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  • Investigation of pyrimidine nucleoside analogues as chemical probes to assess compound effects on the proliferation of Trypanosoma cruzi intracellular parasites

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    Author(s)
    Sykes, Melissa Louise
    Hilko, David Hugh
    Kung, Livia Isabella
    Poulsen, Sally-Ann
    Avery, Vicky Marie
    Griffith University Author(s)
    Poulsen, Sally-Ann
    Sykes, Melissa L.
    Hilko, David H.
    Avery, Vicky M.
    Year published
    2020
    Metadata
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    Abstract
    Trypanosoma cruzi parasites utilise de novo pyrimidine biosynthesis to produce DNA and survive within mammalian host cells. This pathway can be hijacked to assess the replication of intracellular parasites with the exogenous addition of a DNA specific probe. To identify suitable probe compounds for this application, a collection of pyrimidine nucleoside analogues was assessed for incorporation into T. cruzi intracellular amastigote DNA using image-based technology and script-based analysis. Associated mammalian cell toxicity of these compounds was also determined against both the parasite host cells (3T3 cells) and HEK293 ...
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    Trypanosoma cruzi parasites utilise de novo pyrimidine biosynthesis to produce DNA and survive within mammalian host cells. This pathway can be hijacked to assess the replication of intracellular parasites with the exogenous addition of a DNA specific probe. To identify suitable probe compounds for this application, a collection of pyrimidine nucleoside analogues was assessed for incorporation into T. cruzi intracellular amastigote DNA using image-based technology and script-based analysis. Associated mammalian cell toxicity of these compounds was also determined against both the parasite host cells (3T3 cells) and HEK293 cells. Incorporation of 5-ethynyl-20-deoxyuridine (EdU) into parasite DNA was the most effective of the probes tested, with minimal growth inhibition observed following either two or four hours EdU exposure. EdU was subsequently utilised as a DNA probe, followed by visualisation with click chemistry to a fluorescent azide, to assess the impact of drugs and compounds with previously demonstrated activity against T. cruzi parasites, on parasite replication. The inhibitory profiles of these molecules highlight the benefit of this approach for identifying surviving parasites post-treatment in vitro and classifying compounds as either fast or slow-acting. F-ara-EdU resulted in <50% activity observed against T. cruzi amastigotes following 48 hours incubation, at 73 μM. Collectively, this supports the further development of pyrimidine nucleosides as chemical probes to investigate replication of the parasite T. cruzi.
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    Journal Title
    PLOS Neglected Tropical Diseases
    Volume
    14
    Issue
    3
    DOI
    https://doi.org/10.1371/journal.pntd.0008068
    Copyright Statement
    © 2020 Sykes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
    Subject
    Biological sciences
    Biomedical and clinical sciences
    Health sciences
    Science & Technology
    Life Sciences & Biomedicine
    Infectious Diseases
    Parasitology
    Tropical Medicine
    Publication URI
    http://hdl.handle.net/10072/395815
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    • Journal articles

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