Molecules incorporating a benzothiazole core scaffold inhibit the N-myristoyltransferase of Plasmodium falciparum

Paul W Bowyer , Ruwani S Gunaratne , Munira Grainger , Chrislaine Withers-Martinez , Sasala R Wickramsinghe , Edward W Tate , Robin J Leatherbarrow , Katherine A Brown , Anthony A Holder , Deborah F Smith (1)

1 Department of Biology [York]

Recombinant N-myristoyltransferase of Plasmodium falciparum (PfNMT) has been used in the development of a scintillation proximity assay (SPA) 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 to previous studies. Specifically, yields of pure protein have been increased from 12 µg L -1} to > 400 µg L -1} by use of a synthetic gene with codon usage optimised 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 IC 50} values < 50 µM, which demonstrate selectivity over human NMT1. Two of these compounds, when tested against cultured parasites in vitro, reduce parasitaemia by > 80% at 10 µM.

Mots clés: Life Sciences

Paul W Bowyer, Ruwani S Gunaratne, Munira Grainger, Chrislaine Withers-Martinez, Sasala R Wickramsinghe, et al.. Molecules incorporating a benzothiazole core scaffold inhibit the N-myristoyltransferase of Plasmodium falciparum. Biochemical Journal, 2007, 408 (2), pp.173-180. ⟨10.1042/BJ20070692⟩. ⟨hal-00478814⟩