Sertraline and Astemizole Enhance the Deubiquitinase Activity of USP7 by Binding to Its Switching Loop Region.

The heterozygous loss-of-function mutations of USP7 lead to the occurrence of Hao-Fountain syndrome, and chemical activators targeting USP7 could potentially serve as a treatment option for the disease. Here, in this study, two drugs Sertraline and Astemizole were identified to act as the agonists of USP7 by binding to its switching loop region. Moreover, although two compounds and USP7's self-activation C-terminal peptide (CTP) share the same binding pocket in the enzyme, joint activation toward full-length USP7 was observed for sertraline/astemizole and the CTP. According to the published data and our results, we propose that two chemical activators activate USP7 through interacting with those USP7 molecules with the binding pocket unoccupied by the CTP and thus promote their transition to active conformation. Finally, as anticipated, Sertraline and Astemizole were demonstrated to enhance the enzymatic activities of USP7 pathogenic mutants, and this observation sheds a light on the treatment against Hao-Fountain syndrome.