title: Molecules incorporating a benzothiazole core scaffold inhibit the N-myristoyltransferase of Plasmodium falciparum.
abstract: Recombinant N-myristoyltransferase of Plasmodium falciparum (termed PfNMT) has been used in the development of a SPA (scintillation proximity assay) suitable for automation and high-throughput screening of inhibitors against this enzyme. The ability to use the SPA has been facilitated by development of an expression and purification system which yields considerably improved quantities of soluble active recombinant PfNMT compared with previous studies. Specifically, yields of pure protein have been increased from 12 microg x l(-1) to >400 microg x l(-1) by use of a synthetic gene with codon usage optimized for expression in an Escherichia coli host. Preliminary small-scale 'piggyback' inhibitor studies using the SPA have identified a family of related molecules containing a core benzothiazole scaffold with IC50 values <50 microM, which demonstrate selectivity over human NMT1. Two of these compounds, when tested against cultured parasites in vitro, reduced parasitaemia by >80% at a concentration of 10 microM.
authors: Wellcome Trust Laboratories for Molecular Parasitology, Imperial College London, London SW7 2AZ, UK.
authors: Paul W
authors: PW
authors: Bowyer
authors: Ruwani S
authors: RS
authors: Gunaratne
authors: Munira
authors: M
authors: Grainger
authors: Chrislaine
authors: C
authors: Withers-Martinez
authors: Sasala R
authors: SR
authors: Wickramsinghe
authors: Edward W
authors: EW
authors: Tate
authors: Robin J
authors: RJ
authors: Leatherbarrow
authors: Katherine A
authors: KA
authors: Brown
authors: Anthony A
authors: AA
authors: Holder
authors: Deborah F
authors: DF
authors: Smith
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000737:chemistry*; D052160:Benzothiazoles / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000962:Antimalarials; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase; C005465:benzothiazole
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