Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7

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 prot...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 113; no. 8; pp. 2080 - 2085
Main Authors Ismail, Hanafy M., Barton, Victoria, Phanchana, Matthew, Charoensutthivarakul, Sitthivut, Wong, Michael H. L., Hemingway, Janet, Biagini, Giancarlo A., O’Neill, Paul M., Ward, Stephen A.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 23.02.2016
National Acad Sciences
Subjects
Antimalarials - chemical synthesis
Antimalarials - chemistry
Antimalarials - pharmacology
Antioxidants
Artemisinins - chemical synthesis
Artemisinins - chemistry
Artemisinins - pharmacology
Biological Sciences
Chromatography
Click Chemistry
Hemoglobin
Humans
Lactones - chemical synthesis
Lactones - chemistry
Lactones - pharmacology
Life Cycle Stages - drug effects
Liquid chromatography
Malaria
Molecular Probes - chemical synthesis
Molecular Probes - chemistry
Molecular Probes - pharmacology
Parasites
Plasmodium falciparum
Plasmodium falciparum - metabolism
Probes
Protein synthesis
Protozoan Proteins - antagonists & inhibitors
Protozoan Proteins - metabolism
Vector-borne diseases
artemisinin
chemical proteomics
antimalarial
molecular targets
bioactivation
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Summary: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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Reviewers: K.C., University of Cape Town; G.P., John Hopkins University; and D.T., Universita di Milano.
Contributed by Janet Hemingway, January 12, 2016 (sent for review December 24, 2015; reviewed by Kelly Chibale, Gary Posner, and Donatella Taramelli)
Author contributions: H.M.I., P.M.O., and S.A.W. designed research; H.M.I. and M.P. performed research; V.B., S.C., M.H.L.W., P.M.O., and S.A.W. contributed new reagents/analytic tools; H.M.I., V.B., M.P., J.H., and G.A.B. analyzed data; H.M.I. and S.A.W. wrote the paper; H.M.I. contributed to the initial concept, carried out the initial biological studies, validated the methodology, and wrote the initial draft of the manuscript; V.B. and S.C. were responsible for the generation of probe molecules; M.P. carried out confirmatory biological studies independent of H.M.I.; and P.M.O. and S.A.W. conceived of the original concept and were responsible for the biological materials and chemistry, respectively.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1600459113