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Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

DOI: 10.1038/nchem.1830 DOI Help
PMID: 24451586 PMID Help

Authors: Megan H. Wright (Department of Chemistry, Imperial College London) , Barbara Clough (Division of Parasitology, MRC National Institute for Medical Research) , Mark D. Rackham (Department of Chemistry, Imperial College London) , Kaveri Rangachari (Division of Parasitology, MRC National Institute for Medical Research) , James A. Brannigan (University of York) , Munira Grainger (Division of Parasitology, MRC National Institute for Medical Research) , David Moss (Division of Parasitology, MRC National Institute for Medical Research) , Andrew R. Bottrill (University of Leicester) , William P. Heal (Department of Chemistry, Imperial College London) , Malgorzata Broncel (Department of Chemistry, Imperial College London) , Remigiusz A. Serwa (Department of Chemistry, Imperial College London) , Declan Brady (University of Nottingham) , David J. Mann (Imperial College London) , Robin J. Leatherbarrow (Department of Chemistry, Imperial College London) , Rita Tewari (University of Nottingham) , Anthony Wilkinson (University of York) , Anthony A. Holder (Division of Parasitology, MRC National Institute for Medical Research) , Edward W. Tate (Department of Chemistry, Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemistry , VOL 6 (2) , PAGES 112 - 121

State: Published (Approved)
Published: December 2013
Diamond Proposal Number(s): 7864

Abstract: Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase.

Journal Keywords: Acyltransferases; Animals; Antimalarials; Binding; Biomimetic; Cell; Crystallography; X-Ray; Cycloaddition; Disease; Animal; Enzyme; Humans; Malaria; Plasmodium; Plasmodium; Protein; Tertiary; Recombinant; Substrate Specificity

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography