T-705 (favipiravir) activity against lethal H5N1 influenza A viruses.
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.
Kiso
Maki
M
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.
Takahashi
Kazumi
K
Sakai-Tagawa
Yuko
Y
Shinya
Kyoko
K
Sakabe
Saori
S
Le
Quynh Mai
QM
Ozawa
Makoto
M
Furuta
Yousuke
Y
Kawaoka
Yoshihiro
Y
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
D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; D053139:Oseltamivir; D012254:Ribavirin; D004259:DNA-Directed DNA Polymerase; C462182:favipiravir