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.

Flavonoids as Antiviral Agents for Enterovirus A71 (EV-A71)

“…Apigenin inhibited EV-A71 infection by suppressing viral internal ribosome entry site (IRES) activity. Apigenin was found to disrupt the viral RNA association with hnRNP A1 and A2 proteins [70].…”

Antiviral effect of phytochemicals from medicinal plants: Applications and drug delivery strategies

“…Apigenin (4′,5,7-trihydroxyflavone), an aglycone of the flavone class, is found in many plants and has broad antiviral activities against enterovirus-71 [63], foot and mouth disease virus [64], HCV [65], African swine fever virus (ASFV) [66], and influenza A virus [67]. Of note, many flavonoids of plant origin have known antiviral properties.…”

Inhibition of Epstein-Barr virus reactivation by the flavonoid apigenin

“…As a large family of natural compounds, the flavonoids have been less well studied for their anti-virus functions. Among them, apigenin was reported to inhibit enterovirus-71 infection by disrupting viral RNA associated factors [39] and it also inhibits hepatitis C virus replication by decreasing microRNA122 [40] and restricts FMDV infection by inhibiting viral translational activity [41]. Moreover, although several flavonoids have been reported to have anti-EBV activity, these studies did not explore their inhibitory mechanisms and most such studies were made using the B cell system [42, 43].…”