title: Apigenin inhibits enterovirus-71 infection by disrupting viral RNA association with trans-acting factors.
abstract: Flavonoids are widely distributed natural products with broad biological activities. Apigenin is a dietary flavonoid that has recently been demonstrated to interact with heterogeneous nuclear ribonucleoproteins (hnRNPs) and interferes with their RNA editing activity. We investigated whether apigenin possessed antiviral activity against enterovirus-71 (EV71) infection since EV71 infection requires of hnRNP proteins. We found that apigenin selectively blocks EV71 infection by disrupting viral RNA association with hnRNP A1 and A2 proteins. The estimated EC50 value for apigenin to block EV71 infection was determined at 10.3 µM, while the CC50 was estimated at 79.0 µM. The anti-EV71 activity was selective since no activity was detected against several DNA and RNA viruses. Although flavonoids in general share similar structural features, apigenin and kaempferol were among tested compounds with significant activity against EV71 infection. hnRNP proteins function as trans-acting factors regulating EV71 translation. We found that apigenin treatment did not affect EV71-induced nucleocytoplasmic redistribution of hnRNP A1 and A2 proteins. Instead, it prevented EV71 RNA association with hnRNP A1 and A2 proteins. Accordingly, suppression of hnRNP A1 and A2 expression markedly reduced EV71 infection. As a positive sense, single strand RNA virus, EV71 has a type I internal ribosome entry site (IRES) that cooperates with host factors and regulates EV71 translation. The effect of apigenin on EV71 infection was further demonstrated using a bicistronic vector that has the expression of a GFP protein under the control of EV71 5'-UTR. We found that apigenin treatment selectively suppressed the expression of GFP, but not a control gene. In addition to identification of apigenin as an antiviral agent against EV71 infection, this study also exemplifies the significance in antiviral agent discovery by targeting host factors essential for viral replication.
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Haishi
authors.initials: H
authors.lastname: Qiao
authors.affiliation: College of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Yuanzi
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, China; College of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Renxiang
authors.initials: R
authors.lastname: Tan
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.
authors.forename: Erguang
authors.initials: E
authors.lastname: Li
mesh_terms: D047310:Apigenin / Q000008:administration & dosage*; D029821:Enterovirus A, Human / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D004769:Enterovirus Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D015967:Gene Expression Regulation, Viral; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics; D006801:Humans; D000067556:Internal Ribosome Entry Sites / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering; D012367:RNA, Viral / Q000187:drug effects* / Q000235:genetics; D014771:Virion / Q000187:drug effects / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D000067556:Internal Ribosome Entry Sites; D034741:RNA, Small Interfering; D012367:RNA, Viral; D047310:Apigenin