Identification of a small molecule inhibitor of Ebola virus genome replication and transcription using in silico screening

Antiviral Res. 2018 Aug:156:46-54. doi: 10.1016/j.antiviral.2018.06.003. Epub 2018 Jun 2.

Abstract

Ebola virus (EBOV) causes a severe haemorrhagic fever in humans and has a mortality rate over 50%. With no licensed drug treatments available, EBOV poses a significant threat. Investigations into possible therapeutics have been severely hampered by the classification of EBOV as a BSL4 pathogen. Here, we describe a drug discovery pathway combining in silico screening of compounds predicted to bind to a hydrophobic pocket on the nucleoprotein (NP); with a robust and rapid EBOV minigenome assay for inhibitor validation at BSL2. One compound (MCCB4) was efficacious (EC50 4.8 μM), exhibited low cytotoxicity (CC50 > 100 μM) and was specific, with no effect on either a T7 RNA polymerase driven firefly luciferase or a Bunyamwera virus minigenome. Further investigations revealed that this small molecule inhibitor was able to outcompete established replication complexes, an essential aspect for a potential EBOV treatment.

Keywords: Drug discovery; Ebola virus (EBOV); Minigenome; Nucleoprotein (NP); Small molecule inhibitors (SMIs).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / isolation & purification*
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / toxicity
  • Cell Line
  • Drug Evaluation, Preclinical / methods
  • Ebolavirus / genetics*
  • Ebolavirus / physiology
  • Molecular Dynamics Simulation
  • Nucleoproteins / metabolism
  • Protein Binding
  • Transcription, Genetic / drug effects*
  • Viral Proteins / metabolism
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Nucleoproteins
  • Viral Proteins