Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs.
Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs.
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DOI：
10.1371/journal.pntd.0001625
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发表时间：
2012
影响因子：
3.8
通讯作者：
Smith DF
中科院分区：
文献类型：
--
作者：
Bell AS;Mills JE;Williams GP;Brannigan JA;Wilkinson AJ;Parkinson T;Leatherbarrow RJ;Tate EW;Holder AA;Smith DF
N-肉豆蔻酰转移酶的抑制已在临床前被验证为使用物种特异性抑制剂治疗真菌和锥虫感染的靶点。为了鉴定原生动物NMT的抑制剂，我们选择针对恶性疟原虫和杜氏利什曼原虫NMT筛选辉瑞公司收集的不同子集。对任一酶的初步筛选命中进行了测试，以确定对两种人NMT亚型（Hs 1和Hs 2）的选择性以及对布氏锥虫NMT的广谱抗原虫活性。筛选结果的分析表明，利什曼原虫NMT的结构-活性关系（SAR）与所有其他测试的NMT不同，这一发现不是通过序列相似性计算预测的，从而鉴定出四种新的利什曼原虫选择性NMT抑制剂系列。我们发现疟原虫NMT和两种人NMT的SAR之间存在很强的重叠，这表明实现适当的选择性特征更具挑战性。然而，我们确实在本研究中发现了两个对疟原虫NMT具有选择性的新系列，以及另外两个对利什曼原虫NMT具有选择性的结构不同的系列。我们相信，将这项研究的结果发布到公共领域将加速发现NMT抑制剂来治疗疟疾和利什曼病。我们的检查计划是另一个例子，说明由制药业、学术机构和政府/非政府组织（如医学研究理事会和惠康信托基金）三方合作，如何促进对被忽视疾病的研究。N-肉豆蔻酰转移酶的抑制已在临床前被验证为使用物种特异性抑制剂治疗真菌和锥虫感染的靶点。为了鉴定原生动物NMT的抑制剂，我们选择针对恶性疟原虫和杜氏利什曼原虫NMT筛选辉瑞公司收集的不同子集。对任一酶的初步筛选命中进行了测试，以确定对两种人NMT亚型（HsNMT 1和HsNMT 2）的选择性，以及对来自布氏锥虫的NMT的广谱抗原生动物活性。我们已经确定了8个系列的原生动物NMT抑制剂，6个具有良好的选择性，无论是疟原虫或利什曼原虫NMT在本研究中的其他直系同源物。我们相信，所有这些系列可以形成药物化学计划的基础，以提供针对疟疾或利什曼病的候选药物。我们的筛查计划是另一个例子，说明制药业、学术机构和政府/非政府组织（如英国医学研究理事会和惠康信托基金）三方合作如何促进对被忽视疾病的研究。
Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results has shown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding not predicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMT inhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting that achieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series with selectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinct series with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain will accelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/non-governmental organisations such as Medical Research Council and Wellcome Trust can stimulate research for neglected diseases. Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (HsNMT1 and HsNMT2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. We have identified eight series of protozoan NMT inhibitors, six having good selectivity for either Plasmodium or Leishmania NMTs over the other orthologues in this study. We believe that all of these series could form the basis of medicinal chemistry programs to deliver drug candidates against either malaria or leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/non-governmental organisations such as the UK Medical Research Council and Wellcome Trust can stimulate research for neglected diseases.
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