Cross-Family Mechanistic Analysis of Plant Alkaloids Against Neglected Arboviruses and Related RNA Viruses

Neglected arboviruses dengue (DENV), Zika (ZIKV), yellow fever (YFV), Japanese encephalitis (JEV), and chikungunya collectively affect hundreds of millions of people annually, yet no specific antiviral drug has been approved for any of them. Alkaloids, nitrogen-containing specialized me-tabolites produced by diverse plant families, have emerged as a promising source of broad-spectrum antiviral scaffolds. This review compiles and critically analyzes ~100 alkaloid antiviral activities across several RNA virus families, providing a comparative mechanistic analysis. Lycorine, narciclasine, emetine, and berbamine, among others, exhibit potent activity against phylogenetically distant viruses, with the most potent interactions reported against fla-viviruses (narciclasine: EC₅₀ 0.02 µM against DENV, ZIKV, YFV, and JEV; pancratistatine: 0.0063 µM against ZIKV). Structure-activity analysis of multiple alkaloid classes identifies key pharma-cophoric features, including the phenanthridone nucleus (lycorine derivatives) and the bis-benzylisoquinoline scaffold (tetrandrine, berbamine), as determinants of antiviral potency, se-lectivity, and broad-spectrum activity. Genetic resistance data and replicon experiments challenge the widely accepted model of lycorine as a nucleoside inhibitor of flaviviruses, instead indicating that the membrane-associated NS4A-2K-NS4B replication complex is the actual functional target. Converging structural, biochemical, and transcriptomic evidence suggests that ribosome-mediated translational stress may represent an additional host-directed mechanism for isoquinoline-type alkaloids, though this hypothesis requires formal validation. The present analysis highlights that in vivo validation remains limited to a few compound-virus combinations. Unbiased target de-convolution and formal testing of the ribosome/integrated stress response hypothesis stand out as essential research priorities.