Filovirus drug discovery using novel combinations of approved drugs

The goal of this proposal is to find novel combinations of approved drugs for the treatment and/or prevention of infection with filoviruses. Ebola and Marburg viruses, the only filoviruses, cause an acute hemorrhagic fever syndrome which has a high mortality rate and poses a significant bio-terrorism threat. There are currently no therapeutic agents available to treat filovirus infections and the development of such drugs is important for bio-defense. Apath has developed a novel, cell-based, infection-independent screening method that is based on replication of an Ebola virus minigenome. This proposal focuses on a strategy of combining existing drugs to discover combinations that have novel anti-filovirus activity. The Apath screening method is very amenable to identifying drug combinations that inhibit EBOV replication. This method streamlines the process of defining chemical relationships to enable the discovery of combinations of drugs that exhibit novel synergistic activity. The use of a library of approved drugs together with inhibitors discovered by Apath should facilitate the development of a therapeutic drug combination. We will characterize the most potent combinations for antiviral activity and perform preliminary medicinal chemistry and pharmacokinetic studies.