RESEARCH ARTICLE Antiviral Effect of Methylated Flavonol Isorhamnetin against Influenza

Influenza is an infectious respiratory disease with frequent seasonal epidemics that causes a high rate of mortality and morbidity in humans, poultry, and animals. Influenza is a serious economic concern due to the costly countermeasures it necessitates. In this study, we com-pared the antiviral activities of several flavonols and other flavonoids with similar, but dis-tinct, hydroxyl or methyl substitution patterns at the 3, 30, and 40 positions of the 15-carbon flavonoid skeleton, and found that the strongest antiviral effect was induced by isorhamne-tin. Similar to quercetin and kaempferol, isorhamnetin possesses a hydroxyl group on the C ring, but it has a 30-methyl group on the B ring that is absent in quercetin and kaempferol. Co-treatment and pre-treatment with isorhamnetin produced a strong antiviral effect against the influenza virus A/PR/08/34(H1N1). However, isorhamnetin showed the most potent an-tiviral potency when administered after viral exposure (post-treatment method) in vitro. Iso-rhamnetin treatment reduced virus-induced ROS generation and blocked cytoplasmic lysosome acidification and the lipidation of microtubule associated protein1 light chain 3-B (LC3B). Oral administration of isorhamnetin in mice infected with the influenza A virus signif-icantly decreased lung virus titer by 2 folds, increased the survival rate which ranged from 70–80%, and decreased body weight loss by 25%. In addition, isorhamnetin decreased the virus titer in ovo using embryonated chicken eggs. The structure-activity relationship (SAR) of isorhamnetin could explain its strong anti-influenza virus potency; the methyl group locat-ed on the B ring of isorhamnetin may contribute to its strong antiviral potency against influ-enza virus in comparison with other flavonoids