Antiviral Potential of a Novel Compound CW-33 against Enterovirus A71 via Inhibition of Viral 2A Protease
AbstractEnterovirus 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
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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.
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(6):3155-3171.Chicago/Turabian Style
Wang, Ching-Ying; Huang, An-Cheng; Hour, Mann-Jen; Huang, Su-Hua; Kung, Szu-Hao; Chen, Chao-Hsien; Chen, I-Chieh; Chang, Yuan-Shiun; Lien, Jin-Cherng; Lin, Cheng-Wen. 2015. "Antiviral Potential of a Novel Compound CW-33 against Enterovirus A71 via Inhibition of Viral 2A Protease." Viruses 7, no. 6: 3155-3171.