Inhibition of ZIKA virus replication by novel inhibitors of NS2B/NS3 complex

Zika virus (ZIKV) is an RNA virus of the Flaviviridae family, which is responsible for a condition known as Zika fever. While initially, the infection was endemic only in Africa and Asia, now it is spread all over the world. ZIKV is a viral ailment transmitted by Aedes mosquitoes, mainly located in the equatorial zone. The symptoms are generally mild. Nevertheless, during pregnancy this infection can cause the birth of infants with microcephaly or other inborn malformation. The NS2B / NS3 viral protease complex is implicated in virus replication and immune system escape, so that there is growing interest in the design of new ZIKV inhibitors with this target. Preliminary studies with molecular models provided insights into the molecular determinants responsible for its high affinity toward the target enzyme. On these bases, we have designed and synthesized 14 new potential allosteric inhibitors of the NS2B / NS3 complex, characterized by an indole with a benzyl or benzoyl group in position 3 [1]. Two of these new compounds, showed strong activity in both enzymatic and cellular assays. As a proof of concept, the most promising compound was evaluated in a mouse animal model. (Figure 1). Not only the compound has significantly reduced NS2B / NS3 synthesis and viral replication, but also it prevented the mice from a life-threatening infection showing a powerful reduction of the brain damages produced by the viral infection. These results pave the way to new ZIKV drug candidates able to cross the blood-brain barrier to reach the neural cells. References [1] A. Coluccia et al. ACS Med. Chem. Lett. 2020, 11, 10, 1869–1874.