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.