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 metabolites produced by diverse plant families, have emerged as a promising source of broad-spectrum antiviral scaffolds. This review compiles and critically analyzes over 100 alkaloid-virus pairs 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 activities reported against flaviviruses (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 pharmacophoric features, including the phenanthridine nucleus (lycorine derivatives) and the bis-benzylisoquinoline scaffold (tetrandrine, berbamine), as determinants of antiviral potency, selectivity, and broad-spectrum activity. Genetic resistance data in West Nile virus challenge the widely accepted model of lycorine as a direct nucleoside inhibitor, instead pointing toward the involvement of the membrane-associated NS4A-2K-NS4B replication complex, though direct validation remains limited for other flaviviruses. Converging structural, biochemical, and transcriptomic evidence suggests that ribosome-mediated translational stress may represent an additional host-directed antiviral mechanism for isoquinoline-type alkaloids, though the causal chain from ribosome binding to activation of the integrated stress response and to antiviral effect has not been established. The present analysis highlights that in vivo validation remains limited to a few alkaloid-virus pairs. Unbiased target deconvolution and formal testing of the ribosome/integrated stress response hypothesis stand out as essential research priorities.