Inhibition of in vitro Ebola infection by anti-parasitic quinoline derivatives.

Shawn Goyal,Beth Binnington,Philippe M Loiseau,Didier Desmaële,Donald R Branch,Laurent Férrié,Bruno Figadère,Stephen D.S Mccarthy

doi:10.12688/f1000research.22352.1

Abstract

There continues to be no approved drugs for the treatment of Ebola virus disease (EVD). Despite a number of candidate drugs showing limited efficacy in vitro and/or in non-human primate studies, EVD continues to plaque certain areas of Africa without any efficacious treatments yet available. Recently, we have been exploring the potential for anti-malarial drugs to inhibit an in vitro model of Ebola Zaire replication using a transcription-competent virus-like particle (trVLP) assay. We examined the efficacy of chloroquine, amodiaquine and 36 novel anti-parasite quinoline derivatives at inhibiting Ebola virus replication. Drug efficacy was tested by trVLP assay and toxicity by MTT assay. Both chloroquine and amodiaquine were effective for inhibition of Ebola virus replication without significant toxicity. The half-maximal inhibitory concentration (IC 50) of chloroquine and amodiaquine to inhibit Ebola virus replication were IC 50, Chl = 3.95 µM and IC 50, Amo = 1.45 µM, respectively. Additionally, three novel quinoline derivatives were identified as having inhibitory activity and low toxicity for Ebola trVLP replication, with 2NH2Q being the most promising derivative, with an IC 50 of 4.66 µM. Quinoline compounds offer many advantages for disease treatment in tropical climates as they are cheap to produce, easy to synthesize and chemically stable. In this report, we have demonstrated the potential of anti-parasite quinolines for further investigation for use in EVD.

Highlights

Since its discovery in 1976, Ebola virus has been responsible for numerous outbreaks, with case fatalities varying from 20% to 90%1,2
TrVLP infection To evaluate the efficacy of quinoline compounds of possible inhibition of Ebola virus, a replication competent mini-genome system developed by Hoenen et al.[27] was adopted
To assess the ability of quinolines to inhibit Ebola virus infection, we employed an established mini-genome model of Ebola replication, transcription-competent virus-like particle (trVLP), allowing us to work under biosafety containment level 2 (CL 2) conditions[27,28,29,30,31]

Summary

Introduction

Since its discovery in 1976, Ebola virus has been responsible for numerous outbreaks, with case fatalities varying from 20% to 90%1,2. A vaccine for Ebola virus (rVSV-EBOV) has been developed by the National Microbiological Laboratory in Winnipeg, Manitoba, Canada, and has been shown to be highly protective[4]. The rVSV-EBOV vaccine is to be a powerful defense against future Ebola outbreaks. The unstable political environment of many affected African countries further complicates the effective administration of vaccines; as seen in the Democratic Republic of Congo during the current Ebola outbreak[2,7]. These factors emphasize the need for acute infection therapies

Methods

Results

Conclusion