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Antimicrobial Agents and Chemotherapy, March 2005, p. 981-986, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.981-986.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mechanism of Action of T-705 against Influenza Virus

Research Laboratories, Toyama Chemical Co., Ltd.,¹ Department of Virology, Toyama Medical and Pharmaceutical University, Toyama, Japan²

Received 25 May 2004/ Returned for modification 14 July 2004/ Accepted 11 November 2004

T-705, a substituted pyrazine compound, has been found to exhibit potent anti-influenza virus activity in vitro and in vivo. In a time-of-addition study, it was indicated that T-705 targeted an early to middle stage of the viral replication cycle but had no effect on the adsorption or release stage. The anti-influenza virus activity of T-705 was attenuated by addition of purines and purine nucleosides, including adenosine, guanosine, inosine, and hypoxanthine, whereas pyrimidines did not affect its activity. T-705-4-ribofuranosyl-5'-triphosphate (T-705RTP) and T-705-4-ribofuranosyl-5'-monophosphate (T-705RMP) were detected in MDCK cells treated with T-705. T-705RTP inhibited influenza virus RNA polymerase activity in a dose-dependent and a GTP-competitive manner. Unlike ribavirin, T-705 did not have an influence on cellular DNA or RNA synthesis. Inhibition of cellular IMP dehydrogenase by T-705RMP was about 150-fold weaker than that by ribavirin monophosphate, indicating the specificity of the anti-influenza virus activity and lower level of cytotoxicity of T-705. These results suggest that T-705RTP, which is generated in infected cells, may function as a specific inhibitor of influenza virus RNA polymerase and contributes to the selective anti-influenza virus activity of T-705.

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