Chemogenetic Characterization of Inositol Phosphate Metabolic Pathway Reveals Druggable Enzymes for Targeting Kinetoplastid Parasites
Chemogenetic Characterization of Inositol Phosphate Metabolic Pathway Reveals Druggable Enzymes for Targeting Kinetoplastid Parasites
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DOI：
10.1016/j.chembiol.2016.03.015
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发表时间：
2016-05-19
影响因子：
8.6
通讯作者：
Stuart, Ken
中科院分区：
文献类型：
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作者：
Cestari, Igor;Haas, Paige;Stuart, Ken
动质体引起恰加斯病、人类非洲锥虫病和利什曼病。目前对这些疾病的治疗是有毒和低效的，我们对药物靶点和抑制剂的有限知识极大地阻碍了新药的开发。在这里，我们使用了化学遗传学的方法来确定新的动质体药物靶点和抑制剂。我们有条件地敲低了布氏锥虫肌醇磷酸（IP）途径基因，并表明几乎每一个途径步骤都是寄生虫生长和感染所必需的。利用遗传和化学筛选，我们鉴定了靶向IP途径酶的抑制剂，并对T。布鲁塞。这两个系列的抑制剂作用于T.布鲁氏菌肌醇多磷酸多激酶（IPMK）阻止Ins（1，4，5）P3和Ins（1，3，4，5）P4磷酸化。我们表明，IPMK是动质体之间的功能保守，它的抑制也是致命的克氏锥虫。因此，IP酶是动质体中可行的药物靶标，IPMK抑制剂可能有助于新药的开发。
Kinetoplastids cause Chagas disease, human African trypanosomiasis, and leishmaniases. Current treatments for these diseases are toxic and inefficient, and our limited knowledge of drug targets and inhibitors has dramatically hindered the development of new drugs. Here we used a chemogenetic approach to identify new kinetoplastid drug targets and inhibitors. We conditionally knocked down Trypanosoma brucei inositol phosphate (IP) pathway genes and showed that almost every pathway step is essential for parasite growth and infection. Using a genetic and chemical screen, we identified inhibitors that target IP pathway enzymes and are selective against T. brucei. Two series of these inhibitors acted on T. brucei inositol polyphosphate multikinase (IPMK) preventing Ins(1,4,5)P3 and Ins(1,3,4,5)P4 phosphorylation. We show that IPMK is functionally conserved among kinetoplastids and that its inhibition is also lethal for Trypanosoma cruzi. Hence, IP enzymes are viable drug targets in kinetoplastids, and IPMK inhibitors may aid the development of new drugs.