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

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...

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Autores principales: Skinner-Adams, Tina S., Fisher, Gillian M., Riches, Andrew G., Hutt, Oliver E., Jarvis, Karen E., Wilson, Tony, von Itzstein, 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499835/
https://www.ncbi.nlm.nih.gov/pubmed/31069275
http://dx.doi.org/10.1038/s42003-019-0397-3
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author Skinner-Adams, Tina S.
Fisher, Gillian M.
Riches, Andrew G.
Hutt, Oliver E.
Jarvis, Karen E.
Wilson, Tony
von Itzstein, 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.
author_facet Skinner-Adams, Tina S.
Fisher, Gillian M.
Riches, Andrew G.
Hutt, Oliver E.
Jarvis, Karen E.
Wilson, Tony
von Itzstein, 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.
author_sort Skinner-Adams, Tina S.
collection PubMed
description 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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spelling pubmed-64998352019-05-08 Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone Skinner-Adams, Tina S. Fisher, Gillian M. Riches, Andrew G. Hutt, Oliver E. Jarvis, Karen E. Wilson, Tony von Itzstein, 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. Commun Biol Article 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. Nature Publishing Group UK 2019-05-03 /pmc/articles/PMC6499835/ /pubmed/31069275 http://dx.doi.org/10.1038/s42003-019-0397-3 Text en © The Author(s) 2019 Open Access 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Skinner-Adams, Tina S.
Fisher, Gillian M.
Riches, Andrew G.
Hutt, Oliver E.
Jarvis, Karen E.
Wilson, Tony
von Itzstein, 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.
Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone
title Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone
title_full Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone
title_fullStr Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone
title_full_unstemmed Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone
title_short Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone
title_sort cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499835/
https://www.ncbi.nlm.nih.gov/pubmed/31069275
http://dx.doi.org/10.1038/s42003-019-0397-3
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