Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum

• DOI: 10.1038/ncomms10111
• Publication Date: 2015-12-22T16:41:00Z
• Authors: Jigang Wang; Chong-Jing Zhang; Wan Ni Chia; Cheryl C. Y. Loh; Zhengjun Li; Yew Mun Lee; Yingke He; Li-Xia Yuan; Teck Kwang Lim; Min Liu; Chin Xia Liew; Yan Quan Lee; Jianbin Zhang; Nianci Lu; Chwee Teck Lim; Zi-Chun Hua; Bin Liu; Han-Ming Shen; Kevin S. W. Tan; Qingsong Lin
• Keywords: Models, Molecular; 0303 health sciences; Molecular Structure; Protein Conformation; Plasmodium falciparum; Protozoan Proteins; Heme; Chemical Engineering; Article; Artemisinins; 3. Good health; Antimalarials; 03 medical and health sciences

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