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Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum

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      The mechanism of action of artemisinin and its derivatives, the most potent of the anti-malarial drugs, is not completely understood. Here we present an unbiased chemical proteomics analysis to directly explore this mechanism in Plasmodium falciparum. 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. Such a broad targeting spectrum disrupts the biochemical landscape of the parasite and causes its death. 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. The haem derives primarily from the parasite's haem biosynthesis pathway at the early ring stage and from haemoglobin digestion at the latter stages. Our results support a unifying model to explain the action and specificity of artemisinin in parasite killing.


      The mechanism of action of artemisinin, an antimalarial drug, is not well understood. Here, the authors use a labelled artemisinin analogue to show that the drug is mainly activated by haem and then binds covalently to over 120 proteins in the malaria parasite, affecting many of its cellular processes.

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      Most cited references 60

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      Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.

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        Artemisinin resistance in Plasmodium falciparum malaria.

        Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border, historically a site of emerging antimalarial-drug resistance. In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance. We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate-mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P=0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups. P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. ( number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.) 2009 Massachusetts Medical Society
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          ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks

          Summary: We have developed ClueGO, an easy to use Cytoscape plug-in that strongly improves biological interpretation of large lists of genes. ClueGO integrates Gene Ontology (GO) terms as well as KEGG/BioCarta pathways and creates a functionally organized GO/pathway term network. It can analyze one or compare two lists of genes and comprehensively visualizes functionally grouped terms. A one-click update option allows ClueGO to automatically download the most recent GO/KEGG release at any time. ClueGO provides an intuitive representation of the analysis results and can be optionally used in conjunction with the GOlorize plug-in. Availability: Contact: Supplementary information: Supplementary data are available at Bioinformatics online.

            Author and article information

            [1 ]Department of Biological Sciences, National University of Singapore , Singapore 117543, Singapore
            [2 ]The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University , Nanjing 210023, China
            [3 ]Interdisciplinary Research Group in Infectious Diseases, Singapore-MIT Alliance for Research & Technology (SMART) , Singapore 138602, Singapore
            [4 ]Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore 117597, Singapore
            [5 ]Department of Chemical and Biomolecular Engineering, National University of Singapore , Singapore 117585, Singapore
            [6 ]Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore 117545, Singapore
            [7 ]NUS Environmental Research Institute , Singapore 117411, Singapore
            [8 ]Department of Anaesthesiology, Singapore General Hospital , Singapore 169608, Singapore
            [9 ]School of Traditional Chinese Medicine, Southern Medical University , Guangzhou 510515, China
            [10 ]College of Life Science and Technology, Beijing University of Chemical Technology , Beijing 100029, China
            [11 ]Department of Biomedical Engineering, National University of Singapore , Singapore 117583, Singapore
            [12 ]Department of Mechanical Engineering, National University of Singapore , Singapore 117575, Singapore
            Author notes

            These authors contributed equally to this work.

            Nat Commun
            Nat Commun
            Nature Communications
            Nature Publishing Group
            22 December 2015
            : 6
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