Tubacin, an HDAC6 Selective Inhibitor, Reduces the Replication of the Japanese Encephalitis Virus via the Decrease of Viral RNA Synthesis
AbstractJapanese encephalitis virus (JEV), a neurotropic flavivirus, annually causes over 30,000 Japanese Encephalitis (JE) cases in East and Southeast Asia. Histone deacetylases (HDACs) modulate lysine acetylation of histones and non-histone proteins, regulating many processes including inflammation and antiviral immune response. This study investigated antiviral activity of pan- and selective-HDAC inhibitors as host-targeting agents against JEV. Among HDAC inhibitors, selective HDAC6 inhibitors (tubastatin-A (TBSA) and tubacin) concentration-dependently inhibited JEV-induced cytopathic effect and apoptosis, as well as reduced virus yield in human cerebellar medulloblastoma cells. The 50% inhibitory concentration (IC50) values of virus yield was 0.26 μM for tubacin and 1.75 μM for TBSA, respectively. Tubacin (IC50 of 1.52 μM), but not TBSA, meaningfully blocked the production of intracellular infectious virus particles. In time-of-addition assays, the greatest potency of antiviral activity was observed in the mode of pre-treatment with tubacin (IC50 of 1.89 μM) compared to simultaneous (IC50 of 4.88 μM) and post-treatment (IC50 of 2.05 μM) modes. Interestingly, tubacin induced the hyperacetylation of a HDAC6 substrate Hsp90 and reduced the interaction of Hsp90 with JEV NS5 protein. Novobiocin, an Hsp90 inhibitor, diminished the NS5 protein amount and virus replication in JEV-infected cells. Meantime, tubacin suppressed the NS5 expression and antisense RNA genome synthesis in infected cells. Tubacin-induced Hsp90 hyperacetylation was suggested to influence the NS5 activity in JEV replication. Therefore, tubacin had a high potential of a host-targeting agent against JEV, exhibiting preventive and therapeutic activities against JEV infection. View Full-Text
- Supplementary File 1:
PDF-Document (PDF, 188 KB)
Scifeed alert for new publicationsNever miss any articles matching your research from any publisher
- Get alerts for new papers matching your research
- Find out the new papers from selected authors
- Updated daily for 49'000+ journals and 6000+ publishers
- Define your Scifeed now
Lu, C.-Y.; Chang, Y.-C.; Hua, C.-H.; Chuang, C.; Huang, S.-H.; Kung, S.-H.; Hour, M.-J.; Lin, C.-W. Tubacin, an HDAC6 Selective Inhibitor, Reduces the Replication of the Japanese Encephalitis Virus via the Decrease of Viral RNA Synthesis. Int. J. Mol. Sci. 2017, 18, 954.
Lu C-Y, Chang Y-C, Hua C-H, Chuang C, Huang S-H, Kung S-H, Hour M-J, Lin C-W. Tubacin, an HDAC6 Selective Inhibitor, Reduces the Replication of the Japanese Encephalitis Virus via the Decrease of Viral RNA Synthesis. International Journal of Molecular Sciences. 2017; 18(5):954.Chicago/Turabian Style
Lu, Chien-Yi; Chang, Yi-Chih; Hua, Chun-Hung; Chuang, Chieh; Huang, Su-Hua; Kung, Szu-Hao; Hour, Mann-Jen; Lin, Cheng-Wen. 2017. "Tubacin, an HDAC6 Selective Inhibitor, Reduces the Replication of the Japanese Encephalitis Virus via the Decrease of Viral RNA Synthesis." Int. J. Mol. Sci. 18, no. 5: 954.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.