A small-molecule inhibitor of deubiquitinating enzyme USP14 inhibits Dengue virus replication.

The ubiquitin-proteasome system (UPS) is a key player in maintaining cellular protein homeostasis and is associated with various human diseases, including neurodegenerative disorders, cancer, and infectious diseases. Viruses from several families reprogram the UPS to make the cellular environment conducive to viral replication, and inhibition of the UPS interferes with viral propagation. Here we show that IU1, a small-molecule inhibitor of the proteasome-associated deubiquitinating enzyme USP14, inhibits replication of several flaviviruses. IU1 has been shown to enhance proteasome activity, an effect that may underlie its influence on flavivirus propagation. Inhibition of dengue virus replication was more pronounced than other flaviviruses used in the study. These results open new targets for therapeutic intervention against viruses from multiple families.