Diverse Inhibitor Chemotypes Targeting Trypanosoma cruzi CYP51
Diverse Inhibitor Chemotypes Targeting Trypanosoma cruzi CYP51
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DOI：
10.1371/journal.pntd.0001736
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发表时间：
2012-07-01
影响因子：
3.8
通讯作者：
Podust, Larissa M.
中科院分区：
文献类型：
--
作者：
Gunatilleke, Shamila S.;Calvet, Claudia M.;Podust, Larissa M.
背景资料：查加斯病是一种世卫组织和美国国立卫生研究院指定的被忽视的热带疾病，是拉丁美洲的地方病，也是由于人口流动而在北美和欧洲出现的一种新感染。尽管恰加斯病是心力衰竭引起的发病率和死亡率的主要原因，并在受影响地区造成沉重的经济负担，但由于不利的经济刺激，制药业很少注意到它。发现和开发恰加斯病化疗的新途径是一个明确的优先事项。方法学/主要发现：致病真菌的膜固醇需求与寄生原生动物克氏锥虫（恰加斯人心脏病的病原体）的膜固醇需求之间的相似性，导致人们重新利用抗真菌唑类固醇抑制剂14 α-脱甲基酶（CYP 51）来治疗恰加斯病。为了使抗Chagglutinase候选药物的治疗管道多样化，我们开发了一种方法，包括直接探测T。cruzi CYP 51活性位点与合成小分子文库。基于靶标的高通量筛选将类似于104，000个小分子的文库减少到185个命中，估计具有纳摩尔K-D值，而针对T. cruzi感染的骨骼肌成肌细胞产生57个活性命中，EC 50
Background: Chagas Disease, a WHO- and NIH-designated neglected tropical disease, is endemic in Latin America and an emerging infection in North America and Europe as a result of population moves. Although a major cause of morbidity and mortality due to heart failure, as well as inflicting a heavy economic burden in affected regions, Chagas Disease elicits scant notice from the pharmaceutical industry because of adverse economic incentives. The discovery and development of new routes to chemotherapy for Chagas Disease is a clear priority.Methodology/Principal Findings: The similarity between the membrane sterol requirements of pathogenic fungi and those of the parasitic protozoon Trypanosoma cruzi, the causative agent of Chagas human cardiopathy, has led to repurposing anti-fungal azole inhibitors of sterol 14 alpha-demethylase (CYP51) for the treatment of Chagas Disease. To diversify the therapeutic pipeline of anti-Chagasic drug candidates we exploited an approach that included directly probing the T. cruzi CYP51 active site with a library of synthetic small molecules. Target-based high-throughput screening reduced the library of similar to 104,000 small molecules to 185 hits with estimated nanomolar K-D values, while cross-validation against T. cruzi-infected skeletal myoblast cells yielded 57 active hits with EC50