The Compound SBI-0090799 Inhibits Zika Virus Infection by Blocking <i>De Novo</i> Formation of the Membranous Replication Compartment
Laura Riva, Sarah Goellner, Scott B. Biering, Chun‐Teng Huang, Andrey Rubanov, Uta Haselmann, Colin M. Warnes, Paul D. De Jesus, Laura Martin‐Sancho, Alexey V. Terskikh, Eva Harris, Anthony B. Pinkerton, Ralf Bartenschlager, Sumit K. Chanda
Abstract
This study describes the elucidation of (2E)-N-benzyl-3-(4-butoxyphenyl)prop-2-enamide (SBI-0090799) as a selective and potent inhibitor of Zika virus (ZIKV) replication using a high-throughput screening approach. Mapping and resistance studies, supported by electron microscopy observations, indicate that the small molecule is functioning through inhibition of NS4A-mediated formation of ZIKV replication compartments in the endoplasmic reticulum (ER). Intriguingly, this defines a novel nonenzymatic target and chemical matter for the development of a new class of ZIKV antivirals. Moreover, chemical modulation affecting this nonstructural protein mirrors the identification and development of hepatitis C virus (HCV) NS5A inhibitor daclatasvir and its derivatives, similarly interfering with the formation of the viral replication compartment and also targeting a protein with no enzymatic activity, which have been part of a curative strategy for HCV.