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

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.

• Authors: Megan H Wright, Barbara Clough, Mark D Rackham, Kaveri Rangachari, James A Brannigan, Munira Grainger, David K Moss, Andrew R Bottrill, William P Heal, Malgorzata Broncel, Remigiusz A Serwa, Declan Brady, David J Mann, Robin J Leatherbarrow, Rita Tewari, Anthony J Wilkinson, Anthony A Holder, Edward W Tate
• Journal: Nature chemistry (Nat Chem) Vol. 6 Issue 2 Pg. 112-21 (Feb 2014) ISSN: 1755-4349 [Electronic] England
• PMID: 24451586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acyl Coenzyme A
• Antimalarials
• CAPRIN1 protein, human
• Cell Cycle Proteins
• Enzyme Inhibitors
• Recombinant Proteins
• S-tetradecanoyl-coenzyme A
• Acyltransferases
• glycylpeptide N-tetradecanoyltransferase

Topics

• Acyl Coenzyme A (chemistry, metabolism)
• Acyltransferases (antagonists & inhibitors, genetics, metabolism)
• Animals
• Antimalarials (chemistry, pharmacology, therapeutic use)
• Binding Sites
• Biomimetic Materials (chemistry, metabolism)
• Cell Cycle Proteins (metabolism)
• Crystallography, X-Ray
• Cycloaddition Reaction
• Disease Models, Animal
• Enzyme Inhibitors (chemistry, pharmacology, therapeutic use)
• Humans
• Malaria (drug therapy, parasitology)
• Molecular Docking Simulation
• Plasmodium falciparum (drug effects)
• Plasmodium vivax (drug effects)
• Protein Structure, Tertiary
• Recombinant Proteins (biosynthesis, chemistry, genetics)
• Substrate Specificity