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Viruses 2015, 7(6), 3155-3171; doi:10.3390/v7062764

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
3
Department of Nursing, St. Mary's Junior College of Medicine, Nursing and Management, Yilan County 266, Taiwan
4
School of Pharmacy, China Medical University, Taichung 40402, Taiwan
5
Department of Biotechnology, Asia University, Wufeng, Taichung 41354, Taiwan
6
Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming University, Taipei 11221, Taiwan
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Curt Hagedorn
Received: 15 April 2015 / Revised: 4 June 2015 / Accepted: 10 June 2015 / Published: 17 June 2015
(This article belongs to the Section Antivirals & Vaccines)
View Full-Text   |   Download PDF [3413 KB, uploaded 17 June 2015]   |  

Abstract

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
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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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