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  • Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone

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    Author(s)
    Skinner-Adams, Tina S
    Fishers, Gillian M
    Riches, Andrew G
    Hutt, Oliver E
    Jarvis, Karen E
    Wilson, Tony
    von Ltzstein, Mark
    Chopra, Pradeep
    Antonova-Koch, Yevgeniya
    Meister, Stephan
    Winzeler, Elizabeth A
    Clarke, Mary
    Fidock, David A
    Burrows, Jeremy N
    Ryan, John H
    Andrews, Katherine T
    Griffith University Author(s)
    Skinner-Adams, Tina
    von Itzstein, Mark
    Andrews, Katherine T.
    Fisher, Gill M.
    Year published
    2019
    Metadata
    Show full item record
    Abstract
    Atovaquone-proguanil (Malarone®) is used for malaria prophylaxis and treatment. While the cytochrome bc1-inhibitor atovaquone has potent activity, proguanil’s action is attributed to its cyclization-metabolite, cycloguanil. Evidence suggests that proguanil has limited intrinsic activity, associated with mitochondrial-function. Here we demonstrate that proguanil, and cyclization-blocked analogue tBuPG, have potent, but slow-acting, in vitro anti-plasmodial activity. Activity is folate-metabolism and isoprenoid biosynthesis-independent. In yeast dihydroorotate dehydrogenase-expressing parasites, proguanil and tBuPG slow-action ...
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    Atovaquone-proguanil (Malarone®) is used for malaria prophylaxis and treatment. While the cytochrome bc1-inhibitor atovaquone has potent activity, proguanil’s action is attributed to its cyclization-metabolite, cycloguanil. Evidence suggests that proguanil has limited intrinsic activity, associated with mitochondrial-function. Here we demonstrate that proguanil, and cyclization-blocked analogue tBuPG, have potent, but slow-acting, in vitro anti-plasmodial activity. Activity is folate-metabolism and isoprenoid biosynthesis-independent. In yeast dihydroorotate dehydrogenase-expressing parasites, proguanil and tBuPG slow-action remains, while bc1-inhibitor activity switches from comparatively fast to slow-acting. Like proguanil, tBuPG has activity against P. berghei liver-stage parasites. Both analogues act synergistically with bc1-inhibitors against blood-stages in vitro, however cycloguanil antagonizes activity. Together, these data suggest that proguanil is a potent slow-acting anti-plasmodial agent, that bc1 is essential to parasite survival independent of dihydroorotate dehydrogenase-activity, that Malarone® is a triple-drug combination that includes antagonistic partners and that a cyclization-blocked proguanil may be a superior combination partner for bc1-inhibitors in vivo.
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    Journal Title
    Communications Biology
    Volume
    2
    Issue
    1
    DOI
    https://doi.org/10.1038/s42003-019-0397-3
    Funder(s)
    NHMRC
    Grant identifier(s)
    APP1071659
    Copyright Statement
    © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
    Subject
    Biological sciences
    Science & Technology
    Life Sciences & Biomedicine
    Biology
    Multidisciplinary Sciences
    Life Sciences & Biomedicine - Other Topics
    Publication URI
    http://hdl.handle.net/10072/387852
    Collection
    • Journal articles

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