Unique Domain for a Unique Target: Selective Inhibitors of Host Cell DDX3X to Fight Emerging Viruses

Abstract

Emerging viruses like Dengue, West Nile, Chikungunya and Zika can cause widespread viral epidemics. Developing novel drugs or vaccines against specific targets for each virus is a difficult task. As obligate parasites, all viruses exploit common cellular pathways opening the possibility to develop broad-spectrum antiviral agents targeting host factors. The human DEAD-box RNA helicase DDX3X is an essential cofactor for viral replication but dispensable for cell via-bility. Herein, we exploited the presence of a unique structural motif of DDX3X not shared by other cellular enzymes to develop a theoretical model to aid in the design of a novel class of highly selective inhibitors acting against such specific target, thus limiting off-targeting effects. High throughput virtual screening led us to identify hit compound 5, endowed of promising anti-enzymatic activity. To improve its aqueous solubility, 5 and its two enantiomers were synthesized and converted into their corresponding acetate salts (compounds 11, 12 and 13) . In vitro mutagenesis and biochemical and cellular assays further confirmed that the developed molecules were selective for DDX3X and were able to suppress replication of West Nile and Dengue viruses in infected cells in micromolar range while showing no toxicity for uninfected cells. These results provide proof-of-principle for a novel strategy in developing highly selec-tive and broad-spectrum antiviral molecules active against emerging and dangerous viral pathogens. This study paves the way for the development of larger focused libraries targeting such domain, in order to expand SAR studies and fully characterize their mode of interaction.