Mechanism of Action of T-705 against Influenza Virus

Abstract

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.Influenza is responsible for much morbidity and mortality in the world (7), and effective treatment is required. We now have two classes of drugs for the treatment of influenza, the ion channel blockers and the neuraminidase inhibitors. The ion channel blockers amantadine and rimantadine are of limited use because of a lack of activity against influenza B virus, side effects, and the rapid emergence of resistant virus strains (9). Neuraminidase inhibitors are effective against both influenza A and B viruses, and their usefulness in clinical treatment has been reported (2, 11). Ribavirin is a guanosine analogue and inhibits various RNA and DNA viruses, including influenza viruses (19). Its clinical efficacy against influenza virus after aerosol treatment of infected individuals has been reported (5), but it has been approved for use in only a few countries. Influenza viruses are able to undergo rapid antigenic changes, especially in the surface glycoproteins, and novel influenza virus variants which have high levels of virulence may emerge in the human population and cause severe disease. Therefore, exploration for novel anti-influenza virus agents is of most importance.T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has been found to have potent inhibitory activity against RNA viruses in vitro, especially influenza A, B, and C viruses. The selectivity index (the ratio of the 50% cell-inhibitory concentration [CC 50 ]/50% influenza virus-inhibitory concentration [IC 50 ]) was more than 6,000 (Table 1) (6). T-705 showed therapeutic efficacy in mouse infection models and had a profile different from those of ribavirin and oseltamivir (16).The present study describes an experimental approach to clarifying the mode of action of T-705, and the ...

Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans

“…Reversal of antiviral activity by guanosine or adenosine was performed as described previously with modifications (Furuta et al, 2005). The antiviral activity of MPA was assessed as in the plaque reduction assay, except that guanosine or adenosine were mixed with the MPA before addition to the MDCK cells.…”

T-705 (favipiravir) activity against lethal H5N1 influenza A viruses

“…Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide), known as T-705, has potent inhibitory activity against influenza A, B, and C viruses in vitro and in vivo (16)(17)(18)(19)(20)(21). Favipiravir negatively affects the synthesis of influenza viral RNA, but not cellular DNA or RNA (17).…”

Existing Influenza Antivirals: Their Mechanisms of Action and Potential in the Face of Avian Influenza

“…1.12 ), T -705 RTP would then inhibit infl uenza virus RNA polymerase in a GTP -competitive manner. 107 Unlike ribavirin 5 ′ -monophosphate, T -705 RMP did not signifi cantly inhibit IMP dehydrogenase, indicating that it owes its anti -infl uenza virus activity mainly, if not exclusively, to an inhibition of the infl uenza virus RNA polymerase.…”