Inhibition of Zika virus replication by G-quadruplex-binding ligands

Abstract

Zika virus (ZIKV), a mosquito-transmitted Flavivirus, emerged in the last decade causing serious diseases and affecting human health globally. Currently, no licensed vaccines or antivirals are available to combat ZIKV, although several vaccine candidates are in the pipeline. In recent years, the presence of non-canonical G-quadruplex (GQ) secondary structures in viral genomes has ignited significant attention as potential targets for antiviral strategy. In this study, we identified several novel conserved potential GQ structures by analyzing published ZIKV genome sequences using an in-house algorithm. Biophysical and biochemical analysis of the RNA sequences containing these potential GQ sequences suggested the existence of such structures in the ZIKV genomes. Studies with known GQ structure-binding and -stabilizing ligands such as Braco-19 and TMPyP4 provided support for this contention. The presence of these ligands in cell culture media led to significant inhibition of infectious ZIKV yield, as well as reduced viral genome replication and viral protein production. Overall, our results, for the first time, show that ZIKV replication can be inhibited by GQ structure-binding and -stabilizing compounds and suggest a new strategy against ZIKV infection mitigation and control. © 2020G-quadruplex structures are non-canonical secondary structures present in nucleic acid. In this manuscript, we targeted the Zika GQ structures with GQ-binding ligands like Braco-19 and TMPyP4 to inhibit ZIKV genome replication and transcription. Overall, 100 μM Braco-19 treatment produced >80-fold (96 hpi) reduction in viral titer production in cell culture, having a potential anti-viral effect. © 2020