AAK1 and GAK inhibitors demonstrate activity against Filoviruses

Ebola virus (EBOV) and Marburg virus (MARV) are highly pathogenic members of the family filoviridae . The recent West Africa epidemic of Ebola virus disease was a grave reminder of the unmet need for post exposure therapeutics to combat filovirus infection. Our group has reported that multiple unrelated viruses, including EBOV, commandeer host kinases AP2-associated protein kinase-1 (AAK1) and cyclin G-associated kinase (GAK) during viral entry, assembly, and/or egress. This shared attribute makes AAK1 and GAK desirable broad-spectrum targets for the treatment of multiple viral infections without necessitating species identification. As the targets of these inhibitors are host cell factors, this may allow for the reduction in the likelihood that the virus will develop drug resistance. We have demonstrated that treatment with sunitinib and erlotinib, approved anticancer drugs with anti-AAK1 or GAK activity, is effective in inhibiting replication of Ebola, Hepatitis C and Dengue (DENV) viruses in vitro. Additionally, the combination of sunitinib and erlotinib has demonstrated efficacy in reducing morbidity and mortality following challenge with EBOV and DENV in the relevant mouse models. In an effort to improve toxicity and survival, we are developing novel, chemically distinct, more selective inhibitors of AAK1 and GAK. Here we describe the capability of these next generation AAK1 and GAK inhibitors to reduce in vitro infection of Ebola virus and Marburg virus.