Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum

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 () and Qingsong Lin ()
Additional contact information
Jigang Wang: National University of Singapore
Chong-Jing Zhang: National University of Singapore
Wan Ni Chia: Yong Loo Lin School of Medicine, National University of Singapore
Cheryl C. Y. Loh: Yong Loo Lin School of Medicine, National University of Singapore
Zhengjun Li: NUS Environmental Research Institute
Yew Mun Lee: National University of Singapore
Yingke He: Singapore General Hospital
Li-Xia Yuan: School of Traditional Chinese Medicine, Southern Medical University
Teck Kwang Lim: National University of Singapore
Min Liu: Interdisciplinary Research Group in Infectious Diseases, Singapore-MIT Alliance for Research & Technology (SMART)
Chin Xia Liew: NUS Environmental Research Institute
Yan Quan Lee: Yong Loo Lin School of Medicine, National University of Singapore
Jianbin Zhang: Yong Loo Lin School of Medicine, National University of Singapore
Nianci Lu: College of Life Science and Technology, Beijing University of Chemical Technology
Chwee Teck Lim: National University of Singapore
Zi-Chun Hua: The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University
Bin Liu: National University of Singapore
Han-Ming Shen: Yong Loo Lin School of Medicine, National University of Singapore
Kevin S. W. Tan: Yong Loo Lin School of Medicine, National University of Singapore
Qingsong Lin: National University of Singapore

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms10111

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