P lasmodium falciparum, the most pathogenic human malaria parasite, infects millions of human beings and poses a serious public health threat. Our results support a unifying model to explain the action and specificity of artemisinin in parasite killing. The haem derives primarily from the parasite’s haem biosynthesis pathway at the early ring stage and from haemoglobin digestion at the latter stages. Furthermore, using alkyne-tagged artemisinin coupled with a fluorescent dye to monitor protein binding, we show that haem, rather than free ferrous iron, is predominantly responsible for artemisinin activation. Such a broad targeting spectrum disrupts the biochemical landscape of the parasite and causes its death. We use an alkyne-tagged artemisinin analogue coupled with biotin to identify 124 artemisinin covalent binding protein targets, many of which are involved in the essential biological processes of the parasite. Here we present an unbiased chemical proteomics analysis to directly explore this mechanism in Plasmodium falciparum. The mechanism of action of artemisinin and its derivatives, the most potent of the anti-malarial drugs, is not completely understood.
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