title: N-Myristoyltransferase as a potential drug target in malaria and leishmaniasis.
abstract: Infections caused by protozoan parasites are among the most widespread and intractable transmissible diseases affecting the developing world, with malaria and leishmaniasis being the most costly in terms of morbidity and mortality. Although new drugs are urgently required against both diseases in the face of ever-rising resistance to frontline therapies, very few candidates passing through development pipelines possess a known and novel mode of action. Set in the context of drugs currently in use and under development, we present the evidence for N-myristoyltransferase (NMT), an enzyme that N-terminally lipidates a wide range of specific target proteins through post-translational modification, as a potential drug target in malaria and the leishmaniases. We discuss the limitations of current knowledge regarding the downstream targets of this enzyme in protozoa, and our recent progress towards potent cell-active NMT inhibitors against the most clinically-relevant species of parasite. Finally, we outline the next steps required in terms of both tools to understand N-myristoylation in protozoan parasites, and the generation of potential development candidates based on the output of our recently-reported high-throughput screens.
authors.affiliation: Department of Chemistry, Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK.
authors.forename: Edward W
authors.initials: EW
authors.lastname: Tate
authors.affiliation: Department of Chemistry, Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Bell
authors.affiliation: Department of Chemistry, Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Rackham
authors.affiliation: Department of Chemistry, Institute of Chemical Biology, Imperial College London, London SW7 2AZ, UK.
authors.forename: Megan H
authors.initials: MH
authors.lastname: Wright
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D007896:Leishmaniasis / Q000188:drug therapy; D008288:Malaria / Q000188:drug therapy; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D019814:Myristic Acid / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D019814:Myristic Acid; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase