title: T-705 (favipiravir) activity against lethal H5N1 influenza A viruses.
abstract: The neuraminidase inhibitors oseltamivir and zanamivi are used to treat H5N1 influenza. However, oseltamivir-resistant H5N1 viruses have been isolated from oseltamivir-treated patients. Moreover, reassortment between H5N1 viruses and oseltamvir-resistant human H1N1 viruses currently circulating could create oseltamivir-resistant H5N1 viruses, rendering the oseltamivir stockpile obsolete. Therefore, there is a need for unique and effective antivirals to combat H5N1 influenza viruses. The investigational drug T-705 (favipiravir; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has antiviral activity against seasonal influenza viruses and a mouse-adapted H5N1 influenza virus derived from a benign duck virus. However, its efficacy against highly pathogenic H5N1 viruses, which are substantially more virulent, remains unclear. Here, we demonstrate that T-705 effectively protects mice from lethal infection with oseltamivir-sensitive or -resistant highly pathogenic H5N1 viruses. Furthermore, our biochemical analysis suggests that T-705 ribofuranosyl triphosphate, an active form of T-705, acts like purines or purine nucleosides in human cells and does not inhibit human DNA synthesis. We conclude that T-705 shows promise as a therapeutic agent for the treatment of highly pathogenic H5N1 influenza patients.
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Kiso
authors.forename: Kazumi
authors.initials: K
authors.lastname: Takahashi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sakai-Tagawa
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shinya
authors.forename: Saori
authors.initials: S
authors.lastname: Sakabe
authors.forename: Quynh Mai
authors.initials: QM
authors.lastname: Le
authors.forename: Makoto
authors.initials: M
authors.lastname: Ozawa
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Furuta
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000368:Aged; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002648:Child; D004261:DNA Replication / Q000187:drug effects; D004259:DNA-Directed DNA Polymerase / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D024882:Drug Resistance, Viral; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects*; D007251:Influenza, Human / Q000188:drug therapy* / Q000401:mortality; D007668:Kidney; D007700:Kinetics; D008168:Lung / Q000187:drug effects; D053139:Oseltamivir / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D012254:Ribavirin / Q000494:pharmacology
chemical_list: D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; D053139:Oseltamivir; D012254:Ribavirin; D004259:DNA-Directed DNA Polymerase; C462182:favipiravir