Discovery of Zika Virus NS2B/NS3 Inhibitors That Prevent Mice from Life-Threatening Infection and Brain Damage

ABSTRACT: Zika virus (ZIKV) infection, which initially was endemic only in Africa and Asia, is rapidly spread-ing throughout Europe, Oceania, and the Americas. Although there have been enormous efforts, there is still no approved drug to treat ZIKV infection. Herein, we report the synthesis and biological evaluation of agents with non-competitive mechanism of the ZIKV NS2B/NS3 protease inhibition through the binding to an allo-steric site. Compounds 1 and 2 showed potent activity in both enzymatic and cellular assays. Derivative 1 effi-ciently reduced the ZIKV protein synthesis and the RNA replication, and prevented the mice from life-threatening infection and the brain damage caused by ZIKV infection in a ZIKV mouse model.