Identification of a small molecule inhibitor of Ebola virus genome replication and transcription usingin silicoscreening

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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 4.8μM), exhibited low cytotoxicity (CC50>100μM) 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.HIGHLIGHTSAn EBOV drug discovery pathway which is performed at BSL2 and successfully identifies SMIs.MCCB4 is a SMI of EBOV which is effective, specific and not cytotoxic.The effect of MCCB4 was demonstrated in two cell types.MCCB4 is able to outcompete established EBOV replication complexes.SAR analysis was performed with 2nd generation compounds.

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