Marine-derived ascofuranone as a novel inhibitor of Zika virus with therapeutic potential.

The Zika virus (ZIKV), a mosquito-borne Flaviviridae Orthoflavivirus, poses global health risks through its association with severe congenital and neurological complications. Despite urgent needs, no approved therapies or vaccines exist against ZIKV infection. This therapeutic gap has accelerated drug discovery efforts, where marine-derived compounds show particular promise. Their structural uniqueness and antiviral potential position marine ecosystems as vital sources for novel anti-ZIKV agents. In this study, a natural product of marine fungi, ascofuranone (ASC) demonstrated prominent antiviral activity, and its efficacy against ZIKV infection was validated in three ZIKV-susceptible cell culture models using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), plaque assays, and western blotting analysis. Furthermore, cell immunofluorescence revealed that ASC protects host cells from ZIKV infection. Subsequent targeted virtual docking predictions identified the RNA-dependent RNA polymerase (RdRp) as its putative molecular target. Based on Surface Plasmon Resonance (SPR) analysis and ZIKV Gaussia luciferase (Gluc) reporter system, ASC showed strong binding affinity to ZIKV RdRp and effectively suppressed its RNA synthesis. In addition, qRT-PCR demonstrated significant downregulation of pro-inflammatory cytokines, indicating ASC's anti-inflammatory potential. In conclusion, the marine-derived compound ASC exhibits anti-ZIKV activity, offering a potential candidate for antiviral drug development.