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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

Yousuke Furuta,1* Kazumi Takahashi,1 Masako Kuno-Maekawa,1 Hidehiro Sangawa,1 Sayuri Uehara,1 Kyo Kozaki,1 Nobuhiko Nomura,1 Hiroyuki Egawa,1 and Kimiyasu Shiraki2

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.

* Corresponding author. Mailing address: Research Laboratories, Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Toyama 930-8508, Japan. Phone: 81-76-431-8254. Fax: 81-76-431-8208. E-mail: YOUSUKE_FURUTA{at}toyama-chemical.co.jp.

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.



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