T-705 (favipiravir) activity against lethal H5N1 influenza A viruses

被引:165
作者
Kiso, Maki [1 ]
Takahashi, Kazumi [3 ]
Sakai-Tagawa, Yuko [1 ]
Shinya, Kyoko [5 ]
Sakabe, Saori [1 ]
Le, Quynh Mai [4 ]
Ozawa, Makoto [2 ,7 ]
Furuta, Yousuke [3 ]
Kawaoka, Yoshihiro [1 ,2 ,5 ,6 ,7 ]
机构
[1] Univ Tokyo, Dept Microbiol & Immunol, Div Virol, Tokyo 1088639, Japan
[2] Univ Tokyo, Inst Med Sci, Int Res Ctr Infect Dis, Tokyo 1088639, Japan
[3] Toyama Chem Co Ltd, Res Labs, Toyama 9308508, Japan
[4] Natl Inst Hyg & Epidemiol, Hanoi, Vietnam
[5] Kobe Univ, Dept Microbiol & Infect Dis, Kobe, Hyogo 6500017, Japan
[6] Japan Sci & Technol Agcy, Exploratory Res Adv Technol Infect Induced Host R, Kawaguchi, Saitama 3320012, Japan
[7] Univ Wisconsin, Dept Pathol Sci, Influenza Res Inst, Madison, WI 53706 USA
基金
日本学术振兴会;
关键词
antiviral compounds; murine lethal-infection model; neuraminidase; ORALLY-ADMINISTERED T-705; RESISTANT INFLUENZA; NEURAMINIDASE INHIBITORS; A/VIETNAM/1203/04; H5N1; IN-VITRO; AMANTADINE; INFECTION; MICE; EFFICACY; VIRULENCE;
D O I
10.1073/pnas.0909603107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:882 / 887
页数:6
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