Mechanism of action of T-705 against influenza virus.
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.
Furuta
Yousuke
Y
Research Laboratories, Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Toyama 930-8508, Japan. YOUSUKE_FURUTA@toyama-chemical.co.jp
Takahashi
Kazumi
K
Kuno-Maekawa
Masako
M
Sangawa
Hidehiro
H
Uehara
Sayuri
S
Kozaki
Kyo
K
Nomura
Nobuhiko
N
Egawa
Hiroyuki
H
Shiraki
Kimiyasu
K
D000577:Amides / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000096:biosynthesis; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D009975:Orthomyxoviridae / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis
D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; D012313:RNA; D004247:DNA; D007168:IMP Dehydrogenase; D012321:DNA-Directed RNA Polymerases; C462182:favipiravir
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