The emergence and re-emergence of flaviviruses such as Zika virus (ZIKV), dengue virus (DENV), and yellow fever virus (YFV) continue to threaten global health, particularly in endemic regions like Brazil. With no licensed antiviral therapies available for these infections, the search for effective treatments remains a priority. This study evaluates the antiviral potential of trametinib, a clinically approved MEK inhibitor, against Brazilian strains of ZIKV, DENV2, DENV3, and the YFV 17DD vaccine strain in human cell lines. Trametinib was selected due to its established safety profile in oncology patients and its ability to inhibit the MEK/ERK signaling pathway—a host cascade hijacked by multiple viruses during replication.
Cytotoxicity assays were conducted in both BHK-21 and Vero cells using crystal violet staining after 24- and 48-hour exposures. Results revealed that trametinib exhibited minimal toxicity at concentrations up to 20 µM in Vero cells, with a CC50 exceeding 170 µM, indicating a high therapeutic window.59-05-2 Formula In contrast, bosutinib showed significant cytotoxicity even at low doses, limiting its utility. Antiviral efficacy was assessed via plaque assay following infection with ZIKV PE-243 (MOI 0.1), DENV2 PI59, DENV3 MG20, or YFV 17DD. Cells were treated with increasing concentrations of trametinib (5–40 µM) for 24 hours post-infection. Notably, trametinib reduced viral titers by over 1,000-fold for ZIKV and nearly 100-fold for DENV2, DENV3, and YFV at optimal concentrations. These effects were dose-dependent and statistically significant (p < 0.001). Importantly, trametinib also demonstrated activity against the ZIKV African MR766 strain, reducing viral titers by 10-fold, confirming its broad-spectrum potential.HOXD10 Antibody Description No direct virucidal activity was observed when viruses were pre-incubated with trametinib, suggesting that the compound acts intracellularly by disrupting viral replication processes rather than destroying viral particles. The EC50 values for ZIKV, DENV2, DENV3, and YFV were consistently low—ranging from 2.46 to 6.33 µM—while the SI values exceeded 50, highlighting a favorable balance between potency and safety. Compared to other inhibitors tested—including selumetinib, saracatinib, and bosutinib—trametinib displayed superior efficacy and tolerability.PMID:34687746
Mechanistically, this antiviral effect is likely linked to the inhibition of ERK phosphorylation, which plays a crucial role in regulating cellular processes essential for flavivirus propagation, including viral RNA synthesis, protein translation, and assembly. Previous studies have shown that MEK/ERK activation is induced by DENV and YFV infection, and its blockade impairs viral yield in both cell culture and animal models. Trametinib’s ability to disrupt these pathways may explain its pan-antiviral activity. Furthermore, prior reports indicate that trametinib reduces HIV infectivity by interfering with capsid uncoating and inhibits influenza virus spread by blocking nuclear export of viral ribonucleoproteins—mechanisms consistent with disruption of ERK-dependent trafficking.
Given that trametinib is already FDA-approved for BRAF-mutated melanoma, its repurposing for flavivirus treatment could be expedited through clinical trials. Its strong performance across multiple flaviviruses, combined with an excellent safety margin, positions it as a leading candidate for broad-spectrum antiviral therapy. Future research should focus on validating these findings in primary human cells and in vivo models, as well as exploring combination therapies to enhance antiviral efficacy and prevent resistance. This work underscores the value of targeting host factors in antiviral drug development and provides compelling evidence for trametinib’s potential as a frontline therapeutic against emerging and re-emerging flaviviral diseases.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com