title: Therapeutic efficacy of peramivir against H5N1 highly pathogenic avian influenza viruses harboring the neuraminidase H275Y mutation.
abstract: High morbidity and mortality associated with human cases of highly pathogenic avian influenza (HPAI) viruses, including H5N1 influenza virus, have been reported. The purpose of the present study was to evaluate the antiviral effects of peramivir against HPAI viruses. In neuraminidase (NA) inhibition and virus replication inhibition assays, peramivir showed strong inhibitory activity against H5N1, H7N1 and H7N7 HPAI viruses with sub-nanomolar activity in enzyme assays. In H5N1 viruses containing the NA H275Y mutation, the antiviral activity of peramivir against the variant was lower than that against the wild-type. Evaluation of the in vivo antiviral activity showed that a single intravenous treatment of peramivir (10 mg/kg) prevented lethality in mice infected with wild-type H5N1 virus and also following infection with H5N1 virus with the H275Y mutation after a 5 day administration of peramivir (30 mg/kg). Furthermore, mice injected with peramivir showed low viral titers and low levels of proinflammatory cytokines in the lungs. These results suggest that peramivir has therapeutic activity against HPAI viruses even if the virus harbors the NA H275Y mutation.
authors.affiliation: Drug Discovery & Disease Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Drug Discovery & Disease Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kodama
authors.affiliation: Drug Discovery & Disease Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Noshi
authors.affiliation: Drug Discovery & Disease Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Ryu
authors.initials: R
authors.lastname: Yoshida
authors.affiliation: Research Laboratory for Development, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Takushi
authors.initials: T
authors.lastname: Kanazu
authors.affiliation: Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan; Laboratory for Biologics Development, Research Center for Zoonosis Control, Hokkaido University, Hokkaido, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nomura
authors.affiliation: Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan; Avian Zoonosis Research Center, Faculty of Agriculture, Tottori University, Tottori, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Soda
authors.affiliation: Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan; Global Station for Zoonosis Control, Global Institute for Collaborative Research and Education (GI-CoRE), Hokkaido University, Hokkaido, Japan; Unit of Risk Analysis and Management, Research Center for Zoonosis Control, Hokkaido University, Hokkaido, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Isoda
authors.affiliation: Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Okamatsu
authors.affiliation: Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan; Global Station for Zoonosis Control, Global Institute for Collaborative Research and Education (GI-CoRE), Hokkaido University, Hokkaido, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sakoda
authors.affiliation: Drug Discovery & Disease Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamano
authors.affiliation: Drug Discovery & Disease Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan; Research Center for Zoonosis Control, Hokkaido University, Hokkaido, Japan. Electronic address: akihiko.sato@shionogi.co.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sato
authors.affiliation: Research Center for Zoonosis Control, Hokkaido University, Hokkaido, Japan; Global Station for Zoonosis Control, Global Institute for Collaborative Research and Education (GI-CoRE), Hokkaido University, Hokkaido, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
mesh_terms: D000146:Acids, Carbocyclic; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003517:Cyclopentanes / Q000008:administration & dosage / Q000627:therapeutic use*; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D006146:Guanidines / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics* / Q000472:pathogenicity; D057916:Influenza A Virus, H7N1 Subtype / Q000187:drug effects / Q000201:enzymology; D053126:Influenza A Virus, H7N7 Subtype / Q000187:drug effects / Q000201:enzymology; D007251:Influenza, Human / Q000188:drug therapy; D008168:Lung / Q000276:immunology / Q000821:virology; D051379:Mice; D009154:Mutation; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000235:genetics*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000821:virology; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D016207:Cytokines; D006146:Guanidines; D009439:Neuraminidase; C414210:peramivir
keywords: H5N1; HPAI; Influenza; Mouse model; NAI; Peramivir