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

作者：Bowyer Paul W; Gunaratne Ruwani S; Grainger Munira; Withers Martinez Chrislaine; Wickramsinghe Sasala R; Tate Edward W; Leatherbarrow Robin J; Brown Katherine A; Holder Anthony A^*; Smith Deborah F

来源：Biochemical Journal, 2007, 408(2): 173-180.

DOI：10.1042/BJ20070692

• benzothiazole
• codon optimization
• inhibition
• N-myristoylation
• plasmodium falciparum
• scintillation proximity assay (SPA)

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 mu g .l(-1) to > 400 mu g .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 MM, which demonstrate selectivity over human NMT 1. Two of these compounds, when tested against cultured parasites in vitro, reduced parasitaemia by > 80 % at a concentration of 10 mu M.

• 出版日期2007-12-1
• 单位河北医科大学