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<p>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 <b>Jun11787</b> and <b>Jun11695</b> 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. <b>Jun11787</b> and <b>Jun11695</b> 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, <b>Jun11787</b> and <b>Jun11695</b> represent promising leads for treating EV-D68 infection.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月10日

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  • Kan Li,
  • Michael J. Rudy,
  • Thomas Klose,
  • Haozhou Tan,
  • Xiangmeng Wu,
  • Hiwot A. Demssie,
  • Jacqueline S. Anderson,
  • Prakash Jadhav,
  • Qing-Yu Zhang,
  • Penny Clarke,
  • Richard J. Kuhn,
  • Kenneth L. Tyler,
  • Jun Wang

摘要

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.