Marine-Derived Natural Products Against Flaviviruses: Mechanisms, Evidence, and Future Directions

Although flaviviruses, including DENV, ZIKV and JEV, remain important causes of febrile, congenital, and neurological diseases, treatment options remain largely supportive, with limited availability of virus-specific antiviral therapies. Marine organisms and marine-derived microorganisms produce chemically distinct antiviral materials, including sulfated polysaccharides, terpenoids, alkaloids, peptides, cyclodepsipeptides, and polyketides. However, their activities range from preliminary extract-level inhibition to direct biochemical target validation, making mechanistic comparison difficult. This review critically evaluates marine-derived anti-flaviviral agents using two complementary dimensions, the infection stage implicated by experimental assays and the strength of evidence supporting that assignment. DENV evidence is dominated by sulfated algal macromolecules that interfere with adsorption or internalization, whereas ZIKV studies encompass lipophilic algal metabolites, fungal alkaloids, cyclodepsipeptides, and a few target-oriented candidates. Across the field, most reports remain stage-associated rather than target-validated. Cross-study potency comparisons are constrained by differences in virus strains, cell models, assay formats, and treatment schedules. JEV-specific evidence is particularly sparse. Based on the DENV and ZIKV evidence map, we propose concise priorities for JEV-oriented discovery: early compound-level dereplication, parallel cytotoxicity testing, orthogonal confirmation of productive infection, stage-resolved assays, and biochemical or genetic validation of conserved flaviviral targets. This evidence-based framework can help distinguish promising chemical candidate scaffolds from preliminary antiviral signals and guide mechanism-informed development of marine-derived natural products against flaviviruses.