A rationally designed 2C inhibitor prevents enterovirus D68-infected mice from developing paralysis
Abstract 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...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61083-8 |
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| author | Kan Li Michael J. Rudy Yanmei Hu Haozhou Tan George Lambrinidis Xiangmeng Wu Kyriakos Georgiou Bin Tan Joshua Frost Courtney Wilson Penny Clarke Antonios Kolocouris Qing-yu Zhang Kenneth L. Tyler Jun Wang |
| author_facet | Kan Li Michael J. Rudy Yanmei Hu Haozhou Tan George Lambrinidis Xiangmeng Wu Kyriakos Georgiou Bin Tan Joshua Frost Courtney Wilson Penny Clarke Antonios Kolocouris Qing-yu Zhang Kenneth L. Tyler Jun Wang |
| author_sort | Kan Li |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-15ffa79b8786459dafb1b6f80cd1ed91 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-15ffa79b8786459dafb1b6f80cd1ed912025-08-20T03:03:41ZengNature PortfolioNature Communications2041-17232025-07-0116111810.1038/s41467-025-61083-8A rationally designed 2C inhibitor prevents enterovirus D68-infected mice from developing paralysisKan Li0Michael J. Rudy1Yanmei Hu2Haozhou Tan3George Lambrinidis4Xiangmeng Wu5Kyriakos Georgiou6Bin Tan7Joshua Frost8Courtney Wilson9Penny Clarke10Antonios Kolocouris11Qing-yu Zhang12Kenneth L. Tyler13Jun Wang14Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New JerseyDepartment of Neurology, University of Colorado School of MedicineDepartment of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New JerseyDepartment of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New JerseyLaboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-ZografouDepartment of Pharmacology and Toxicology, R. Ken Coit College of Pharmacy, The University of ArizonaLaboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-ZografouDepartment of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New JerseyDepartment of Neurology, University of Colorado School of MedicineDepartment of Neurology, University of Colorado School of MedicineDepartment of Neurology, University of Colorado School of MedicineLaboratory of Medicinal Chemistry, Section of Pharmaceutical Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis-ZografouDepartment of Pharmacology and Toxicology, R. Ken Coit College of Pharmacy, The University of ArizonaDepartment of Neurology, University of Colorado School of MedicineDepartment of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New JerseyAbstract 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.https://doi.org/10.1038/s41467-025-61083-8 |
| spellingShingle | Kan Li Michael J. Rudy Yanmei Hu Haozhou Tan George Lambrinidis Xiangmeng Wu Kyriakos Georgiou Bin Tan Joshua Frost Courtney Wilson Penny Clarke Antonios Kolocouris Qing-yu Zhang Kenneth L. Tyler Jun Wang A rationally designed 2C inhibitor prevents enterovirus D68-infected mice from developing paralysis Nature Communications |
| title | A rationally designed 2C inhibitor prevents enterovirus D68-infected mice from developing paralysis |
| title_full | A rationally designed 2C inhibitor prevents enterovirus D68-infected mice from developing paralysis |
| title_fullStr | A rationally designed 2C inhibitor prevents enterovirus D68-infected mice from developing paralysis |
| title_full_unstemmed | A rationally designed 2C inhibitor prevents enterovirus D68-infected mice from developing paralysis |
| title_short | A rationally designed 2C inhibitor prevents enterovirus D68-infected mice from developing paralysis |
| title_sort | rationally designed 2c inhibitor prevents enterovirus d68 infected mice from developing paralysis |
| url | https://doi.org/10.1038/s41467-025-61083-8 |
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