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. 2026 Feb 10.
doi: 10.1038/s41467-026-69351-x. Online ahead of print.

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

Kan Li #  1 , Michael J Rudy #  2 , Thomas Klose #  3 , Haozhou Tan  1 , Xiangmeng Wu  4 , Hiwot A Demssie  1 , Jacqueline S Anderson  3 , Prakash Jadhav  1 , Qing-Yu Zhang  4 , Penny Clarke  2 , Richard J Kuhn  5   6 , Kenneth L Tyler  7   8   9   10 , Jun Wang  11
Affiliations
Free article

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

Kan Li et al. Nat Commun. .
Free article

Abstract

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.

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Conflict of interest statement

Competing interests: Rutgers, the State University of New Jersey, has applied for a provisional patent that covers the VP1 inhibitors reported in this manuscript and related compounds. The inventors include K.L. and J.W. The remaining authors declare that they have no competing interests.

References

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