Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach.
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.
1] Department of Chemistry, Imperial College London, London SW7 2AZ, UK [2] Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK.
Megan H
MH
Wright
Division of Parasitology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Barbara
B
Clough
Department of Chemistry, Imperial College London, London SW7 2AZ, UK.
Mark D
MD
Rackham
Division of Parasitology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Kaveri
K
Rangachari
York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, UK.
James A
JA
Brannigan
Division of Parasitology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Munira
M
Grainger
Division of Parasitology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
David K
DK
Moss
Protein and Nucleic Acid Chemistry Laboratory, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.
Andrew R
0000000251823643
AR
Bottrill
1] Department of Chemistry, Imperial College London, London SW7 2AZ, UK [2].
William P
WP
Heal
Department of Chemistry, Imperial College London, London SW7 2AZ, UK.
Malgorzata
M
Broncel
Department of Chemistry, Imperial College London, London SW7 2AZ, UK.
Remigiusz A
RA
Serwa
Centre for Genetics and Genomics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham NG2 7UH, UK.
Declan
D
Brady
1] Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK [2] Division of Molecular Biosciences, Department of Life Sciences, Imperial College London, London SW7 2AZ, UK.
David J
DJ
Mann
1] Department of Chemistry, Imperial College London, London SW7 2AZ, UK [2] Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK [3].
Robin J
RJ
Leatherbarrow
Centre for Genetics and Genomics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham NG2 7UH, UK.
Rita
R
Tewari
York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, UK.
Anthony J
AJ
Wilkinson
Division of Parasitology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Anthony A
AA
Holder
1] Department of Chemistry, Imperial College London, London SW7 2AZ, UK [2] Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK.
Edward W
EW
Tate
D000214:Acyl Coenzyme A / Q000737:chemistry / Q000378:metabolism; D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D040761:Biomimetic Materials / Q000737:chemistry / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D018360:Crystallography, X-Ray; D061565:Cycloaddition Reaction; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000187:drug effects; D010966:Plasmodium vivax / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013379:Substrate Specificity
D000214:Acyl Coenzyme A; D000962:Antimalarials; C486562:CAPRIN1 protein, human; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C040349:S-tetradecanoyl-coenzyme A; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase