Giuseppe
Emeritus
T-705 (favipiravir) activity against lethal H5N1 influenza A viruses (Proc Natl Acad Sci USA, abstract, edited)
T-705 (favipiravir) activity against lethal H5N1 influenza A viruses
1. Maki Kiso a, 2. Kazumi Takahashi b, 3. Yuko Sakai-Tagawa a, 4. Kyoko Shinya c, 5. Saori Sakabe a, 6. Quynh Mai Le d, 7. Makoto Ozawa e,f, 8. Yousuke Furuta b, and 9. Yoshihiro Kawaoka a,c,e,f,g,1
Author Affiliations
1. aDivision of Virology, Department of Microbiology and Immunology, and
2. eInternational Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639 Japan;
3. bResearch Laboratories, Toyama Chemical Co., Ltd., Toyama, 930-8508 Japan;
4. d National Institute of Hygiene and Epidemiology, Hanoi, Vietnam;
5. cDepartment of Microbiology and Infectious Diseases, Kobe University, Hyogo, 650-0017 Japan;
6. gExploratory Research for Advanced Technology Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, 332-0012 Japan; and
7. fInfluenza Research Institute, Department of Pathological Sciences, University of Wisconsin-Madison, WI 53706.
1. Edited by Mary K. Estes, Baylor College of Medicine, Houston, TX, and approved November 24, 2009 (received for review August 24, 2009).
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.
* antiviral compounds
* murine lethal-infection model
* neuraminidase
Footnotes
1To whom correspondence should be addressed. E-mail: kawaoka@ims.u-tokyo.ac.jp.
Author contributions:
M.K., K.T., Y.F., and Y.K. designed research; M.K., K.T., Y.S.-T., K.S., and S.S. performed research; Q.M.L. contributed new reagents/analytic tools; M.K., K.T., K.S., S.S., M.O., Y.F., and Y.K. analyzed data; and M.K., K.T., K.S., S.S., M.O., Y.F., and Y.K. wrote the paper.
Conflict of interest statement:
Y.K. has received speaker?s honoraria from Chugai Pharmaceuticals, Novartis, Daiichi-Sankyo Co., Ltd., Toyama Chemical, Wyeth, and GlaxoSmithKline; a grant of support from Chugai Pharmaceuticals, Daiichi Sankyo Co., Ltd. and Toyama Chemical; and is a consultant for Theraclone and is a founder of FluGen.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0909603107/DCSupplemental.
-
<cite cite="http://www.pnas.org/content/107/2/882.short?rss=1">T-705 (favipiravir) activity against lethal H5N1 influenza A viruses ? PNAS</cite>1. Maki Kiso a, 2. Kazumi Takahashi b, 3. Yuko Sakai-Tagawa a, 4. Kyoko Shinya c, 5. Saori Sakabe a, 6. Quynh Mai Le d, 7. Makoto Ozawa e,f, 8. Yousuke Furuta b, and 9. Yoshihiro Kawaoka a,c,e,f,g,1
Author Affiliations
1. aDivision of Virology, Department of Microbiology and Immunology, and
2. eInternational Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639 Japan;
3. bResearch Laboratories, Toyama Chemical Co., Ltd., Toyama, 930-8508 Japan;
4. d National Institute of Hygiene and Epidemiology, Hanoi, Vietnam;
5. cDepartment of Microbiology and Infectious Diseases, Kobe University, Hyogo, 650-0017 Japan;
6. gExploratory Research for Advanced Technology Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, 332-0012 Japan; and
7. fInfluenza Research Institute, Department of Pathological Sciences, University of Wisconsin-Madison, WI 53706.
1. Edited by Mary K. Estes, Baylor College of Medicine, Houston, TX, and approved November 24, 2009 (received for review August 24, 2009).
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.
* antiviral compounds
* murine lethal-infection model
* neuraminidase
Footnotes
1To whom correspondence should be addressed. E-mail: kawaoka@ims.u-tokyo.ac.jp.
Author contributions:
M.K., K.T., Y.F., and Y.K. designed research; M.K., K.T., Y.S.-T., K.S., and S.S. performed research; Q.M.L. contributed new reagents/analytic tools; M.K., K.T., K.S., S.S., M.O., Y.F., and Y.K. analyzed data; and M.K., K.T., K.S., S.S., M.O., Y.F., and Y.K. wrote the paper.
Conflict of interest statement:
Y.K. has received speaker?s honoraria from Chugai Pharmaceuticals, Novartis, Daiichi-Sankyo Co., Ltd., Toyama Chemical, Wyeth, and GlaxoSmithKline; a grant of support from Chugai Pharmaceuticals, Daiichi Sankyo Co., Ltd. and Toyama Chemical; and is a consultant for Theraclone and is a founder of FluGen.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0909603107/DCSupplemental.
-