title: Efficacy of favipiravir (T-705) and T-1106 pyrazine derivatives in phlebovirus disease models.
abstract: Several studies have reported favipiravir (T-705) to be effective in treating a number of viral diseases modeled in rodent systems. Notably, the related pyrazine derivative, T-1106, was found to be more effective than T-705 in treating yellow fever virus infection in hamsters. Based on these findings, we hypothesized that T-1106 may be more effective in treating hepatotropic Punta Toro virus (PTV, Phlebovirus) infection in rodents. In cell culture, the inhibitory concentrations of the compounds against various phleboviruses ranged from 3 to 55microM for T-705 and from 76 to 743microM for T-1106. In PTV-challenged hamsters, a model that generally presents with high liver viral loads, T-1106 was more effective at reducing mortality. However, in mice infected with PTV, a model wherein systemic infection is more prominent, the greater efficacy exhibited by T-1106 in the hamster system was not apparent. In contrast, T-705 was superior in preventing mortality in hamsters challenged with Pichinde virus (PICV, Arenavirus), an infection characterized as diffuse and pantropic. Remarkably, T-1106 has proven more active in vivo than would have been expected from our cell culture results, and our in vivo findings suggest that it is more effective in infections characterized predominantly by high levels of hepatic viral burden.
authors.affiliation: Institute for Antiviral Research and Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT 84322-5600, USA. brian.gowen@cc.usu.edu
authors.forename: Brian B
authors.initials: BB
authors.lastname: Gowen
authors.forename: Min-Hui
authors.initials: MH
authors.lastname: Wong
authors.forename: Kie-Hoon
authors.initials: KH
authors.lastname: Jung
authors.forename: Donald F
authors.initials: DF
authors.lastname: Smee
authors.forename: John D
authors.initials: JD
authors.lastname: Morrey
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Furuta
mesh_terms: D000577:Amides / Q000627:therapeutic use*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D002044:Bunyaviridae Infections / Q000188:drug therapy*; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004195:Disease Models, Animal; D005260:Female; D008099:Liver / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009705:Nucleosides / Q000627:therapeutic use*; D011719:Pyrazines / Q000627:therapeutic use*; D044967:Serum / Q000821:virology; D016019:Survival Analysis; D016896:Treatment Outcome; D014709:Vero Cells; D019562:Viral Load
chemical_list: D000577:Amides; D000998:Antiviral Agents; D009705:Nucleosides; D011719:Pyrazines; C541936:T 1106; C462182:favipiravir