Agathisflavone, a Biflavonoid from Anacardium occidentale L., Inhibits Influenza Virus Neuraminidase

Background: Neuraminidase inhibitors (NAIs) are the only class of antivirals in clinical use against influenza virus approved worldwide. However, approximately 1-3% of circulating strains present resistance mutations to oseltamivir (OST), the most used NAI. Therefore, it is important to catalogue new molecules to inhibit influenza virus, especially OST-resistant strains. Natural products from tropical plants used for human consumption represent a worthy class of substances. Their use could be stimulated in resource-limited setting where the access to expensive antiviral therapies is restricted. Methods: We evaluated the anti-influenza virus activity of agathisflavone derived from Anacardium occidentale L. Results: The neuraminidase (NA) activity of wild-type and OST-resistant influenza virus was inhibited by agathisflavone, with IC50 values ranging from 20 to 2.0 μM, respectively. Agathisflavone inhibited influenza virus replication with EC50 of 1.3 μM. Sequential passages of the virus in the presence of agathisflavone revealed the emergence of mutation R249S, A250S and R253Q in the NA gene. These changes are outside the OST binding region, meaning that agathisflavone targets this viral enzyme at a region different than conventional NAIs. Conclusion: Altogether our data suggest that agathisflavone has a promising chemical structure for the development of anti-influenza drugs.