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Antiviral Activity of a Novel Compound CW-33 against Japanese Encephalitis Virus through Inhibiting Intracellular Calcium Overload.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2016 Aug 24; Vol. 17 (9). Date of Electronic Publication: 2016 Aug 24. - Publication Year :
- 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 Ca(2+) 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.<br />Competing Interests: Jin-Cherng Lien, An-Cheng Huang, Chia-Fong Ping, and Cheng-Wen Lin had patents on CW-33.
- Subjects :
- Animals
Antiviral Agents chemistry
Apoptosis drug effects
Cell Line
Cell Line, Tumor
Cricetinae
GTPase-Activating Proteins
Humans
Membrane Potential, Mitochondrial drug effects
Mesocricetus
Quinolines chemistry
Quinolines pharmacology
STAT1 Transcription Factor metabolism
Tandem Mass Spectrometry
Virus Replication drug effects
Antiviral Agents pharmacology
Calcium metabolism
Encephalitis Virus, Japanese drug effects
Encephalitis Virus, Japanese metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 17
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 27563890
- Full Text :
- https://doi.org/10.3390/ijms17091386