Plasmodium falciparum artemisinin-targeted proteins

The artemisinin-targeted proteins of Plasmodium falciparum represent a broad spectrum of the parasite's proteome that undergoes covalent modification by artemisinin-derived radicals [Wang et al., 2015]. Artemisinin and its derivatives are activated by the cleavage of their internal endoperoxide bridge, a process triggered by intra-parasitic heme or ferrous iron [Ismail et al., 2016]. This activation generates highly reactive carbon-centered radicals that indiscriminately alkylate nearby proteins, including those involved in glycolysis (e.g., PfGAPDH), protein folding (e.g., PfHSP70), and redox balance [Mok et al., 2015]. This promiscuous targeting mechanism induces severe proteotoxic stress, disrupting multiple essential pathways simultaneously and leading to rapid parasite death. While specific proteins such as the sarco/endoplasmic reticulum Ca2+-ATPase (PfATP6) and the translationally controlled tumor protein (PfTCTP) were initially proposed as primary targets, current evidence suggests that the collective damage to the parasite's proteome is the definitive mode of action [Wang et al., 2015]. This multi-target approach is a key factor in the high efficacy of artemisinin-based combination therapies, although resistance mediated by mutations in the Kelch 13 (K13) protein has emerged as a significant clinical challenge [Ariey et al., 2014].

Other names

Artemisinin-binding proteomeArtemisinin-alkylated proteinsPf-ABPArtemisinin proteome targets

Covalent alkylation of multiple essential parasite proteins by artemisinin-derived carbon-centered radicals following activation by heme or ferrous iron [Wang et al., 2015].