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.
Highlights
The Ebolavirus genus, alongside Cuevavirus and Marburgvirus, is classified within the Filoviridae family within the order Mononegavirales
All hit compounds showed chemical diversity in heterocycles and functional groups, of the 11 active compounds, MCCB4 was chosen for further investigation as it had typical physicochemical properties: a molecular weight of 485 daltons, a calculated logP of 4.8, and contained no hydrogen-bond donors
There are two distinct paths for potential Ebola virus (EBOV) treatments: postexposure prophylaxis and treatment of symptomatic patients. Both have different challenges but a common strategy might be to limit virus replication to allow the adaptive and innate immune systems time to fight infection (Bray and Paragas, 2002; Feldmann et al, 2005). In this regard we demonstrated that MCCB4 can inhibit EBOV replication with a single dose at the time of transfection, and was able to effectively inhibit replication when added at 24 hpt, supporting the possible use of MCCB4 as a post-exposure drug
Summary
The Ebolavirus genus, alongside Cuevavirus and Marburgvirus, is classified within the Filoviridae family within the order Mononegavirales. There are 5 species within the genus: Bundibugyo (BDBV), Reston (RESTV), Sudan (SUDV), Taï Forest (TAFV) and Zaire (previously known as ZEBOV) the type species referred to as Ebola virus (EBOV) (Amarasinghe et al, 2017; Kuhn et al, 2010). For example EBOV can exhibit disease mortality rates of up to 90% in humans (Rollin, 2009), while RESTV is not known to cause disease in humans (Miranda and Miranda, 2011). The high pathogenicity of EBOV, the ease of transmission via bodily fluids (Bausch et al, 2007), the rapid infection progression (CDC, 2014), and the current lack of licenced treatments has resulted in its classification as a Biosafety Level 4 (BSL4) pathogen, hampering development of effective therapies. Despite much research on EBOV replication and potential therapeutics there are currently no licenced treatments for infection
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