Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach.
Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach.
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DOI：
10.1038/nchem.1830
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发表时间：
2014-02
期刊：
影响因子：
21.8
通讯作者：
Tate EW
中科院分区：
文献类型：
--
作者：
Wright MH;Clough B;Rackham MD;Rangachari K;Brannigan JA;Grainger M;Moss DK;Bottrill AR;Heal WP;Broncel M;Serwa RA;Brady D;Mann DJ;Leatherbarrow RJ;Tewari R;Wilkinson AJ;Holder AA;Tate EW
疟疾是一种由疟原虫属寄生虫引起的传染病，每年在全世界造成约一百万人死亡。鉴于对现有药物的抗药性不断上升，迫切需要对新的抗疟靶点进行化学验证。一个这样的推定的目标是酶N-肉豆蔻酰转移酶（NMT），其催化蛋白质底物的N-肉豆蔻酰化。在这里，我们报告了一个综合的化学生物学方法来探索蛋白豆蔻酰化的主要人类寄生虫恶性疟原虫，结合化学蛋白质组学工具，用于识别豆蔻酰化和糖基磷脂酰肌醇锚定的蛋白质组与选择性小分子NMT抑制剂。我们表明，NMT是一个重要的和化学上易于处理的目标，在疟疾寄生虫在体外和体内，并显示N-豆蔻酰化的选择性抑制导致灾难性的和不可逆的失败，组装内膜复合物，一个关键的亚细胞器在寄生虫的生命周期。我们的研究为开发以NMT为靶点的新型抗疟药物提供了基础。
Malaria is an infectious disease caused by parasites of the genus Plasmodium that inflicts approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase (NMT), which catalyzes N-myristoylation of protein substrates. Here we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small molecule NMT inhibitors. We demonstrate that NMT is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for development of new antimalarials targeting NMT.