Identification of Trypanocidal Activity for Known Clinical Compounds Using a New Trypanosoma cruzi Hit-Discovery Screening Cascade
Identification of Trypanocidal Activity for Known Clinical Compounds Using a New Trypanosoma cruzi Hit-Discovery Screening Cascade
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DOI：
10.1371/journal.pntd.0004584
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发表时间：
2016-04-01
影响因子：
3.8
通讯作者：
Gray, David W.
中科院分区：
文献类型：
--
作者：
De Rycker, Manu;Thomas, John;Gray, David W.
恰加斯病是拉丁美洲的一个重大健康问题，现有的治疗方法在毒性和疗效方面存在重大问题。因此，迫切需要通过再利用策略或通过开发新的化学实体来开发新的治疗方法。关键的第一步是从化合物库中鉴定具有抗克氏锥虫活性的化合物。在这里，我们描述了一个命中发现筛选级联，旨在专门确定命中，有适当的抗寄生虫的性能，以保证进一步发展。该级联包括一个基于成像的主要测定，然后是新开发的和适当规模的次要测定，以预测化合物的毒性和杀灭率。最后，我们纳入了细胞色素P450 CYP51生化测定，以消除化合物，欠他们的表型反应，抑制这种酶。我们报告使用的级联分析两个小的图书馆，含有临床测试的化合物，并确定氯马斯汀，氮卓斯汀，艾芬地尔，齐拉西酮和氯贝特作为分子具有适当的配置文件。临床衍生的药代动力学和毒性数据的分析表明，这些都不适合重新利用，但它们可能代表了进一步优化恰加斯病治疗的合适起点。
Chagas disease is a significant health problem in Latin America and the available treatments have significant issues in terms of toxicity and efficacy. There is thus an urgent need to develop new treatments either via a repurposing strategy or through the development of new chemical entities. A key first step is the identification of compounds with anti-Trypanosoma cruzi activity from compound libraries. Here we describe a hit discovery screening cascade designed to specifically identify hits that have the appropriate anti-parasitic properties to warrant further development. The cascade consists of a primary imaging-based assay followed by newly developed and appropriately scaled secondary assays to predict the cidality and rate-of-kill of the compounds. Finally, we incorporated a cytochrome P450 CYP51 biochemical assay to remove compounds that owe their phenotypic response to inhibition of this enzyme. We report the use of the cascade in profiling two small libraries containing clinically tested compounds and identify Clemastine, Azelastine, Ifenprodil, Ziprasidone and Clofibrate as molecules having appropriate profiles. Analysis of clinical derived pharmacokinetic and toxicity data indicates that none of these are appropriate for repurposing but they may represent suitable start points for further optimisation for the treatment of Chagas disease.