期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 8, 页码 2080-2085出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1600459113
关键词
artemisinin; antimalarial; bioactivation; chemical proteomics; molecular targets
资金
- Wellcome Trust
- Medical Research Council
- Mahidol-Liverpool Chamlong Harinasuta PhD Scholarship
- MRC [MC_PC_12017, MC_PC_13069, MC_PC_15040, MC_PC_14111] Funding Source: UKRI
- Medical Research Council [MC_PC_13069, MC_PC_14111, MC_PC_12017, MC_PC_15040] Funding Source: researchfish
The artemisinin (ART)-based antimalarials have contributed significantly to reducing global malaria deaths over the past decade, but we still do not know how they kill parasites. To gain greater insight into the potential mechanisms of ART drug action, we developed a suite of ART activity-based protein profiling probes to identify parasite protein drug targets in situ. Probes were designed to retain biological activity and alkylate the molecular target(s) of Plasmodium falciparum 3D7 parasites in situ. Proteins tagged with the ART probe can then be isolated using click chemistry before identification by liquid chromatography-MS/MS. Using these probes, we define an ART proteome that shows alkylated targets in the glycolytic, hemoglobin degradation, antioxidant defense, and protein synthesis pathways, processes essential for parasite survival. This work reveals the pleiotropic nature of the biological functions targeted by this important class of antimalarial drugs.
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