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Small Molecule Inhibitors of Metabolic Enzymes Repurposed as a New Class of Anthelmintics
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-05-02 00:00:00 , DOI: 10.1021/acsinfecdis.8b00090 Rahul Tyagi 1 , Amarendar Reddy Maddirala 2 , Mostafa Elfawal 3 , Chelsea Fischer 4 , Christina A. Bulman 4 , Bruce A. Rosa 1 , Xin Gao 1 , Ryan Chugani 2 , Mingzhou Zhou 2 , Jon Helander 2 , Paul J. Brindley 5 , Chih-Chung Tseng 6 , Iain R. Greig 6 , Judy Sakanari 4 , Scott A. Wildman 7 , Raffi Aroian 3 , James W. Janetka 2 , Makedonka Mitreva 1, 8
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-05-02 00:00:00 , DOI: 10.1021/acsinfecdis.8b00090 Rahul Tyagi 1 , Amarendar Reddy Maddirala 2 , Mostafa Elfawal 3 , Chelsea Fischer 4 , Christina A. Bulman 4 , Bruce A. Rosa 1 , Xin Gao 1 , Ryan Chugani 2 , Mingzhou Zhou 2 , Jon Helander 2 , Paul J. Brindley 5 , Chih-Chung Tseng 6 , Iain R. Greig 6 , Judy Sakanari 4 , Scott A. Wildman 7 , Raffi Aroian 3 , James W. Janetka 2 , Makedonka Mitreva 1, 8
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The enormous prevalence of infections caused by parasitic nematodes worldwide, coupled to the rapid emergence of their resistance to commonly used anthelmintic drugs, presents an urgent need for the discovery of new drugs. Herein, we have identified several classes of small molecules with broad spectrum activity against these pathogens. Previously, we reported the identification of carnitine palmitoyltransferases (CPTs) as a representative class of enzymes as potential targets for metabolic chokepoint intervention that was elucidated from a combination of chemogenomic screening and experimental testing in nematodes. Expanding on these previous findings, we have discovered that several chemical classes of known small molecule inhibitors of mammalian CPTs have potent activity as anthelmintics. Cross-clade efficacy against a broad spectrum of adult parasitic nematodes was demonstrated for multiple compounds from different series. Several analogs of these initial hit compounds were designed and synthesized. The compounds we report represent a good starting point for further lead identification and optimization for development of new anthelmintic drugs with broad spectrum activity and a novel mechanism of action.
中文翻译：
代谢酶的小分子抑制剂被重新用作新型驱虫药
在世界范围内，由寄生线虫引起的大量感染，加上它们对常用驱虫药的抗性迅速出现，迫切需要发现新药。在本文中，我们确定了几类对这些病原体具有广谱活性的小分子。以前，我们报道了肉毒碱棕榈酰转移酶（CPTs）作为代表性代表的一类酶，它们是代谢扼流点干预的潜在目标，这一点已通过化学基因组学筛选和线虫实验测试的结合加以阐明。在扩展这些先前发现的基础上，我们发现，已知几种化学类别的哺乳动物CPT的小分子抑制剂具有有效的驱虫药活性。对于来自不同系列的多种化合物，证明了其对多种成虫寄生线虫的跨谱疗效。设计并合成了这些初始命中化合物的几种类似物。我们报告的化合物为进一步鉴定和优化开发具有广谱活性和新作用机制的新型驱虫药提供了一个良好的起点。
更新日期：2018-05-02
中文翻译：
代谢酶的小分子抑制剂被重新用作新型驱虫药
在世界范围内，由寄生线虫引起的大量感染，加上它们对常用驱虫药的抗性迅速出现，迫切需要发现新药。在本文中，我们确定了几类对这些病原体具有广谱活性的小分子。以前，我们报道了肉毒碱棕榈酰转移酶（CPTs）作为代表性代表的一类酶，它们是代谢扼流点干预的潜在目标，这一点已通过化学基因组学筛选和线虫实验测试的结合加以阐明。在扩展这些先前发现的基础上，我们发现，已知几种化学类别的哺乳动物CPT的小分子抑制剂具有有效的驱虫药活性。对于来自不同系列的多种化合物，证明了其对多种成虫寄生线虫的跨谱疗效。设计并合成了这些初始命中化合物的几种类似物。我们报告的化合物为进一步鉴定和优化开发具有广谱活性和新作用机制的新型驱虫药提供了一个良好的起点。
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