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Int. J. Mol. Sci. 2017, 18(5), 954; doi:10.3390/ijms18050954

Tubacin, an HDAC6 Selective Inhibitor, Reduces the Replication of the Japanese Encephalitis Virus via the Decrease of Viral RNA Synthesis

1
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan
2
Department of Otolaryngology, China Medical University Hospital, Taichung 40402, Taiwan
3
Department of Biotechnology, Asia University, Taichung 41354, Taiwan
4
Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming University, Taipei 11221, Taiwan
5
School of Pharmacy, China Medical University, Taichung 40402, Taiwan
The authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Susanna K. P. Lau
Received: 31 March 2017 / Revised: 26 April 2017 / Accepted: 28 April 2017 / Published: 1 May 2017
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Abstract

Japanese 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
Keywords: Japanese encephalitis virus; histone deacetylase 6; tubacin; heat shock protein 90 (Hsp90); non-structural protein 5 (NS5) Japanese encephalitis virus; histone deacetylase 6; tubacin; heat shock protein 90 (Hsp90); non-structural protein 5 (NS5)
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MDPI and ACS Style

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.

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