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

被引：55

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. ^{[1
]}

Smith, Deborah F.

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Wellcome Trust Labs Mol Parasitol, London SW7 2AZ, England

[2] Univ London Imperial Coll Sci Technol & Med, Div Cell & Mol Biol, Ctr Mol Microbiol & Infect, London SW7 2AZ, England

[3] Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AZ, England

[4] MRC, Natl Inst Med Res, Div Parasitol, London NW7 1AA, England

[5] Univ York, Hull York Med Sch, Dept Biol, Immunol & Infect Unit, York YO10 5YW, N Yorkshire, England

来源：

BIOCHEMICAL JOURNAL | 2007年 / 408卷

基金：

英国医学研究理事会; 英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

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

D O I：

10.1042/BJ20070692

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：173 / 180

页数：8