,3]dioxolo[4,5-s="""">c]phenanthridin-5(4s="""">H)-one (HA-719) was found to be the most active with a 50 % effective concentration of 0.063 ¡À 0.010 ¦ÌM in LucNeo#2 cells. The compound did not show apparent cytotoxicity to the host cells at concentrations up to 40 ¦ÌM. Western blot analysis demonstrated that HA-719 reduced the levels of NS3 and NS5A proteins in a dose-dependent fashion in the replicon cells. Interestingly, the phenanthridinone derivatives including HA-719 were less potent inhibitors of JFH1 strain (genobtype 2a HCV) in cell-free virus infection assay. Although biochemical assays revealed that HA-719 proved not to inhibit NS3 protease or NS5B RNA polymerase activity at the concentrations capable of inhibiting viral replication, their molecular target (mechanism of inhibition) remains unknown. Considering the fact that most of the anti-HCV agents currently approved or under clinical trials are protease and polymerase inhibitors, the phenanthridinone derivatives are worth pursuing for their mechanism of action and potential as novel anti-HCV agents.