Cell Cycle Inhibition To Treat Sleeping Sickness.
Cell Cycle Inhibition To Treat Sleeping Sickness.
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DOI：
10.1128/mbio.01427-17
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发表时间：
2017-09-19
期刊：
影响因子：
6.4
通讯作者：
Engman DM
中科院分区：
文献类型：
--
作者：
Epting CL;Emmer BT;Du NY;Taylor JM;Makanji MY;Olson CL;Engman DM
非洲锥虫病由原生动物寄生虫布氏锥虫感染引起。在感染过程中，这种病原体以类似于白血病的方式在其哺乳动物宿主的血流中迅速分裂成高密度。与所有真核生物一样，布氏锥虫的细胞周期涉及由核糖核苷酸还原酶（RNR）调节的DNA从头合成，RNR催化核糖核苷酸转化为脱氧形式。作为细胞周期的必需酶，RNR是癌症化疗的常见靶点。我们假设通过遗传或药理学手段抑制RNR会损害体外寄生虫的生长并延长受感染动物的存活时间。我们的研究结果表明，RNR抑制是非常有效的抑制寄生虫生长在体外和体内。这些结果支持了针对细胞周期的药物发现工作，不仅针对非洲锥虫，还可能针对真核病原体的其他感染。开发治疗真核病原体感染的药物具有挑战性，因为许多关键毒力因子在人类中具有密切相关的同源物。药物毒性极大地限制了这些开发工作。对于以高速率复制的病原体，特别是在血液中，另一种方法是直接靶向细胞周期，就像治疗某些血液恶性肿瘤一样。本文提供的结果表明，通过抑制核糖核苷酸还原酶靶向细胞周期可有效杀死锥虫并延长受感染动物的存活时间。
African trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei. During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Like all eukaryotes, T. brucei has a cell cycle involving the de novo synthesis of DNA regulated by ribonucleotide reductase (RNR), which catalyzes the conversion of ribonucleotides into their deoxy form. As an essential enzyme for the cell cycle, RNR is a common target for cancer chemotherapy. We hypothesized that inhibition of RNR by genetic or pharmacological means would impair parasite growth in vitro and prolong the survival of infected animals. Our results demonstrate that RNR inhibition is highly effective in suppressing parasite growth both in vitro and in vivo. These results support drug discovery efforts targeting the cell cycle, not only for African trypanosomiasis but possibly also for other infections by eukaryotic pathogens. The development of drugs to treat infections with eukaryotic pathogens is challenging because many key virulence factors have closely related homologues in humans. Drug toxicity greatly limits these development efforts. For pathogens that replicate at a high rate, especially in the blood, an alternative approach is to target the cell cycle directly, much as is done to treat some hematologic malignancies. The results presented here indicate that targeting the cell cycle via inhibition of ribonucleotide reductase is effective at killing trypanosomes and prolonging the survival of infected animals.