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Antimicrob. Agents Chemother. doi:10.1128/AAC.00356-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

In vitro and in vivo activity of T-705 against arenavirus and bunyavirus infections

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

^* To whom correspondence should be addressed. Email: bgowen{at}cc.usu.edu tel.

	Abstract

There is a need for the development of effective antivirals for the treatment of severe viral diseases caused by members of the Bunyaviridae and Arenaviridae virus families. 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 (Furuta et al., Antimicrob. Agents Chemother., 46: 977-81, 2002). Here we report that T-705 is highly active against a panel of bunyaviruses (La Crosse, Punta Toro, Rift Valley fever, Sandfly fever) and arenaviruses (Junin, Pichinde, Tacaribe) by cytopathic effect and virus yield reduction cell-based assays. The 50% effective concentrations for T-705 ranged from 5-30 µg/ml and 0.7-1.2 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 5-6 days, beginning 4 h pre- or 24 h post-Punta Toro virus challenge, a 30 mg/kg/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.