title: Activities of JNJ63623872 and oseltamivir against influenza A H1N1pdm and H3N2 virus infections in mice.
abstract: JNJ63623872 (formerly known as VX-787) is an inhibitor of influenza A virus polymerases through interaction with the viral PB2 subunit. This interaction blocks the cap-snatching activity of the virus that is essential for virus replication. Previously published work has documented antiviral activity of JNJ63623872 in cell culture and mouse infection studies. In this report, we extend the in vivo observations by comparing the efficacies of JNJ63623872 and oseltamivir in mice infected with influenza A/California/04/2009 (H1N1pdm) and A/Victoria/3/75 (H3N2) viruses. Animals received JNJ63623872 or oseltamivir orally twice daily for 10 days starting 2 h pre-infection. JNJ63623872 (2, 6, and 20 mg/kg/day) and oseltamivir (20 mg/kg/day) completely prevented death in the H1N1pdm virus infection. Weight loss at nadir was only 12% in mice receiving 2 mg/kg/day of JNJ63623872 compared to 23% and 32%, respectively, in oseltamivir-treated (20 mg/kg/day) and placebo groups. Lung hemorrhage scores, lung weights, and lung virus titers on day 6 were reduced in a dose-responsive manner by JNJ63623872 treatments, whereas oseltamivir treatments were not as effective. JNJ63623872 was less active against H3N2 virus infection, with more body weight loss occurring and only 30% survival at the 2-mg/kg/day dose. Lung scores, lung weights, and H3N2 viral titers in lungs of mice were reduced less by JNJ63623872 treatments compared to the H1N1pdm infection. Nevertheless, the 20-mg/kg/day dose of JNJ63623872 was more effective than oseltamivir (20 mg/kg/day) in improving body weight and reducing the severity of lung infection. JNJ63623872 appears to be an important new drug candidate to treat influenza A H1N1pdm and H3N2 virus infections.
authors: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT 84322-5600, USA. Electronic address: don.smee@usu.edu.
authors: Donald F
authors: DF
authors: Smee
authors: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT 84322-5600, USA.
authors: Dale L
authors: DL
authors: Barnard
authors: Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, Boston, MA 02210, USA.
authors: Steven M
authors: SM
authors: Jones
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D055808:Drug Discovery; D004359:Drug Therapy, Combination; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects*; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects*; D008168:Lung / Q000821:virology; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000821:virology; D053139:Oseltamivir / Q000008:administration & dosage / Q000627:therapeutic use*; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007211:Indoles; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D053139:Oseltamivir; C000605010:pimodivir
keywords: Antiviral; Influenza; JNJ63623872; Mice; Oseltamivir; PB2 inhibitor