Development of small molecule inhibitors of Ebola virus genome replication (360G-Wellcome-109713_Z_15_Z)

Development of small molecule inhibitors of Ebola virus genome replicationThis Pathfinder project will address infection with Ebola virus (EBOV), which has a human mortality rate of over 50%. EBOV is a member of the Filoviridae family (genus Ebolavirus), a negative strand RNA virus that is highly transmissible and causes severe haemorrhagic fever. The recent outbreak of EBOV in West Africa has highlighted the lack of effective therapeutic options for the treatment of this infection. Efficacious small molecule inhibitors of the virus are therefore needed for the rapid treatment of EBOV infected individuals, but their development has been hampered by the requirement to propagate EBOV under Biological Safety Level 4 (BSL4) containment.The project team, led by Professor Mark Harris at University of Leeds, propose to use a combination of in silico drug design and a mini-genome system, which accurately and faithfully recapitulates the essential processes of EBOV gene transcription and genome replication under BSL2 conditions. The team will design small molecule inhibitors based on known high-resolution structures of EBOV proteins involved in these processes, in particular focussing on the essential nucleocapsid protein. This approach builds on existing strengths at the University of Leeds, combining an innovative approach to in silico drug design with extensive experience in both virology and structural biology. The project aims to deliver drug-like lead compounds that can be further developed into therapeutic agents.