Case Study Layout

Using Ligand Express™ to understand an anti-viral’s mechanism-of-action

Using Ligand Express™ to understand an anti-viral’s mechanism-of-action

PROBLEM

Phenotypic screens rapidly identify drug candidates, but provide insufficient data on the underlying mechanism-of-action to support validation studies and drug development 

TECHNOLOGY

Ligand Express™ tools:
PROBEX Proteome Docking

SOLUTION

Sertraline, which exhibited anti-Ebola activity, was examined using PROBEX proteome-wide screening to uncover the protein targets responsible for its anti-viral activity

Introduction

Ebola virus disease is a severe, often fatal, illness in humans caused by the pathogen Ebolavirus, a genus in the family Filoviridae1. It is highly contagious and presents as a hemorrhagic fever that is fatal in 50% of cases1. The most recent global outbreak of Ebola began December 2013 and ended two and half years later in June 2016. e outbreak, which spread from West Africa and into the developing world, highlighted the need for an approved treatment for the deadly virus. Several laboratories, including the U.S. Army Medical Research Institute of Infectious Diseases, investigated small molecule, FDA-approved drugs for their ability to attenuate Ebola virulence to quickly bridge this therapeutic gap. A preliminary in vitro fluorescence-based screening assay, using engineered Ebola virus expressing green uorescent protein (GFP), rapidly identied potential anti-viral agents. An Ebola virus-like particle (VLP) host-entry assay was used in conjuction with the GFP experiments. Candidates capable of impeding viral protein expression were identied in the GFP imaging assay, including the anti-depressant sertraline (Zoloft®), a selective serotonin reuptake inhibitor (Figure 1)2.  Sertraline also prevented VLP entry in a follow-up assay2. While results were promising, sertraline’s underlying target(s)-of-action could not be elucidated solely from these preliminary phenotypic experiments nor from deep learning approaches.

METHODOLOGY

RESULTS

SUMMARY

RESOURCES

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