Plasmodium heme-activated endoperoxide mechanism

The phrase “Plasmodium iron/heme-activated endoperoxide mechanism” refers to a pharmacological activation process rather than a single molecular target. In Plasmodium-infected erythrocytes, antimalarial endoperoxides (e.g., artemisinin derivatives and synthetic ozonides) are bioactivated primarily by heme, especially ferrous heme released during hemoglobin digestion, which cleaves the endoperoxide bridge to generate reactive carbon-centered radicals. These radicals covalently alkylate numerous parasite proteins across pathways (“promiscuous targeting”) and also alkylate heme to form hematin–drug adducts that can perturb iron/heme homeostasis and antagonize hemozoin formation, contributing to parasite killing. Evidence indicates heme, rather than free chelatable Fe2+, is the predominant activator in parasites, helping explain stage specificity (greater potency at trophozoite/schizont stages with abundant heme) and aspects of artemisinin resistance that reduce heme availability or heme–drug adduct formation.

Other names

heme-activated artemisinin mechanismheme-mediated activation of endoperoxidesiron/heme-dependent activation of endoperoxidesartemisinin heme-activation mechanismFe(II)-heme activation of endoperoxides

heme-dependent reductive activation of the endoperoxide to carbon-centered radicals that covalently alkylate parasite proteins and heme; promiscuous covalent modification/inactivation of multiple parasite enzymes upon activation; formation of hematin–drug adducts that can disrupt heme detoxification/biomineralization to hemozoin