tetano
Editor, Senior Moderator
Antimicrob Agents Chemother. 2016 Aug 29. pii: AAC.01156-16. [Epub ahead of print]
[h=1]Distinct effects of T-705 (favipiravir) and ribavirin on influenza virus replication and viral RNA synthesis.[/h] Vanderlinden E[SUP]1[/SUP], Vrancken B[SUP]1[/SUP], Van Houdt J[SUP]2[/SUP], Rajwanshi VK[SUP]3[/SUP], Gillemot S[SUP]1[/SUP], Andrei G[SUP]1[/SUP], Lemey P[SUP]1[/SUP], Naesens L[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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. Besides, the cellular nucleotide pools were quantified as well as direct inhibition of the viral polymerase enzyme. We demonstrate that the anti-influenza 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 μM, whereas exposure to lower drug concentrations induces formation of non-infectious particles and accumulation of random point mutations in the viral genome. This mutagenic effect is two-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.
Copyright ? 2016, American Society for Microbiology. All Rights Reserved.
PMID: 27572398 DOI: 10.1128/AAC.01156-16
[PubMed - as supplied by publisher]
[h=1]Distinct effects of T-705 (favipiravir) and ribavirin on influenza virus replication and viral RNA synthesis.[/h] Vanderlinden E[SUP]1[/SUP], Vrancken B[SUP]1[/SUP], Van Houdt J[SUP]2[/SUP], Rajwanshi VK[SUP]3[/SUP], Gillemot S[SUP]1[/SUP], Andrei G[SUP]1[/SUP], Lemey P[SUP]1[/SUP], Naesens L[SUP]4[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] 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. Besides, the cellular nucleotide pools were quantified as well as direct inhibition of the viral polymerase enzyme. We demonstrate that the anti-influenza 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 μM, whereas exposure to lower drug concentrations induces formation of non-infectious particles and accumulation of random point mutations in the viral genome. This mutagenic effect is two-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.
Copyright ? 2016, American Society for Microbiology. All Rights Reserved.
PMID: 27572398 DOI: 10.1128/AAC.01156-16
[PubMed - as supplied by publisher]