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Int. J. Mol. Sci. 2016, 17(9), 1386; doi:10.3390/ijms17091386

Antiviral Activity of a Novel Compound CW-33 against Japanese Encephalitis Virus through Inhibiting Intracellular Calcium Overload

1
Department of Biotechnology, Asia University, Wufeng, Taichung 413, Taiwan
2
School of Pharmacy, China Medical University, Taichung 404, Taiwan
3
Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
4
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan
5
Department of Nursing, St. Mary’s Junior College of Medicine, Nursing and Management, Yilan County 266, Taiwan
*
Authors to whom correspondence should be addressed.
Academic Editor: Chang Won Choi
Received: 24 June 2016 / Revised: 26 July 2016 / Accepted: 18 August 2016 / Published: 24 August 2016
(This article belongs to the Section Bioactives and Nutraceuticals)
View Full-Text   |   Download PDF [3973 KB, uploaded 25 August 2016]   |  

Abstract

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, has five genotypes (I, II, III, IV, and V). JEV genotype I circulates widely in some Asian countries. However, current JEV vaccines based on genotype III strains show low neutralizing capacities against genotype I variants. In addition, JE has no specific treatment, except a few supportive treatments. Compound CW-33, an intermediate synthesized derivative of furoquinolines, was investigated for its antiviral activities against JEV in this study. CW-33 exhibited the less cytotoxicity to Syrian baby hamster kidney (BHK-21) and human medulloblastoma (TE761) cells. CW-33 dose-dependently reduced the cytopathic effect and apoptosis of JEV-infected cells. Supernatant virus yield assay pinpointed CW-33 as having potential anti-JEV activity with IC50 values ranging from 12.7 to 38.5 μM. Time-of-addition assay with CW-33 indicated that simultaneous and post-treatment had no plaque reduction activity, but continuous and simultaneous treatments proved to have highly effective antiviral activity, with IC50 values of 32.7 and 48.5 μM, respectively. CW-33 significantly moderated JEV-triggered Ca2+ overload, which correlated with the recovery of mitochondria membrane potential as well as the activation of Akt/mTOR and Jak/STAT1 signals in treated infected cells. Phosphopeptide profiling by LC-MS/MS revealed that CW-33 upregulated proteins from the enzyme modulator category, such as protein phosphatase inhibitor 2 (I-2), Rho GTPase-activating protein 35, ARF GTPase-activating protein GIT2, and putative 3-phosphoinositide-dependent protein kinase 2. These enzyme modulators identified were associated with the activation of Akt/mTOR and Jak/STAT1 signals. Meanwhile, I-2 treatment substantially inhibited the apoptosis of JEV-infected cells. The results demonstrated that CW-33 exhibited a significant potential in the development of anti-JEV agents. View Full-Text
Keywords: Japanese encephalitis virus; furoquinolines; Ca2+ overload; Akt/mTOR; Jak/STAT1 Japanese encephalitis virus; furoquinolines; Ca2+ overload; Akt/mTOR; Jak/STAT1
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MDPI and ACS Style

Huang, S.-H.; Lien, J.-C.; Chen, C.-J.; Liu, Y.-C.; Wang, C.-Y.; Ping, C.-F.; Lin, Y.-F.; Huang, A.-C.; Lin, C.-W. Antiviral Activity of a Novel Compound CW-33 against Japanese Encephalitis Virus through Inhibiting Intracellular Calcium Overload. Int. J. Mol. Sci. 2016, 17, 1386.

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