DDX3X helicase inhibitors as new strategy to fight West Nile Virus infection.

Increased frequency of arbovirus outbreaks in the last ten years represents an important emergence for global health. Climate warming, extensive urbanization of tropical regions and human migrations flows facilitate the expansion of anthropophilic mosquitos and the emerging or re-emerging of new viral infections. Only recently the human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against infectious diseases. Herein, starting from our previous studies a new family of DDX3X inhibitors was designed, synthesized, validated on the target enzyme and evaluated against West Nile Virus (WNV) infection. Time of addition experiments after virus infection indicated that the compounds exerted their antiviral activities after the entry process, likely at the protein translation step of WNV replication. Finally, the most interesting compounds were then analyzed for their in vitro pharmacokinetic parameters, revealing favorable ADME values. The good safety profile together with a good activity against WNV for which no treatments are currently available, make this new class of molecules a good starting point for further in vivo studies.