Antiviral Efficacy of Flavonoids against Enterovirus 71 Infection in Vitro and in Newborn Mice

Abstract

Enterovirus 71 (EV71) infection is known to cause hand, foot, and mouth disease (HFMD), which is associated with neurological complications; however, there is currently no effective treatment for this infection. Flavonoids are a large group of naturally occurring compounds with multiple bioactivities, and the inhibitory effects of several flavonoids against EV71 have been studied in cell cultures; however, to date, there are no reported data on their effects in animal models. In this study, we confirmed the in vitro activities of eight flavonoids against EV71 infection, based on the inhibition of cytopathic effects. Moreover, these flavonoids were found to reduce viral genomic RNA replication and protein synthesis. We further demonstrated the protective efficacy of these flavonoids in newborn mice challenged with a lethal dose of EV71. Apigenin, luteolin, kaempferol, formononetin, and penduletin conferred survival protection of 88.89%, 91.67%, 88.89%, 75%, and 66.67%, respectively, from the lethal EV71 challenge. In addition, isorhamnetin provided the highest mice survival protection of 100% at a dose of 10 mg/kg. This study, to the best of our knowledge, is the first to evaluate the in vivo anti-EV7l activities of multiple flavonoids, and we accordingly identified flavonoids as potential leading compounds for anti-EV71 drug development.

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

“…Newborn BALB/c mice were also protected from lethal challenge with the virus with 50 mg/Kg of kaempferol. The clinical score and body weight were found to be similar to that of the solvent treated group (negative control) [72].…”

“…When evaluated for its potential to protect newborn BALB/c mice from intracranial lethal challenge with EV-A71, apigenin was found to protect mice at the dose of 50 mg/Kg with 88.89% survival rate. Significant improvement in clinical scores and body mass were also observed in the treatment group as compared to the control group [72].…”

“…It exhibited antiviral activity with an IC 50 of 12.5 µM and significantly reduced viral replication and protein synthesis. It also protected newborn mice with a survival rate of 75% and significantly improved clinical score and animal body weight at a dose of 10 mg/Kg [72].…”

“…Moreover, when luteolin was tested against the prototype BrCr strain and the Fuyang0805 isolate of EV-A71, it was able to prevent virus-induced ROS generation, cellular apoptosis and inflammatory cytokine production such as IL-6 and CCL5 [71]. In another independent study, Dai et al (2019) showed that luteolin exhibited similar inhibition patterns with an IC 50 of 13.5 µM. It was identified to reduce viral replication and protein synthesis.…”

“…In a recent study by Dai et al (2019), apigenin exhibited potent antiviral activity against EV-A71 genotype C4 strain in vitro and in vivo. It was able to reduce the cytopathic effect to 50% at the concentration of 24.74 µM in 293S cells.…”