Emetine inhibits Zika and Ebola virus infections through two molecular mechanisms: inhibiting viral replication and decreasing viral entry

Hengli Tang,Chun Yao Huang ,Chen Farhy,Guo Li Ming ,Xiangguo Qiu,Billy Lu,Shihua He,Wenjun Zhu,Yi Zhou,Dushyantha Jayaweera ,Xin Hu,Wei Zheng,Guang Song,Kirill Gorshkov,Ruili Huang,Shu Yang,Yuying Wu,Adolfo Garcı́a-Sastre ,Carles Martínez-Romero,Khalida Shamim,Sergey A. Shiryaev,Wenwei Huang,Menghang Xia,Miao Xu,Zirui Zhang,Alexey V. Terskikh,Richard Alfred Preston ,Emily M. Lee ,Anil Mathew Tharappel,Yu Cheng ,Antonella Pinto,Wei Sun,Anton Simeonov,Heng Zhu,Hongjun Song

doi:10.1038/s41421-018-0034-1

Abstract

The re-emergence of Zika virus (ZIKV) and Ebola virus (EBOV) poses serious and continued threats to the global public health. Effective therapeutics for these maladies is an unmet need. Here, we show that emetine, an anti-protozoal agent, potently inhibits ZIKV and EBOV infection with a low nanomolar half maximal inhibitory concentration (IC50) in vitro and potent activity in vivo. Two mechanisms of action for emetine are identified: the inhibition of ZIKV NS5 polymerase activity and disruption of lysosomal function. Emetine also inhibits EBOV entry. Cephaeline, a desmethyl analog of emetine, which may be better tolerated in patients than emetine, exhibits a similar efficacy against both ZIKV and EBOV infections. Hence, emetine and cephaeline offer pharmaceutical therapies against both ZIKV and EBOV infection.

Highlights

Introduction The recent spread ofZika virus (ZIKV) infection to the Americas in 2015 and 2016 has quickly motivated research into ZIKV disease pathogenesis and development of therapeutic treatments[1]
We first found that emetine dose-dependently decreased non-structural protein 1 (NS1) protein level in HEK293 cells infected with the African prototype, ZIKV MR766 (IC50 = 52.9 nM; 95% confidence interval (CI) of 35.4–73.2 nM) (Fig. 1b)
To validate that the effect was not viral strain specific, we tested the effect of emetine on ZIKV NS1 protein expression in human glioblastoma SNB-19 cells infected with three different ZIKV isolates PRVABC59 (2016 Puerto Rico isolate), the previously-mentioned MR766, and the 2010 Cambodian isolate FSS13025, as measured by Western blot (Fig. 1c)

Summary

Introduction

Zika virus (ZIKV) infection to the Americas in 2015 and 2016 has quickly motivated research into ZIKV disease pathogenesis and development of therapeutic treatments[1]. We have recently employed a high-throughput assay using a pair of anti-ZIKV non-structural protein 1 (NS1) antibodies for a ZIKV drug repurposing screen[8]. An FDA-approved compound for amoebiasis, has previously demonstrated anti-viral activity against other viruses[9], but its inhibitory effects and mechanism of action in ZIKV are unknown. We investigated emetine and cephaeline in the context of ZIKV and EBOV infection to uncover their effects on both viral machinery and host cell interactions using in vitro and in vivo models

Methods

Results

Conclusion