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Antimicrobial Agents and Chemotherapy, September 2007, p. 3168-3176, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00356-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

In Vitro and In Vivo Activities of T-705 against Arenavirus and Bunyavirus Infections{triangledown}

Brian B. Gowen,1* Min-Hui Wong,1 Kie-Hoon Jung,1 Andrew B. Sanders,1,{dagger} Michelle Mendenhall,1 Kevin W. Bailey,1 Yousuke Furuta,2 and Robert W. Sidwell1

Institute for Antiviral Research and Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah,1 Research Laboratories, Toyama Chemical Company, Ltd., Toyama, Japan2

Received 16 March 2007/ Returned for modification 18 May 2007/ Accepted 14 June 2007

There is a need for the development of effective antivirals for the treatment of severe viral diseases caused by members of the virus families Bunyaviridae and Arenaviridae. The pyrazine derivative T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has demonstrated remarkable antiviral activity against influenza virus and, to a lesser degree, against some other RNA viruses (Y. Furuta, K. Takahashi, Y. Fukuda, M. Kuno, T. Kamiyama, K. Kozaki, N. Nomura, H. Egawa, S. Minami, Y. Watanabe, H. Narita, and K. Shiraki, Antimicrob. Agents Chemother., 46:977-981, 2002). Here, we report that T-705 is highly active against a panel of bunyaviruses (La Crosse, Punta Toro, Rift Valley fever, and sandfly fever viruses) and arenaviruses (Junin, Pichinde, and Tacaribe viruses) by cytopathic effect and virus yield reduction cell-based assays. The 50% effective concentrations for T-705 ranged from 5 to 30 µg/ml and 0.7 to 1.2 µg/ml against the bunyaviruses and arenaviruses examined, respectively. We also demonstrate that orally administered T-705 is efficacious in treating Punta Toro virus in the mouse and hamster infection models, as well as Pichinde virus infection in hamsters. When administered twice daily for 5 to 6 days, beginning 4 h pre- or 24 h post-Punta Toro virus challenge, a 30-mg/kg of body weight/day dose provided complete protection from death and limited viral burden and liver disease. A dose of 50 mg/kg/day was found to be optimal for treating Pichinde infection and limiting viral replication and disease severity. In general, T-705 was found to be more active than ribavirin in cell-based assays and in vivo, as reflected by substantially greater therapeutic indexes. Our results suggest that T-705 may be a viable alternative for the treatment of life-threatening bunyaviral and arenaviral infections.

* Corresponding author. Mailing address: Institute for Antiviral Research, Utah State University, Logan, UT 84322. E-mail: bgowen{at}cc.usu.edu. Phone: (435) 797-3112. Fax: (435) 797-3959

{triangledown} Published ahead of print on 2 July 2007.

{dagger} Present address: Department of Pediatrics, University of Utah, Salt Lake City, UT.

Antimicrobial Agents and Chemotherapy, September 2007, p. 3168-3176, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00356-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Julander, J. G., Shafer, K., Smee, D. F., Morrey, J. D., Furuta, Y. (2009). Activity of T-705 in a Hamster Model of Yellow Fever Virus Infection in Comparison with That of a Chemically Related Compound, T-1106. Antimicrob. Agents Chemother. 53: 202-209 [Abstract] [Full Text]  


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