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

作者：Krumm Stefanie A; Yan Dan; Hovingh Elise S; Evers Taylor J; Enkirch Theresa; Reddy G Prabhakar; Sun Aiming; Saindane Manohar T; Arrendale Richard F; Painter George; Liotta Dennis C; Natchus Michael G; von Messling Veronika; Plemper Richard K^*

来源：Science Translational Medicine, 2014, 6(232): 232ra52.

DOI：10.1126/scitranslmed.3008517

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.

• 出版日期2014-4-16