Investigating AAK1-and GAK-Regulated Virus-Host Interactions Uncovers Broad-Spectrum Antivirals

Abstract : Global health is threatened by emerging viral infections, which largely lack effective vaccines or therapies. Targeting host pathways exploited by multiple viruses could offer broad-spectrum solutions. We previously reported that AAK1 and GAK, kinase regulators of the host adaptor proteins, AP1 and AP2, are essential for hepatitis C virus (HCV) infection, but the underlying mechanism and relevance to other viruses or in vivo infections remained unknown. Here, we discovered that AP1 and AP2 co-traffic with HCV particles in live cells. Moreover, we found that AAK1 and GAK are exploited during entry and infectious virus production of multiple viruses, including dengue and Ebola. Treatment with sunitinib and erlotinib, approved anticancer drugs with anti-AAK1 or GAK activity, or novel, more selective compounds inhibited intracellular HCV trafficking and multiple unrelated RNA viruses in culture with a high barrier to resistance.