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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

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  • Media type: E-Article
  • Title: Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone
  • Contributor: 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.
  • Published: Springer Science and Business Media LLC, 2019
  • Published in: Communications Biology, 2 (2019) 1
  • Language: English
  • DOI: 10.1038/s42003-019-0397-3
  • ISSN: 2399-3642
  • Origination:
  • Footnote:
  • Description: AbstractAtovaquone-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 againstP. bergheiliver-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.
  • Access State: Open Access