A rationally designed 2C inhibitor prevents enterovirus D68-infected mice from developing paralysis

作者：Kan Li, Michael J. Rudy, Yanmei Hu, Haozhou Tan, George Lambrinidis, Xiangmeng Wu, Kyriakos Georgiou, Bin Tan, Joshua Frost, Courtney J. Wilson, Penny Clarke, Antonios Kolocouris, Qingyu Zhang, Kenneth L. Tyler, Jun Wang · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-61083-8 · 被引用次数：9 · 研究领域：Viral Infections and Immunology Research、RNA and protein synthesis mechanisms、Viral gastroenteritis research and epidemiology

Enterovirus D68 (EV-D68) is a respiratory virus that often causes mild to moderate respiratory illnesses and, in severe cases, can lead to paralysis and rarely death, mainly in children. There is currently no vaccine or antiviral for EV-D68. Here, we report the rational design of viral 2 C inhibitors for treating EV-D68 infection-induced paralysis in a neonatal mouse model. Viral 2 C protein is a multi-functional protein vital for viral replication. Structure-based drug design identifies Jun6504 showing potent and broad-spectrum antiviral activity against multiple strains of EV-D68, EV-A71, and CVB3, as well as favorable in vitro and in vivo pharmacokinetic properties. In a neonatal mouse model of EV-D68 infection, Jun6504 significantly improves paralysis score and weight gain when administered immediately or 24 hours post-infection. Jun6504 also reduces viral titers in the spinal cord and the infected quadriceps muscle. Collectively, Jun6504 represents a promising candidate for further development as an EV-D68 antiviral. There are no vaccines or antivirals available against enterovirus D68. Here, the authors report Jun6504 as a 2C inhibitor and show that it provides broad-spectrum antiviral activity against EV-D68, EV-A71, and CVB3 and potent antiviral efficacy in a neonatal neurological mouse model of EV-D68 infection.