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  • Low cost whole-organism screening of compounds for anthelmintic activity

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    Accepted Manuscript (AM)
    Author(s)
    Preston, Sarah
    Jabbar, Abdul
    Nowell, Cameron
    Joachim, Anja
    Ruttkowski, Baerbel
    Baell, Jonathan
    Cardno, Tony
    Korhonen, Pasi K
    Piedrafita, David
    Ansell, Brendan RE
    Jex, Aaron R
    Hofmann, Andreas
    Gasser, Robin B
    Griffith University Author(s)
    Hofmann, Andreas
    Year published
    2015
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    Abstract
    Due to major problems with drug resistance in parasitic nematodes of animals, there is a substantial need and excellent opportunities to develop new anthelmintics via genomic-guided and/or repurposing approaches. In the present study, we established a practical and cost-effective whole-organism assay for the in vitro-screening of compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm). The assay is based on the use of exsheathed L3 (xL3) and L4 stages of H. contortus of small ruminants (sheep and goats). Using this assay, we screened a panel of 522 well-curated kinase inhibitors ...
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    Due to major problems with drug resistance in parasitic nematodes of animals, there is a substantial need and excellent opportunities to develop new anthelmintics via genomic-guided and/or repurposing approaches. In the present study, we established a practical and cost-effective whole-organism assay for the in vitro-screening of compounds for activity against parasitic stages of the nematode Haemonchus contortus (barber's pole worm). The assay is based on the use of exsheathed L3 (xL3) and L4 stages of H. contortus of small ruminants (sheep and goats). Using this assay, we screened a panel of 522 well-curated kinase inhibitors (GlaxoSmithKline, USA; code: PKIS2) for activity against H. contortus by measuring the inhibition of larval motility using an automated image analysis system. We identified two chemicals within the compound classes biphenyl amides and pyrazolo[1,5-a]pyridines, which reproducibly inhibit both xL3 and L4 motility and development, with IC50s of 14-47 卮 Given that these inhibitors were designed as anti-inflammatory drugs for use in humans and fit the Lipinski rule-of-five (including bioavailability), they show promise for hit-to-lead optimisation and repurposing for use against parasitic nematodes. The screening assay established here has significant advantages over conventional methods, particularly in terms of ease of use, throughput, time and cost. Although not yet fully automated, the current assay is readily suited to the screening of hundreds to thousands of compounds for subsequent hit-to-lead optimisation. The current assay is highly adaptable to many parasites of socioeconomic importance, including those causing neglected tropical diseases. This aspect is of major relevance, given the urgent need to deliver the goals of the London Declaration (http://unitingtocombatntds.org/resource/london-declaration) through the rapid and efficient repurposing of compounds in public-private partnerships.
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    Journal Title
    International Journal for Parasitology
    Volume
    45
    Issue
    5
    DOI
    https://doi.org/10.1016/j.ijpara.2015.01.007
    Copyright Statement
    © 2015 Australian Society for Parasitology Inc. Published by Elsevier Ltd. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
    Subject
    Microbiology
    Zoology
    Veterinary sciences
    Medical parasitology
    Publication URI
    http://hdl.handle.net/10072/69241
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    • Journal articles

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