Heme-activated parasite proteins and nucleic acids

Heme-activated parasite proteins and nucleic acids represent the collective molecular targets of artemisinin and its derivatives within malaria-causing parasites, such as Plasmodium falciparum. This targeting mechanism is initiated by the parasite's digestion of host hemoglobin, which releases free heme that subsequently activates the drug's endoperoxide moiety (Meshnick, 2002, International Journal for Parasitology). The resulting reactive radicals indiscriminately alkylate numerous parasite proteins involved in essential pathways such as glycolysis, protein synthesis, and antioxidant defense, as well as parasite DNA and RNA (Wang et al., 2015, Nature Communications). This multi-pronged attack causes rapid parasite death and is the basis for the high efficacy of artemisinin-based combination therapies (ACTs) in treating malaria (WHO, 2023, World Malaria Report). The broad nature of these targets makes it difficult for the parasite to develop resistance through simple target site mutations, although changes in drug activation and stress response pathways, notably involving the Kelch 13 protein, have emerged (Tilley et al., 2016, Trends in Parasitology). Understanding these interactions is vital for developing next-generation antimalarials and managing current resistance trends.

Other names

Artemisinin targetsPlasmodium proteome and genomeHeme-activated endoperoxide targets

Reductive activation of the drug's endoperoxide bridge by ferrous heme (Fe(II)-protoporphyrin IX) leads to the formation of reactive carbon-centered radicals that covalently alkylate and damage a broad spectrum of parasite proteins and nucleic acids (Wang et al., 2015, Nature Communications; Tilley et al., 2016, Trends in Parasitology).