Iron and heme metabolism in Plasmodium falciparum and the mechanism of action of artemisinins

•Artemisinin is a pro-drug that is activated by heme or iron.•Hemoglobin degradation generates an artemisinin activator.•Parasite killing requires exposure to an ‘effective’ dose of artemisinin.•Very early stage rings show artemisinin hypersensitivity.•New synthetic endoperoxides exhibit optimized interactions with iron.

During the asexual blood stage of its lifecycle, the malaria parasite Plasmodium falciparum grows and multiplies in the hemoglobin-rich environment of the human erythrocyte. Although the parasite has evolved unique strategies to survive in this environment, its interaction with iron represents an Achilles’ heel that is exploited by many antimalarial drugs. Recent work has shed new light on how the parasite deals with hemoglobin breakdown products and on the role of iron as a mediator of the action of the antimalarial drug, artemisinin.

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