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

Abstract

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 com-pounds against MAYV and other arboviruses: Sanguinarine, (R)-Shikonin, Fisetin, Honokiol, Tanshinone IIA and alfa-Mangostin. Sanguinarine and Shikonin showed significant cytotoxicity, whereas Fisetin, Honokiol, Tanshinone IIA and alfa-Mangostin were well-tolerated in all the cell lines tested. Honokiol and alfa-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 alfa-Mangostin disrupted MAYV infection at different stages of the virus life cycle. Moreover, these compounds de-creased 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 alfa-Mangostin-treated cells, we observed an upregulation in the expression of type I interferon and specific interferon-stimulated genes, including IFN-alfa, IFN-beta;, MxA, ISG15, OAS2, MDA-5, TNF-alfa and IL-1beta;, which may promote an antiviral cellular state. Our results indicate that Honokiol and alfa-Mangostin present potential broad-spectrum activity against different arboviruses through a possible modulation of the interferon pathway.