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Int. J. Mol. Sci. 2016, 17(9), 1386;

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

Department of Biotechnology, Asia University, Wufeng, Taichung 413, Taiwan
School of Pharmacy, China Medical University, Taichung 404, Taiwan
Proteomics Core Laboratory, Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan
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)
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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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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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