Heme and Plasmodium falciparum macromolecules

Heme and a diverse array of Plasmodium falciparum macromolecules serve as the collective target for artemisinin-based antimalarial therapies. Within the malaria parasite's acidic food vacuole, the digestion of host hemoglobin releases free heme (ferriprotoporphyrin IX), which reacts with the endoperoxide bridge of artemisinin drugs to generate highly reactive carbon-centered free radicals (O'Neill et al., 2010, Molecules). These radicals act as potent alkylating agents, forming covalent adducts with heme itself—preventing its detoxification into hemozoin—and a wide spectrum of essential parasite proteins and lipids (Wang et al., 2015, Nature Communications). While specific proteins like the sarco/endoplasmic reticulum Ca2+-ATPase (PfATP6) and the translationally controlled tumor protein (TCTP) have been identified as targets, the drug's high efficacy is largely attributed to this 'promiscuous' multi-target mechanism that causes widespread cellular damage. This broad-spectrum alkylation disrupts multiple physiological processes, including protein synthesis and membrane integrity, leading to rapid parasite clearance across various stages of the intraerythrocytic cycle (Ismail et al., 2016, Journal of Medicinal Chemistry).

Other names

Ferriprotoporphyrin IXMalaria parasite proteinsPlasmodium falciparum proteomePfATP6Translationally controlled tumor protein (TCTP)

Heme-mediated reductive activation of the drug's endoperoxide bridge generates reactive carbon-centered free radicals that covalently alkylate and inactivate heme and various parasite proteins.