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

03 May 2019

Skinner-Adams TS, Fisher GM, Riches AG, Hutt OE, Jarvis KE, Wilson T, von Itzstein M, Chopra P, Antonova-Koch Y, Meister S, Winzeler EA, Clarke M, Fidock DA, Burrows JN, Ryan JH, Andrews KT

Communications biology
PMID: 31069275

Doi: 10.1038/s42003-019-0397-3

Photo: Izzet Ugutmen/Shutterstock

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 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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