Multiple Plasmodium falciparum proteins and membrane lipids

Multiple Plasmodium falciparum proteins and membrane lipids refers to the broad array of molecular targets affected by artemisinin and its derivatives, which are the frontline treatment for malaria. These compounds function as pro-drugs that are activated by the iron in heme, a byproduct of hemoglobin digestion by the parasite (Wang et al., 2015, Nature Communications). Upon activation, they generate highly reactive carbon-centered radicals that covalently alkylate a wide variety of parasite proteins and membrane lipids (Ismail et al., 2016, Angewandte Chemie). This non-specific damage disrupts essential biological functions, including protein folding, ion transport via PfATP6, and metabolic signaling through PfPI3K (Tilley et al., 2016, International Journal for Parasitology). The simultaneous inhibition of multiple pathways makes it difficult for the parasite to develop resistance through simple target site mutations. However, clinical resistance has emerged via mutations in the Kelch 13 (K13) protein, which reduces the drug's activation and enhances the parasite's stress response (Ariey et al., 2014, Nature). This multi-target mechanism is central to the rapid parasite clearance observed with artemisinin-based combination therapies.

Other names

Plasmodium falciparum proteome and lipidomeArtemisinin targetsMulti-target antimalarial profileArtemisinin-binding proteins

Heme-dependent activation of the drug's endoperoxide bridge leads to the formation of reactive carbon-centered radicals that covalently alkylate and damage a diverse array of parasite proteins and membrane lipids.