Rational design and in vivo validation of capsid inhibitors for enterovirus D68

Enterovirus D68 (EV-D68) is a respiratory virus that causes neurological complications such as acute flaccid myelitis (AFM) and death in children. No vaccine or antiviral is available for EV-D68. We report the structure-based design of the EV-D68 VP1 capsid inhibitors with in vivo antiviral efficacy in a neonatal mouse model of EV-D68-associated paralytic myelitis. Cryo-EM structures show that Jun11787 and Jun11695 bind the hydrophobic canyon region in VP1 and display nanomolar potency against multiple EV-D68 strains and single-digit micromolar potency against EV-A71 and CVB3 in vitro. Jun11787 and Jun11695 also significantly reduce the spinal cord viral titer, prevent the progression of paralysis, and improve weight gain in EV-D68-infected male and female mice when treatment is initiated immediately, 24 h, and even 4–6 days post-infection. Overall, Jun11787 and Jun11695 represent promising leads for treating EV-D68 infection. In this study, the authors designed potent Enterovirus D68 capsid inhibitors that block viral binding and show that the lead compounds reduce virus levels, prevent paralysis and improve survival in EV-D68-challenged mice, even when treatment starts days after infection.