title: Distinct Effects of T-705 (Favipiravir) and Ribavirin on Influenza Virus Replication and Viral RNA Synthesis.
abstract: 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 μM, 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.
authors: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors: Evelien
authors: E
authors: Vanderlinden
authors: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors: Bram
authors: 0000-0001-6547-5283
authors: B
authors: Vrancken
authors: Centre for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
authors: Jeroen
authors: J
authors: Van Houdt
authors: Alios BioPharma, Inc., South San Francisco, California, USA.
authors: Vivek K
authors: VK
authors: Rajwanshi
authors: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors: Sarah
authors: S
authors: Gillemot
authors: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors: Graciela
authors: G
authors: Andrei
authors: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors: Philippe
authors: P
authors: Lemey
authors: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium lieve.naesens@kuleuven.be.
authors: Lieve
authors: L
authors: Naesens
mesh_terms: D000072283:A549 Cells; D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002642:Chick Embryo; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D015967:Gene Expression Regulation, Viral; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D009154:Mutation / Q000187:drug effects; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D012367:RNA, Viral / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016865:Reassortant Viruses / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D012254:Ribavirin / Q000737:chemistry / Q000494:pharmacology*; D017423:Sequence Analysis, RNA; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; D012367:RNA, Viral; D014764:Viral Proteins; D012254:Ribavirin; D007168:IMP Dehydrogenase; D012321:DNA-Directed RNA Polymerases; C462182:favipiravir