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首页> 外文期刊>Antimicrobial agents and chemotherapy. >A novel benzodioxole-containing inhibitor of Toxoplasma gondii growth alters the parasite cell cycle.
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A novel benzodioxole-containing inhibitor of Toxoplasma gondii growth alters the parasite cell cycle.

机译：弓形虫生长的新型含苯并二恶唑的抑制剂可改变寄生虫的细胞周期。

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摘要

Toxoplasma gondii is an obligate intracellular parasite that can cause disease in the developing fetus and in immunocompromised humans. Infections can last for the life of the individual, and to date there are no drugs that eliminate the chronic cyst stages that are characteristic of this parasite. In an effort to identify new chemical scaffolds that could form the basis for new therapeutics, we carried out a chemoinformatic screen for compounds that had the potential to interact with members of a superfamily of parasite-secreted kinases and assayed them for growth inhibition in vitro. Of 17 candidate compounds, we identified one with potent antiparasitic activity. The compound has a 50% inhibitory concentration (IC(50)) of ~2 nM, and structure-function analyses implicate the benzodioxole moiety in its action. The compound does not appear to be cytotoxic to host cells. Using microarray analyses of both parasites and host cells treated with the compound, we found that the levels of very few host cell transcripts are altered by the compound, while a large number of parasite transcripts have a different abundance after compound treatment. Gene ontology analyses of parasite transcripts with a different abundance revealed an enrichment of cell cycle-related genes, suggesting that the compound alters progression of the parasite through the cell cycle. Assaying the nuclear content of treated parasites demonstrated that compound treatment significantly increased the percentage of parasites in the S/M phase of the cell cycle compared to controls. This compound and its analogs represent a novel scaffold with antiparasitic activity.
机译：弓形虫是专性的细胞内寄生虫，可在发育中的胎儿和免疫功能低下的人类中引起疾病​​。感染可以持续到个体的一生，到目前为止，还没有药物可以消除这种寄生虫特有的慢性囊肿阶段。为了确定可能构成新疗法基础的新化学支架，我们对可能与寄生虫分泌激酶超家族成员进行相互作用的化合物进行了化学信息学筛选，并对其体外生长抑制进行了测定。在17种候选化合物中，我们鉴定出一种具有强抗寄生虫活性的化合物。该化合物的50％抑制浓度（IC（50））为〜2 nM，结构功能分析表明苯并二恶唑部分起作用。该化合物对宿主细胞似乎没有细胞毒性。通过对用该化合物处理过的寄生虫和宿主细胞进行的微阵列分析，我们发现该化合物改变了极少数宿主细胞转录本的水平，而在化合物处理后大量的寄生虫转录本具有不同的丰度。具有不同丰度的寄生虫转录本的基因本体论分析显示，与细胞周期相关的基因富集，表明该化合物通过细胞周期改变了寄生虫的进程。分析处理过的寄生虫的核含量表明，与对照相比，化合物处理显着增加了细胞周期S / M期的寄生虫百分比。该化合物及其类似物代表具有抗寄生虫活性的新型支架。

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