Antiviral mechanisms of sorafenib against foot-and-mouth disease virus via c-RAF and AKT/PI3K pathways

Foot-and- mouth disease virus (FMDV) is a highly contagious pathogen that poses a significant threat to the global livestock industry. However, specific antiviral treatments against FMDV are currently unavailable. This study aimed to evaluate the antiviral activity of anticancer drugs, including kinase and non-kinase inhibitors against FMDV replication in BHK-21 cells. Sorafenib, a multi-kinase inhibitor, demonstrated a significant dose-dependent reduction in FMDV replication. It exhibited a half maximal effective concentration (EC50) value of 2.46 mu M at the pre-viral entry stage and 2.03 mu M at the post-viral entry stage. Further intracellular assays revealed that sorafenib effectively decreased 3D(pol) activity with a half maximal inhibitory concentration (IC50) of 155 nM, while not affecting 3C(pro) function. The study indicates that sorafenib influences host protein pathways during FMDV infection, primarily by potentiating the c-RAF canonical pathway and AKT/PI3K pathway. Molecular docking analysis demonstrated specific binding of sorafenib to the active site of FMDV 3D(pol), interacting with crucial catalytic residues, including D245, D338, S298, and N307. Additionally, sorafenib exhibited significant binding affinity to the active site motifs of cellular kinases, namely c-RAF, AKT, and PI3K, which play critical roles in the viral life cycle. The findings suggest that sorafenib holds promise as a therapeutic agent against FMDV infection. Its mechanism of action may involve inhibiting FMDV replication by reducing 3D(pol) activity and regulating cellular kinases. This study provides insights for the development of novel therapeutic strategies to combat FMDV infections.