title: Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7.
abstract: 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.
authors: Research Centre for Drugs and Diagnostics, Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom; Vector Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom;
authors: Hanafy M
authors: HM
authors: Ismail
authors: Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom.
authors: Victoria
authors: V
authors: Barton
authors: Research Centre for Drugs and Diagnostics, Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom;
authors: Matthew
authors: M
authors: Phanchana
authors: Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom.
authors: Sitthivut
authors: S
authors: Charoensutthivarakul
authors: Vector Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom;
authors: Michael H L
authors: MH
authors: Wong
authors: Vector Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom; janet.hemingway@lstmed.ac.uk steve.ward@lstmed.ac.uk.
authors: Janet
authors: J
authors: Hemingway
authors: Research Centre for Drugs and Diagnostics, Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom;
authors: Giancarlo A
authors: GA
authors: Biagini
authors: Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom.
authors: Paul M
authors: PM
authors: O'Neill
authors: Research Centre for Drugs and Diagnostics, Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom; janet.hemingway@lstmed.ac.uk steve.ward@lstmed.ac.uk.
authors: Stephen A
authors: SA
authors: Ward
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D037621:Artemisinins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D057930:Click Chemistry; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008018:Life Cycle Stages / Q000187:drug effects*; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000378:metabolism*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D007783:Lactones; D015335:Molecular Probes; D015800:Protozoan Proteins; C075875:artemisin
keywords: antimalarial; artemisinin; bioactivation; chemical proteomics; molecular targets