Honokiol and alfa-Mangostin inhibit Mayaro virus replication by stimulating the type I interferon pathway

Mayaro virus (MAYV) is an emerging arbovirus with increasing circulation across the Americas. In the present study, we evaluated the potential antiviral activity of the following natural compounds against MAYV and other arboviruses: Sanguinarine, (R)-Shikonin, Fisetin, Honokiol, Tanshinone IIA and -Mangostin. Sanguinarine and Shikonin showed significant cytotoxicity, whereas Fisetin, Honokiol, Tanshinone IIA and -Mangostin were well-tolerated in all the cell lines tested. Honokiol and -Mangostin treatment protected Vero-E6 cells against MAYV-induced damage and resulted in a dose-dependent reduction in viral progeny yields for each of the MAYV strains and human cell lines assessed. Also, Honokiol and -Mangostin disrupted MAYV infection at different stages of the virus life cycle. Moreover, these compounds decreased Una, Chikungunya and Zika viral titers and downmodulated the expression of E1 and nsP1 viral proteins from MAYV, Una and Chikungunya. Finally, in Honokiol- and -Mangostin-treated cells, we observed an upregulation in the expression of type I interferon and specific interferon-stimulated genes, including IFN, IFN{beta}, MxA, ISG15, OAS2, MDA-5, TNF and IL-1{beta}, which may promote an antiviral cellular state. Our results indicate that Honokiol and -Mangostin present potential broad-spectrum activity against different arboviruses through a possible modulation of the interferon pathway.