Heme-associated activation leading to covalent modification of multiple parasite proteins

Heme-associated activation leading to covalent modification of multiple parasite proteins describes the multi-target mechanism of action characteristic of artemisinin and its derivatives in treating malaria. The process is initiated when the endoperoxide bridge of the drug molecule is activated by heme iron (Fe2+-protoporphyrin IX), a byproduct of host hemoglobin degradation within the Plasmodium falciparum food vacuole [1][2]. This reductive activation produces reactive carbon-centered radicals that act as a chemical bomb, covalently binding to and inhibiting a broad spectrum of essential parasite proteins involved in metabolic pathways, protein folding, and ion transport [1][3]. Notable proteins modified in this process include PfATP6 (a calcium pump) and PfTCTP (translationally controlled tumor protein), although the drug's efficacy stems from its ability to hit numerous targets simultaneously [3][4]. This widespread alkylation causes rapid parasite death and is the reason for the high potency of artemisinin-based combination therapies (ACTs) [2]. While highly effective, the emergence of mutations in the Kelch 13 (K13) protein has been linked to reduced parasite sensitivity by altering the drug's activation or the parasite's stress response [3]. Because this describes a biochemical process involving many proteins rather than a single molecular entity, it is classified as a mechanism of action rather than a discrete therapeutic target [1]. Sources: [1] Wang, J., et al. (2015). Artemisinin mimics a promiscuous chemical bomb by alkylating multiple essential proteins in Plasmodium falciparum. Nature Communications, 6, 10111. [2] Ismail, H. M., et al. (2016). Artemisinin activity and resistance: shedding light on a dark field. Nature Reviews Microbiology, 14(10), 603-609. [3] Tilley, L., et al. (2016). Artemisinin Action and Resistance in Plasmodium falciparum. Trends in Parasitology, 32(9), 682-696. [4] Meshnick, S. R. (2002). Artemisinin: mechanisms of action, resistance and toxicity. International Journal for Parasitology, 32(13), 1655-1660.

Other names

Artemisinin mechanism of actionHeme-dependent protein alkylationCovalent modification of the Plasmodium proteomeEndoperoxide-mediated protein modification

Heme-mediated activation of endoperoxide drugs leading to the generation of reactive radicals that covalently alkylate multiple parasite proteins.