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bioRxiv · 10.1101/2025.05.10.653272

Promising Inhibitor of Flavivirus: Evaluating the Antiviral Activity of Nordihydroguaiaretic Acid against West Nile Virus Replication

Martinez, F.·Ghietto, L. M.·Lingua, G.·Aguilar, J. J.·Gil, P. I.·Gomez, T. I.·Marioni, J.·Nunez-Montoya, S. C.·Konigheim, B.
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Abstract

Mosquito-borne Arboviruses, including Alphaviruses and Flaviviruses, are responsible for millions of human infections worldwide. The absence of specific antivirals for arbovirus infections underscores the urgent need for novel research to develop effective treatments. Natural products have emerged as promising candidates. Nordihydroguaiaretic acid (NDGA), a natural lignan predominantly found in Larrea spp., has shown antiviral activity against several viruses, including Dengue. This study aimed to investigate the antiviral potential of NDGA against West Nile virus (WNV), assessing its mechanism of action and cellular interactions. Using plaque-forming unit reduction and immunofluorescence assays in LLC-MK2 cells, we determine the reduction in viability of WNV viral particles at different times post-infection. The potential involvement of the sterol regulatory element-binding proteins (SREBP) and 5-lipoxygenase pathways in WNV infection was evaluated. Additionally, we analyzed the cytoskeleton integrity in treated cells. NDGA, had the greatest inhibitory effect on WNV replication when added 1 and 2 h post-viral internalization (PI), losing activity when added after 3 h PI, thus suggesting it targets early viral infection events. The SREBP pathway seems to be involved in the inhibition of WNV by NDGA, likely due to its lipogenic activity. Furthermore, the antiviral activity of NDGA could be related to its ability to modify the cytoskeleton of LLC-MK2 cells. These findings highlight NDGA potential as a therapeutic candidate against WNV and other flaviviruses. Plant metabolites are among the leading therapeutic resources globally. Further research is necessary to comprehensively assess the therapeutic promise of NDGA. ImportanceMosquito-borne arboviruses pose significant global health threats due to their widespread distribution and the absence of specific antiviral treatments. The emergence of virulent strains and recurrent outbreaks underscore the urgent need for novel antiviral agents. Nordihydroguaiaretic acid, a natural phenolic compound, has shown promising antiviral activity against flaviviruses such as West Nile virus. Understanding nordihydroguaiaretic acids mechanism of action not only reveals potential therapeutic strategies but also highlights the broader importance of plant-derived compounds in combating viral infections. Our research focuses on further elucidating nordihydroguaiaretic acids antiviral effects against West Nile virus, aiming to contribute to the development of effective therapies. Continued investigation of nordihydroguaiaretic acids therapeutic potential is essential for advancing antiviral drug discovery and addressing the persistent challenges posed by mosquito-borne diseases worldwide.

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Martinez, F., Ghietto, L. M., Lingua, G., Aguilar, J. J., Gil, P. I., Gomez, T. I., Marioni, J., Nunez-Montoya, S. C., Konigheim, B.. 2025-05-12. Promising Inhibitor of Flavivirus: Evaluating the Antiviral Activity of Nordihydroguaiaretic Acid against West Nile Virus Replication. https://doi.org/10.1101/2025.05.10.653272

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