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

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

doi:10.1038/s41467-026-69351-x

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

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

Authors

Kan Li^#¹, Michael J Rudy^#², Thomas Klose^#³, Haozhou Tan¹, Xiangmeng Wu⁴, Hiwot A Demssie¹, Jacqueline S Anderson³, Prakash Jadhav¹, Qing-Yu Zhang⁴, Penny Clarke², Richard J Kuhn^{5

6}, Kenneth L Tyler^{7

8

9

10}, Jun Wang¹¹

Affiliations

¹ Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
² Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA.
³ Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
⁴ Department of Pharmacology and Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA.
⁵ Department of Biological Sciences, Purdue University, West Lafayette, IN, USA. kuhnr@purdue.edu.
⁶ Purdue Institute of Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, IN, USA. kuhnr@purdue.edu.
⁷ Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA. ken.tyler@cuanschutz.edu.
⁸ Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. ken.tyler@cuanschutz.edu.
⁹ Division of Infectious Disease, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA. ken.tyler@cuanschutz.edu.
¹⁰ Neurology Service, Rocky Mountain VA Medical Center, Aurora, CO, USA. ken.tyler@cuanschutz.edu.
¹¹ Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA. junwang@pharmacy.rutgers.edu.

^# Contributed equally.

PMID: 41667472
DOI: 10.1038/s41467-026-69351-x

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.

Abstract

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