Enterovirus D68 (EV-D68) is an emerging pathogen responsible for mild to severe respiratory infections that occur mostly in infants, children and teenagers. EV-D68, one of more than 100 non-polio enteroviruses, is acid-labile and biologically similar to human rhinoviruses (HRV) (originally classified as HRV87). However, there is no approved preventive or therapeutic measure against EV-D68, HRV, or other enteroviruses. In this study, we evaluated the antiviral activity of series of dipeptidyl compounds against EV-D68 and HRV strains, and demonstrated that several peptidyl aldehyde and alpha-ketoamide peptidyl compounds are potent inhibitors of EV-D68 and HRV strains with high in-vitro therapeutic indices (>1000). One of the alpha-ketoamide compounds is shown to have favorable pharmacokinetics profiles, including a favorable oral bioavailability in rats. Recent successful development of alpha-ketoamide protease inhibitors against hepatitis C virus suggests these compounds may have a high potential for further optimization and development against emerging EV-D68, as well as HRV. (C) 2015 Elsevier B.V. All rights reserved.