<i>In Vitro</i>and<i>in Vivo</i>Activities of T-705 and Oseltamivir against Influenza Virus

Takahashi, Kohei; Furuta, Yoshihiko; Fukuda, Yoshiko; Kuno, Miyuki; Kamiyama, Tsutomu; Kozaki, Kyo; Nomura, Nobuhiko; Egawa, Hiroyuki; Minami, Shinji; Shiraki, Kimíyasu

doi:10.1177/095632020301400502

Cited by 85 publications

(90 citation statements)

References 24 publications

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“…3. As expected, OC afforded a 2 log 10 gradual decrease in viral yield at micromolar concentrations (26). In contrast, a steep dose-response relationship was observed with compound 3, with viral yields obtained at 0.041 μM but complete inhibition (>4 log 10 decrease) observed at the next-highest concentration of 0.123 μM.…”

Section: Resultsmentioning

confidence: 77%

Inhibition of influenza virus replication via small molecules that induce the formation of higher-order nucleoprotein oligomers

Gerritz

Cianci

Kim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

118

179

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Influenza nucleoprotein (NP) plays multiple roles in the virus life cycle, including an essential function in viral replication as an integral component of the ribonucleoprotein complex, associating with viral RNA and polymerase within the viral core. The multifunctional nature of NP makes it an attractive target for antiviral intervention, and inhibitors targeting this protein have recently been reported. In a parallel effort, we discovered a structurally similar series of influenza replication inhibitors and show that they interfere with NP-dependent processes via formation of higherorder NP oligomers. Support for this unique mechanism is provided by site-directed mutagenesis studies, biophysical characterization of the oligomeric ligand:NP complex, and an X-ray cocrystal structure of an NP dimer of trimers (or hexamer) comprising three NP_A:NP_B dimeric subunits. Each NP_A:NP_B dimeric subunit contains two ligands that bridge two composite, protein-spanning binding sites in an antiparallel orientation to form a stable quaternary complex. Optimization of the initial screening hit produced an analog that protects mice from influenza-induced weight loss and mortality by reducing viral titers to undetectable levels throughout the course of treatment.antiinfluenza | oligomerization | polymerase inhibitor | protein-protein interaction | cooperative inhibition

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Section: Resultsmentioning

confidence: 77%

Inhibition of influenza virus replication via small molecules that induce the formation of higher-order nucleoprotein oligomers

Gerritz

Cianci

Kim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

118

179

View full text Add to dashboard Cite

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“…vir against new and emerging strains of influenza is frequently tested in mice and other animal species and is used as a predictor for efficacy in humans (12)(13)(14)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)), but we demonstrate here that evaluation of antiviral efficacy in in vitro assays as well as in vivo analyses in other animal species should be assessed collectively to ensure that an accurate understanding of antiviral efficacy for humans will be predicted.…”

Section: Discussionmentioning

confidence: 99%

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Ranadheera

Hagan

Leung

et al. 2016

J Virol

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During the first wave of the 2009 pandemic, caused by a H1N1 influenza virus (pH1N1) of swine origin, antivirals were the only form of therapeutic available to control the proliferation of disease until the conventional strain-matched vaccine was produced. Oseltamivir is an antiviral that inhibits the sialidase activity of the viral neuraminidase (NA) protein and was shown to be effective against pH1N1 viruses in ferrets. Furthermore, it was used in humans to treat infections during the pandemic and is still used for current infections without reported complication or exacerbation of illness. However, in an evaluation of the effectiveness of oseltamivir against pH1N1 infection, we unexpectedly observed an exacerbation of disease in virus-infected mice treated with oseltamivir, transforming an otherwise mild illness into one with high morbidity and mortality. In contrast, an identical treatment regime alleviated all signs of illness in mice infected with the pathogenic mouse-adapted virus A/WSN/33 (H1N1). The worsened clinical outcome with pH1N1 viruses occurred over a range of oseltamivir doses and treatment schedules and was directly linked to a reduction in NA enzymatic activity. Our results suggest that the suppression of NA activity with antivirals may exacerbate disease in a host-dependent manner by increasing replicative fitness in viruses that are not optimally adapted for replication in that host. IMPORTANCEHere, we report that treatment of pH1N1-infected mice with oseltamivir enhanced disease progression, transforming a mild illness into a lethal infection. This raises a potential pitfall of using the mouse model for evaluation of the therapeutic efficacy of neuraminidase inhibitors. We show that antiviral efficacy determined in a single animal species may not represent treatment in humans and that caution should be used when interpreting the outcome. Furthermore, increased virulence due to oseltamivir treatment was the effect of a shift in the hemagglutinin (HA) and neuraminidase (NA) activity balance. This is the first study that has demonstrated that altering the HA/NA activity balance by reduction in NA activity can result in an increase in virulence in any animal model from nonpathogenic to lethal and the first to demonstrate a situation in which treatment with a NA activity inhibitor has an effect opposite to the intended therapeutic effect of ameliorating the infection.

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“…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).…”

mentioning

confidence: 99%

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

Kiso¹,

Takahashi

Sakai‐Tagawa³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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198

169

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The neuraminidase inhibitors oseltamivir and zanamivi are used to treat H5N1 influenza. However, oseltamivir-resistant H5N1 viruses have been isolated from oseltamivir-treated patients. Moreover, reassortment between H5N1 viruses and oseltamvir-resistant human H1N1 viruses currently circulating could create oseltamivir-resistant H5N1 viruses, rendering the oseltamivir stockpile obsolete. Therefore, there is a need for unique and effective antivirals to combat H5N1 influenza viruses. The investigational drug T-705 (favipiravir; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has antiviral activity against seasonal influenza viruses and a mouse-adapted H5N1 influenza virus derived from a benign duck virus. However, its efficacy against highly pathogenic H5N1 viruses, which are substantially more virulent, remains unclear. Here, we demonstrate that T-705 effectively protects mice from lethal infection with oseltamivir-sensitive or -resistant highly pathogenic H5N1 viruses. Furthermore, our biochemical analysis suggests that T-705 ribofuranosyl triphosphate, an active form of T-705, acts like purines or purine nucleosides in human cells and does not inhibit human DNA synthesis. We conclude that T-705 shows promise as a therapeutic agent for the treatment of highly pathogenic H5N1 influenza patients.

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In Vitroandin VivoActivities of T-705 and Oseltamivir against Influenza Virus

Cited by 85 publications

References 24 publications

Inhibition of influenza virus replication via small molecules that induce the formation of higher-order nucleoprotein oligomers

Inhibition of influenza virus replication via small molecules that induce the formation of higher-order nucleoprotein oligomers

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

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

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