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Updated: Sep 17, 2025
A Murine Model of Dengue Virus-induced Acute Viral Encephalitis-like Disease
Published on: April 28, 2019
A rationally designed 2C inhibitor prevents enterovirus D68-infected mice from developing paralysis
Kan Li1, Michael J Rudy2, Yanmei Hu1
1Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, USA.
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.
Insights
Researchers developed Jun6504, a novel antiviral targeting Enterovirus D68 (EV-D68) 2C protein. This drug shows promise in treating EV-D68-induced paralysis in mice, offering hope for a new therapeutic option.
Area of Science:
- Virology
- Drug Discovery
- Neuroscience
Background:
- Enterovirus D68 (EV-D68) causes respiratory illness, paralysis, and death, with no existing vaccines or antivirals.
- The viral 2C protein is essential for viral replication and serves as a potential therapeutic target.
Purpose of the Study:
- To rationally design and identify inhibitors of the EV-D68 2C protein.
- To evaluate the efficacy of a novel compound, Jun6504, against EV-D68 infection and associated paralysis.
Main Methods:
- Structure-based drug design was employed to identify viral 2C inhibitors.
- Jun6504's antiviral activity was tested against multiple enterovirus strains (EV-D68, EV-A71, CVB3).
- Efficacy was assessed in a neonatal mouse model of EV-D68 infection, evaluating paralysis scores, weight gain, and viral titers.
Main Results:
- Jun6504 demonstrated potent and broad-spectrum antiviral activity against EV-D68, EV-A71, and CVB3.
- The compound exhibited favorable in vitro and in vivo pharmacokinetic properties.
- Administration of Jun6504 improved paralysis scores and weight gain in infected mice, even when delayed by 24 hours.
- Jun6504 significantly reduced viral loads in the spinal cord and muscle tissue.
Conclusions:
- Jun6504 is a promising antiviral candidate targeting the EV-D68 2C protein.
- The compound effectively ameliorates EV-D68-induced paralysis in a preclinical mouse model.
- Further development of Jun6504 as an EV-D68 therapeutic is warranted.
