Activities per year
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.
Original language | English |
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Pages (from-to) | 112-121 |
Number of pages | 10 |
Journal | Nature Chemistry |
Volume | 6 |
Issue number | 2 |
Early online date | 22 Dec 2013 |
DOIs | |
Publication status | Published - Feb 2014 |
Profiles
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Seminar Lucknow, India - Central Institute of Drug Research
Wilkinson, A. J. (Invited speaker)
12 Mar 2019Activity: Talk or presentation › Invited talk
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3rd Advanced School in Genetic Manipulation of Parasitic Protozoa, Kolkata, India
Wilkinson, A. J. (Invited speaker)
11 Mar 2019 → 15 Mar 2019Activity: Participating in or organising an event › Conference participation
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Protein myristoylation in malaria parasites; dissection of N-myristoyltransferase as a drug target using chemical biology
Wilkinson, A. J. (Invited speaker)
5 Dec 2013Activity: Talk or presentation › Invited talk