1. T-705 (favipiravir) activity against lethal H5N1 influenza A viruses.
- Author
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Kiso M, Takahashi K, Sakai-Tagawa Y, Shinya K, Sakabe S, Le QM, Ozawa M, Furuta Y, and Kawaoka Y
- Subjects
- Aged, Animals, Cell Line, Child, DNA Replication drug effects, DNA-Directed DNA Polymerase drug effects, DNA-Directed DNA Polymerase metabolism, Dogs, Drug Resistance, Viral, Humans, Influenza, Human mortality, Kidney, Kinetics, Lung drug effects, Oseltamivir pharmacology, Ribavirin pharmacology, Amides pharmacology, Antiviral Agents pharmacology, Influenza A Virus, H5N1 Subtype drug effects, Influenza, Human drug therapy, Pyrazines pharmacology
- 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.
- Published
- 2010
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