T 705

T 705(Favipiravir) is a RNA-directed RNA polymerase NS5B inhibitor.

Synthesis of T-705-Ribonucleoside and T-705-Ribonucleotide and Studies of Chemical Stability.[Pubmed:28324644]

ChemMedChem. 2017 May 9;12(9):652-659.

T-705 (favipiravir) is a fluorinated hydroxypyrazine carboxamide that exhibits antiviral activities against a variety of RNA viruses. Given the lack of potent agents to combat these infections caused by a large number of high-impact pathogens, significant emphasis has been put on studies of the antiviral properties of T-705 and its mechanism of action. T-705 acts as a nucleobase analogue; it is therefore metabolized to the corresponding ribonucleoside triphosphate intracellularly. Herein we report a reliable synthesis of T-705-ribonucleoside as well as its 5'-monophosphate. Moreover, we disclose detailed studies on the remarkable lability of the heterocycle when attached to ribose under very mild conditions, as typically applied in biochemical studies.

Distinct Effects of T-705 (Favipiravir) and Ribavirin on Influenza Virus Replication and Viral RNA Synthesis.[Pubmed:27572398]

Antimicrob Agents Chemother. 2016 Oct 21;60(11):6679-6691.

T-705 (favipiravir) is a new antiviral agent in advanced clinical development for influenza therapy. It is supposed to act as an alternative substrate for the viral polymerase, causing inhibition of viral RNA synthesis or virus mutagenesis. These mechanisms were also proposed for ribavirin, an established and broad antiviral drug that shares structural similarity with T-705. We here performed a comparative analysis of the effects of T-705 and ribavirin on influenza virus and host cell functions. Influenza virus-infected cell cultures were exposed to T-705 or ribavirin during single or serial virus passaging. The effects on viral RNA synthesis and infectious virus yield were determined and mutations appearing in the viral genome were detected by whole-genome virus sequencing. In addition, the cellular nucleotide pools as well as direct inhibition of the viral polymerase enzyme were quantified. We demonstrate that the anti-influenza virus effect of ribavirin is based on IMP dehydrogenase inhibition, which results in fast and profound GTP depletion and an imbalance in the nucleotide pools. In contrast, T-705 acts as a potent and GTP-competitive inhibitor of the viral polymerase. In infected cells, viral RNA synthesis is completely inhibited by T-705 or ribavirin at >/=50 muM, whereas exposure to lower drug concentrations induces formation of noninfectious particles and accumulation of random point mutations in the viral genome. This mutagenic effect is 2-fold higher for T-705 than for ribavirin. Hence, T-705 and ribavirin both act as purine pseudobases but profoundly differ with regard to the mechanism behind their antiviral and mutagenic effects on influenza virus.

Clinical and Virological Characteristics of Ebola Virus Disease Patients Treated With Favipiravir (T-705)-Sierra Leone, 2014.[Pubmed:27553371]

Clin Infect Dis. 2016 Nov 15;63(10):1288-1294.

BACKGROUND: During 2014-2015, an outbreak of Ebola virus disease (EVD) swept across parts of West Africa. No approved antiviral drugs are available for Ebola treatment currently. METHODS: A retrospective clinical case series was performed for EVD patients in Sierra Leone-China Friendship Hospital. Patients with confirmed EVD were sequentially enrolled and treated with either World Health Organization (WHO)-recommended supportive therapy (control group) from 10 to 30 October, or treated with WHO-recommended therapy plus favipiravir (T-705) from 1 to 10 November 2014. Survival and virological characteristics were observed for 85 patients in the control group and 39 in the T-705 treatment group. RESULTS: The overall survival rate in the T-705 treatment group was higher than that of the control group (56.4% [22/39] vs 35.3% [30/85]; P = .027). Among the 35 patients who finished all designed endpoint observations, the survival rate in the T-705 treatment group (64.8% [11/17]) was higher than that of the control group (27.8% [5/18]). Furthermore, the average survival time of the treatment group (46.9 +/- 5.6 days) was longer than that of the control group (28.9 +/- 4.7 days). Most symptoms of patients in the treatment group improved significantly. Additionally, 52.9% of patients who received T-705 had a >100-fold viral load reduction, compared with only 16.7% of patients in the control group. CONCLUSIONS: Treatment of EVD with T-705 was associated with prolonged survival and markedly reduced viral load, which makes a compelling case for further randomized controlled trials of T-705 for treating EVD.

T-705 (Favipiravir) suppresses tumor necrosis factor alpha production in response to influenza virus infection: A beneficial feature of T-705 as an anti-influenza drug.[Pubmed:28105854]

Acta Virol. 2017;61(1):48-55.

Influenza virus infection induces the production of various cytokines, which play important roles in the pathogenesis of infection. Among the cytokines induced by influenza, tumor necrosis factor alpha (TNF-alpha) production has been correlated with the severity of lung lesions. We investigated the effects of T-705 (Favipiravir, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) on cytokine production due to influenza virus infection in vitro and in vivo, compared with oseltamivir or GS 4071, an active form of oseltamivir. TNF-alpha production in mouse macrophage-derived P388D1 cells infected with the influenza virus was lower following treatment with T-705 at concentrations of 0.3 to 100 microg/ml than treatment with GS 4071 at the same concentrations. The effect of treatment with T-705 on the cytokine production induced by the influenza virus infection was investigated in mouse influenza virus infection model. At 48 h post-infection (p.i.) T-705 significantly suppressed the viral load in the lungs and TNF-alpha production in the airways of infected mice even when viral loads were high. Furthermore, T-705 suppressed only TNF-alpha production from the early phase of infection. In this study, T-705 showed the antiviral activity of reducing pulmonary viral load compared with oseltamivir, thereby suppressing the TNF-alpha production. This feature of T-705 is benefit against severe influenza infection.

Favipiravir (T-705) is a novel viral RNA polymerase inhibitor, it is phosphoribosylated by cellular enzymes to its active form, Favipiravir-ribofuranosyl-5′-triphosphate (RTP). Favipiravir-RTP inhibits the influenza viral RNA-dependent RNA polymerase (RdRP) activity with IC50 of 341 nM.

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