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Author Notes:

Richard K Plemper: rplemper@gsu.edu

S.A.K., D.Y., E.H. and T.E. performed the experiments; A.S. and M.T.S. performed chemical synthesis; T.J.E., G.P.R. and R.F.A. performed mass-spectrometry and pharmacokinetic analyses; G.P., D.C.L., M.G.N., V.v.M. and R.K.P. provided study design; V.v.M. and R.K.P. supervised the experiments and analyzed data; R.K.P. coordinated the project and wrote the manuscript.

We thank P.A.Rota for providing MeV typing strains from the collection of the CDC; M.L.Moore for RSV replicon plasmids; Y.Yanagi for Vero-hSLAM and Vero-cSLAM cell lines; and M.L.Moore and A.L.Hammond for comments on the manuscript.

A.S. and R.K.P. are inventors on patent application PCT/US2012/030866, which includes the structure and method of use of ERDRP-0519.

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Research Funding:

E.H. received an Erasmus Scholarship.

This work was supported by a Duke-NUS Signature Research Program start-up grant by the Agency for Science, Technology and Research, Ministry of Health, Singapore; funding from the German Ministry of Health (to V.v.M.); and by Public Health Service grants AI071002 and AI057157 from the NIH/NIAID (to R.K.P.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • CANINE-DISTEMPER VIRUS
  • MEASLES-VIRUS
  • IMMUNE-RESPONSES
  • GLOBAL MEASLES
  • VACCINE
  • VIRULENCE
  • FERRETS
  • ENCEPHALITIS
  • PATHOGENESIS
  • STRAINS

An Orally Available, Small-Molecule Polymerase Inhibitor Shows Efficacy Against a Lethal Morbillivirus Infection in a Large Animal Model

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Journal Title:

Science Translational Medicine

Volume:

Volume 6, Number 232

Publisher:

, Pages 232ra52-232ra52

Type of Work:

Article | Post-print: After Peer Review

Abstract:

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 effectivemorbillivirus therapy that could aid measles eradication by synergizing with vaccination to close gaps in herd immunity due to vaccine refusal.

Copyright information:

Copyright © 2014, American Association for the Advancement of Science

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