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A novel endonuclease inhibitor exhibits broad-spectrum anti-influenza activity in vitro

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  • A novel endonuclease inhibitor exhibits broad-spectrum anti-influenza activity in vitro

    Antimicrob Agents Chemother. 2016 Jul 5. pii: AAC.00888-16. [Epub ahead of print]
    A novel endonuclease inhibitor exhibits broad-spectrum anti-influenza activity in vitro.

    Jones JC1, Marathe BM1, Lerner C2, Kreis L2, Gasser R2, Pascua PN1, Najera I2, Govorkova EA3.
    Author information

    Abstract

    Antiviral drugs are important in preventing and controlling influenza, particularly when vaccines are ineffective or unavailable. A single class of antiviral drugs, the neuraminidase inhibitors (NAIs), is recommended for treating influenza. The limited therapeutic options and the potential risk of antiviral resistance are driving the search for additional small-molecule inhibitors that act on influenza virus proteins. The acid polymerase (PA) of influenza viruses is a promising target for new antivirals because of its essential role in initiating virus transcription. Here, we characterized a novel compound, RO-7, identified as a putative PA endonuclease inhibitor. RO-7 was effective when added before the cessation of genome replication, reduced polymerase activity in cell-free systems, and decreased relative amounts of viral mRNA and genomic RNA during influenza virus infection. RO-7 specifically inhibited the ability of the PA endonuclease domain to cleave a nucleic acid substrate. RO-7 also inhibited influenza A (seasonal and 2009 pandemic H1N1, seasonal H3N2) and B viruses (Yamagata and Victoria lineages), zoonotic viruses (H5N1, H7N9, and H9N2), and NAI-resistant variants in plaque reduction, yield reduction, and cell viability assays in MDCK cells with nanomolar to submicromolar EC50 values, low toxicity, and favorable selective indexes. RO-7 also inhibited influenza virus replication in primary, normal human bronchial epithelial cells. Overall, RO-7 exhibits broad-spectrum activity against influenza A and B in multiple in vitro assays, supporting its further characterization and development as a potential antiviral agent for treating influenza.
    Copyright ? 2016, American Society for Microbiology. All Rights Reserved.


    PMID: 27381402 DOI: 10.1128/AAC.00888-16
    [PubMed - as supplied by publisher]
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