Potent broad-spectrum antiviral activity of the marine natural product Plitidepsin

Viruses pose a critical global health threat, yet therapeutic options remain limited. Finding drugs with broad-spectrum antiviral activity is essential to confront this threat. Here, we investigated whether plitidepsin, a marine-derived anticancer drug targeting the host eukaryotic elongation factor 1A (eEF1A), has such broad-spectrum activity. Using in vitro infection models and complementary assays (MTT, plaque-forming assays, RT-qPCR, Western blot, flow cytometry), we demonstrated that plitidepsin exhibits potent dose-dependent antiviral activity against Mayaro virus (MAYV) and Chikungunya virus (CHIKV). The compound achieved 4-6 log10 reduction in viral titers at nanomolar concentrations across multiple cell lines and viral strains. Plitidepsin protected human dermal fibroblasts from viral cytopathic effects and disrupted both entry and post-entry replication stages by suppressing viral protein expression (E1, nsP1) and RNA synthesis. The compound also demonstrated antiviral activity against other medically important arboviruses, including Una, Punta Toro, Zika, and Oropouche viruses, as well as RNA and DNA viruses such as influenza A virus, vesicular stomatitis virus, and human cytomegalovirus. These findings establish plitidepsin as a potent host-directed antiviral agent with reduced likelihood of resistance development and therapeutic potential against multiple viral families.