Dr. James Cunningham has over 20 years of experience in the identification of viral receptors and mechanisms by which enveloped virus proteins mediate fusion. His recent work on ebolavirus uncovered two essential host factors that function at the entry stages of the replication cycle. This work reveals a two-step mechanism of infection in which the virus glycoprotein is cleaved by the endosomal protease cathepsin B to remove a heavily glycosylated surface domain and expose an internal domain that is the ligand for the lysosome cholesterol transporter Niemann-Pick C1 (NPC1). In this regard, the sequential actions of cathepsin B and NPC1 in ebolavirus infection are analogous to the function of CD4 and CCR5 in HIV infection. Importantly, Dr. Cunningham identified novel small molecules that target NPC1 and block ebolavirus binding and infection. Currently, Dr. Cunningham and his colleagues are investigating the mechanism of action of novel small molecules they have identified that inhibit additional steps in ebolavirus replication.