title: Peptidomimetic inhibitors of N-myristoyltransferase from human malaria and leishmaniasis parasites.
abstract: N-Myristoyltransferase (NMT) has been shown to be essential in Leishmania and subsequently validated as a drug target in Plasmodium. Herein, we discuss the use of antifungal NMT inhibitors as a basis for inhibitor development resulting in the first sub-micromolar peptidomimetic inhibitors of Plasmodium and Leishmania NMTs. High-resolution structures of these inhibitors with Plasmodium and Leishmania NMTs permit a comparative analysis of binding modes, and provide the first crystal structure evidence for a ternary NMT-Coenzyme A/myristoylated peptide product complex.
authors.affiliation: Department of Chemistry, Imperial College London, London, SW7 2AZ, UK. e.tate@imperial.ac.uk.
authors.forename: Tayo O
authors.initials: TO
authors.lastname: Olaleye
authors.forename: James A
authors.initials: JA
authors.lastname: Brannigan
authors.forename: Shirley M
authors.initials: SM
authors.lastname: Roberts
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Leatherbarrow
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Wilkinson
authors.forename: Edward W
authors.initials: EW
authors.lastname: Tate
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007891:Leishmania / Q000187:drug effects / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010961:Plasmodium / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D057786:Peptidomimetics; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase