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Open AccessArticle

Antiviral Potential of a Novel Compound CW-33 against Enterovirus A71 via Inhibition of Viral 2A Protease

1
Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan
2
School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 40402, Taiwan
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Department of Nursing, St. Mary's Junior College of Medicine, Nursing and Management, Yilan County 266, Taiwan
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School of Pharmacy, China Medical University, Taichung 40402, Taiwan
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Department of Biotechnology, Asia University, Wufeng, Taichung 41354, Taiwan
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Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming University, Taipei 11221, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Curt Hagedorn
Viruses 2015, 7(6), 3155-3171; https://doi.org/10.3390/v7062764
Received: 15 April 2015 / Revised: 4 June 2015 / Accepted: 10 June 2015 / Published: 17 June 2015
(This article belongs to the Section Antivirals & Vaccines)
Enterovirus A71 (EV-A71) in the Picornaviridae family causes hand-foot-and-mouth disease, aseptic meningitis, severe central nervous system disease, even death. EV-A71 2A protease cleaves Type I interferon (IFN)-α/β receptor 1 (IFNAR1) to block IFN-induced Jak/STAT signaling. This study investigated anti-EV-A7l activity and synergistic mechanism(s) of a novel furoquinoline alkaloid compound CW-33 alone and in combination with IFN-β Anti-EV-A71 activities of CW-33 alone and in combination with IFN-β were evaluated by inhibitory assays of virus-induced apoptosis, plaque formation, and virus yield. CW-33 showed antiviral activities with an IC50 of near 200 µM in EV-A71 plaque reduction and virus yield inhibition assays. While, anti-EV-A71 activities of CW-33 combined with 100 U/mL IFN-β exhibited a synergistic potency with an IC50 of approximate 1 µM in plaque reduction and virus yield inhibition assays. Molecular docking revealed CW-33 binding to EV-A71 2A protease active sites, correlating with an inhibitory effect of CW33 on in vitro enzymatic activity of recombinant 2A protease IC50 = 53.1 µM). Western blotting demonstrated CW-33 specifically inhibiting 2A protease-mediated cleavage of IFNAR1. CW-33 also recovered Type I IFN-induced Tyk2 and STAT1 phosphorylation as well as 2',5'-OAS upregulation in EV-A71 infected cells. The results demonstrated CW-33 inhibiting viral 2A protease activity to reduce Type I IFN antagonism of EV-A71. Therefore, CW-33 combined with a low-dose of Type I IFN could be applied in developing alternative approaches to treat EV-A71 infection. View Full-Text
Keywords: enterovirus A71; 2A protease; type I interferon; antagonism; inhibitor enterovirus A71; 2A protease; type I interferon; antagonism; inhibitor
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MDPI and ACS Style

Wang, C.-Y.; Huang, A.-C.; Hour, M.-J.; Huang, S.-H.; Kung, S.-H.; Chen, C.-H.; Chen, I.-C.; Chang, Y.-S.; Lien, J.-C.; Lin, C.-W. Antiviral Potential of a Novel Compound CW-33 against Enterovirus A71 via Inhibition of Viral 2A Protease. Viruses 2015, 7, 3155-3171.

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