Plasmodium falciparum cellular macromolecules

This target refers to the collective set of proteins and lipids within the Plasmodium parasite that are damaged by artemisinin-based drugs (Wang et al., 2015, Nature Communications). The interaction is mediated by the reductive cleavage of the drug's endoperoxide bridge in the presence of ferrous iron (Fe2+), which is abundant in the parasite's heme-rich environment (Meshnick, 2002, Int J Parasitol). This chemical reaction generates short-lived, highly reactive carbon-centered radicals that act as potent alkylating agents. These radicals covalently bond to and inhibit a wide variety of essential cellular macromolecules, including the PfATP6 calcium transporter and various metabolic enzymes (O'Neill et al., 2010, Molecules). This broad-spectrum alkylation leads to rapid parasite death across multiple life stages, providing potent antimalarial activity. Because the activation is specific to the iron-rich environment of the parasite, the drugs exhibit high selectivity and low toxicity to host cells. However, mutations in the Kelch 13 protein have been linked to delayed parasite clearance, indicating emerging resistance to this mechanism (Tilley et al., 2016, Annu Rev Microbiol). Therapeutic challenges include the short half-life of these drugs and the necessity of combination therapies to prevent the spread of resistance.

Other names

Parasite proteinsPlasmodium proteomeHeme-activated endoperoxide targetsArtemisinin targets

Reductive cleavage of the endoperoxide bridge by Fe2+ (heme) generates reactive carbon-centered radicals that covalently bind to and inhibit various parasite macromolecules.