Systematic transcriptomic analysis enables targeted drug repurposing for neurotropic flavivirus infections

Emerging infectious diseases, and particularly mosquito-borne orthoflaviviruses such as West Nile virus (WNV) and Usutu virus (USUV), pose significant global health challenges due to their capacity for quick spread, severe neurological outcomes and lack of approved antiviral therapies. Drug repurposing offers a rapid and cost-effective strategy to accelerate therapeutic availability during outbreaks and global health emergencies. In this study, we applied transcriptomic and bioinformatic analyses to characterize host-pathogen interactions and identify molecular pathways relevant to WNV and USUV infection. This approach enabled the prioritization of approved therapeutic candidates to assess their potential antiviral activity. From the resulting data, two compounds were selected for experimental validation, paroxetine and clozapine. Among them, paroxetine, a widely used antidepressant, showed a better antiviral profile than clozapine, making it a promising candidate that deserves further consideration. Our findings highlight the value of integrating transcriptomic profiling with rational drug repurposing to expedite the identification of potential antivirals, thereby enhancing preparedness for emerging viral threats.