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

Viruses

Ching-Ying Wang²  An-Cheng Huang⁵  Mann-Jen Hour¹  Su-Hua Huang⁶  Szu-Hao Kung⁴  Chao-Hsien Chen²  I-Chieh Chen²  Yuan-Shiun Chang³  Jin-Cherng Lien¹  Cheng-Wen Lin² 

[1] School of Pharmacy, China Medical University, Taichung 40402, Taiwan; E-Mail:;Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 40402, Taiwan; E-Mails:;School of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 40402, Taiwan; E-Mail:;Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming University, Taipei 11221, Taiwan; E-Mail:;Department of Nursing, St. Mary’s Junior College of Medicine, Nursing and Management, Yilan County 266, Taiwan; E-Mail:;Department of Biotechnology, Asia University, Wufeng, Taichung 41354, Taiwan; E-Mail:

关键词: enterovirus A71;    2A protease;    type I interferon;    antagonism;    inhibitor;   

DOI  :  10.3390/v7062764

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.