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

• Type of Material: Article
• Authors: Stefanie A Krumm, Georgia State University; Dan Yan, Georgia State University; Elise S Hovingh, Federal Institute for Vaccines and Biomedicines; Taylor J Evers, Emory University; Theresa Enkirch, Federal Institute for Vaccines and Biomedicines; G Prabhakar Reddy, Emory University; Aiming Sun, Emory University; Manohar T Saindane, Emory University; Richard F Arrendale, Emory University; George Painter, Emory University; Dennis Liotta, Emory University; Michael George Natchus, Emory University; Veronika von Messling, Federal Institute for Vaccines and Biomedicines; Richard Karl Plemper, Emory University
• Language: English
• Date: 2014-04-16
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2014, American Association for the Advancement of Science
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.3008517
• Title of Journal or Parent Work: Science Translational Medicine
• ISSN: 1946-6234
• Volume: 6
• Issue: 232
• Start Page: 232ra52
• End Page: 232ra52
• Grant/Funding Information: 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.).; E.H. received an Erasmus Scholarship.
• Keywords: IMMUNE-RESPONSES; Medicine, Research & Experimental; GLOBAL MEASLES; Life Sciences & Biomedicine; VIRULENCE; MEASLES-VIRUS; CANINE-DISTEMPER VIRUS; STRAINS; Science & Technology; Cell Biology; ENCEPHALITIS; VACCINE; FERRETS; PATHOGENESIS; Research & Experimental Medicine
• Research Categories: Health Sciences, Pharmacology; Chemistry, General; Biology, Cell

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.