An Orally Available, Small-Molecule Polymerase Inhibitor Shows Efficacy Against a Lethal Morbillivirus Infection in a Large Animal Model
| Autor: | G. Prabhakar Reddy, Richard K. Plemper, Richard F. Arrendale, Elise S Hovingh, Veronika von Messling, Dan Yan, George R. Painter, Theresa Enkirch, Stefanie A. Krumm, Dennis C. Liotta, Manohar Saindane, Aiming Sun, Taylor J. Evers, Michael G. Natchus |
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| Rok vydání: | 2014 |
| Předmět: |
Male
viruses animal diseases Administration Oral Viremia Measles Article Virus Small Molecule Libraries Measles virus Morbillivirus Chlorocebus aethiops Drug Resistance Viral medicine Animals Enzyme Inhibitors Distemper Virus Canine Vero Cells biology Canine distemper Ferrets virus diseases DNA-Directed RNA Polymerases General Medicine medicine.disease biology.organism_classification Virology Vaccination Disease Models Animal Treatment Outcome Immunology Female Viral load Morbillivirus Infections |
| Zdroj: | Science Translational Medicine. 6 |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | Measles virus is a highly infectious morbillivirus responsible for major morbidity and mortality in unvaccinated humans. The related, zoonotic canine distemper virus (CDV) induces morbillivirus disease in ferrets with 100% lethality. We report an orally available, shelf-stable pan-morbillivirus inhibitor that targets the viral RNA polymerase. Prophylactic oral treatment of ferrets infected intranasally with a lethal CDV dose reduced viremia and prolonged survival. Ferrets infected with the same dose of virus that received post-infection treatment at the onset of viremia showed low-grade viral loads, remained asymptomatic, and recovered from infection, whereas control animals succumbed to the disease. Animals that recovered also mounted a robust immune response and were protected against rechallenge with a lethal CDV dose. Drug-resistant viral recombinants were generated and found to be attenuated and transmission-impaired compared to the genetic parent virus. These findings may pioneer a path toward an effective morbillivirus therapy that could aid measles eradication by synergizing with vaccination to close gaps in herd immunity due to vaccine refusal. |
| Databáze: | OpenAIRE |
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