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  • Targeting human parainfluenza virus type-1 haemagglutinin-neuraminidase with mechanism-based inhibitors

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    Version of Record (VoR)
    Author(s)
    Eveno, Tanguy
    Dirr, Larissa
    El-Deeb, Ibrahim M
    Guillon, Patrice
    von Itzstein, Mark
    Griffith University Author(s)
    von Itzstein, Mark
    Guillon, Patrice M.
    Dirr, Larissa E.
    El-Deeb, Ibrahim Mustafa
    Year published
    2019
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    Abstract
    Human parainfluenza virus (hPIV) infections are a major cause of respiratory tract illnesses in children, with currently no available vaccine or drug treatment. The surface glycoprotein haemagglutinin-neuraminidase (HN) of hPIV has a central role in the viral life cycle, including neuraminic acid-recognising receptor binding activity (early stage) and receptor-destroying activity (late stage), which makes it an ideal target for antiviral drug disovery. In this study, we showed that targeting the catalytic mechanism of hPIV-1 HN by a 2α,3β-difluoro derivative of the known hPIV-1 inhibitor, BCX 2798, produced more potent ...
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    Human parainfluenza virus (hPIV) infections are a major cause of respiratory tract illnesses in children, with currently no available vaccine or drug treatment. The surface glycoprotein haemagglutinin-neuraminidase (HN) of hPIV has a central role in the viral life cycle, including neuraminic acid-recognising receptor binding activity (early stage) and receptor-destroying activity (late stage), which makes it an ideal target for antiviral drug disovery. In this study, we showed that targeting the catalytic mechanism of hPIV-1 HN by a 2α,3β-difluoro derivative of the known hPIV-1 inhibitor, BCX 2798, produced more potent inhibition of the neuraminidase function which is reflected by a stronger inhibition of viral replication. The difluorosialic acid-based inhibitor efficiently blocked the neuraminidase activity of HN for a prolonged period of time relative to its unsaturated neuraminic acid (Neu2en) analogue, BCX 2798 and produced a more efficient inhibition of the HN neuraminidase activity as well as in vitro viral replication. This prolonged inhibition of the hPIV-1 HN protein suggests covalent binding of the inhibitor to a key catalytic amino acid, making this compound a new lead for a novel class of more potent hPIV-1 mechanism-based inhibitors.
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    Journal Title
    Viruses
    Volume
    11
    Issue
    5
    DOI
    https://doi.org/10.3390/v11050417
    Copyright Statement
    © 2019 The Authors. This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
    Subject
    Microbiology
    Publication URI
    http://hdl.handle.net/10072/386393
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    • Journal articles

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