Plasmodium falciparum Heme-Activated Radical Targets

The target "intracellular parasite targets via heme-activated radicals" refers to the collective group of essential proteins and biomolecules within the malaria parasite, Plasmodium falciparum, that are covalently modified and inactivated by reactive intermediates (Wang et al., 2015). This mechanism is the hallmark of artemisinin and its derivatives, which contain a characteristic endoperoxide bridge. Upon entering the parasite's digestive vacuole, these drugs react with ferrous heme (Fe2+-protoporphyrin IX)—released during the degradation of host hemoglobin—triggering the cleavage of the peroxide bond and the formation of highly reactive carbon-centered radicals and reactive oxygen species (ROS). These radicals act as "molecular grenades," alkylating a broad spectrum of parasite proteins, including the phosphatidylinositol 3-kinase (PfPI3K) (Mbengue et al., 2015), the sarco/endoplasmic reticulum Ca2+-ATPase (PfATP6) (Eckstein-Ludwig et al., 2003), and various enzymes involved in glycolysis and protein stress responses. This promiscuous covalent modification leads to the rapid disruption of multiple vital cellular processes, resulting in the potent and fast-acting antimalarial effect of these compounds. Resistance to this mechanism is primarily mediated by mutations in the Kelch 13 (K13) protein, which alters the parasite's ability to manage the resulting cellular stress and drug-induced protein degradation (Ariey et al., 2014).

Other names

Artemisinin targetsParasite proteome (heme-activated)Heme-activated endoperoxide targetsArtemisinin-binding proteinsPfHARTs

Heme-mediated activation of the endoperoxide bridge to generate reactive radicals that covalently alkylate and inhibit multiple parasite proteins.