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Tubacin, an HDAC6 Selective Inhibitor, Reduces the Replication of the Japanese Encephalitis Virus via the Decrease of Viral RNA Synthesis
- Source :
- International Journal of Molecular Sciences; Volume 18; Issue 5; Pages: 954, International Journal of Molecular Sciences, International Journal of Molecular Sciences, Vol 18, Iss 5, p 954 (2017)
- Publication Year :
- 2017
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2017.
-
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.
- Subjects :
- 0301 basic medicine
viruses
Viral Nonstructural Proteins
Histone Deacetylase 6
Hydroxamic Acids
Virus Replication
Hsp90 inhibitor
lcsh:Chemistry
Cricetinae
Anilides
lcsh:QH301-705.5
Spectroscopy
Cytopathic effect
biology
General Medicine
Hsp90
Computer Science Applications
Flavivirus
RNA, Viral
tubacin
Japanese encephalitis virus
histone deacetylase 6
heat shock protein 90 (Hsp90)
non-structural protein 5 (NS5)
Antiviral Agents
Catalysis
Virus
Article
Cell Line
Inorganic Chemistry
03 medical and health sciences
Cricetulus
Cell Line, Tumor
medicine
Animals
Humans
HSP90 Heat-Shock Proteins
Physical and Theoretical Chemistry
Molecular Biology
Organic Chemistry
Japanese encephalitis
medicine.disease
biology.organism_classification
Virology
Molecular biology
Histone Deacetylase Inhibitors
030104 developmental biology
Viral replication
lcsh:Biology (General)
lcsh:QD1-999
Apoptosis
Encephalitis Viruses, Japanese
biology.protein
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences; Volume 18; Issue 5; Pages: 954
- Accession number :
- edsair.doi.dedup.....546a5ea84fbc88bac03f8ea17e6808f9
- Full Text :
- https://doi.org/10.3390/ijms18050954