Toward a Drug Against All Kinetoplastids: From LeishBox to Specific and Potent Trypanothione Reductase Inhibitors,Molecular Pharmaceutics

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Toward a Drug Against All Kinetoplastids: From LeishBox to Specific and Potent Trypanothione Reductase Inhibitors
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-06-13 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00185
Andrea Ilari ₁ , Ilaria Genovese ₂ , Fabiana Fiorillo ₂ , Theo Battista ₂ , Ilenia De Ionna ₂ , Annarita Fiorillo ₂ , Gianni Colotti ₁

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Leishmaniasis, Chagas disease, and sleeping sickness affect millions of people worldwide and lead to the death of about 50 000 humans per year. These diseases are caused by the kinetoplastids Leishmania, Trypanosoma cruzi, and Trypanosoma brucei, respectively. These parasites share many general features, including gene conservation, high amino acid identity among proteins, the presence of subcellular structures as glycosomes and the kinetoplastid, and genome architecture, that may make drug development family specific, rather than species-specific, i.e., on the basis of the inhibition of a common, conserved parasite target. However, no optimal molecular targets or broad-spectrum drugs have been identified to date to cure these diseases. Here, the LeishBox from GlaxoSmithKline high-throughput screening, a 192-molecule set of best antileishmanial compounds, based on 1.8 million compounds, was used to identify specific inhibitors of a validated Leishmania target, trypanothione reductase (TR), while analyzing in parallel the homologous human enzyme glutathione reductase (GR). We identified three specific highly potent TR inhibitors and performed docking on the TR solved structure, thereby elucidating the putative molecular basis of TR inhibition. Since TRs from kinetoplastids are well conserved, and these compounds inhibit the growth of Leishmania, Trypanosoma cruzi, and Trypanosoma brucei, the identification of a common validated target may lead to the development of potent antikinetoplastid drugs.

中文翻译：

对抗所有运动质体的药物：从LeishBox到特异且有效的锥虫硫磷还原酶抑制剂

利什曼病，查加斯病和昏睡病影响全世界数百万人，每年导致约5万人死亡。这些疾病是由运动型利什曼原虫，克鲁斯锥虫和布鲁氏锥虫引起的，分别。这些寄生虫具有许多一般特征，包括基因保守性，蛋白质之间的高度氨基酸同一性，糖体和运动质体等亚细胞结构的存在以及基因组结构，这可能会使药物开发家族具有特异性，而不是物种特异性，即抑制常见的，保守的寄生虫靶标的基础。但是，迄今为止，尚未找到最佳分子靶标或广谱药物来治愈这些疾病。在这里，使用了来自葛兰素史克高通量筛选的LeishBox，该试剂盒是基于180万种化合物的192分子最佳抗真菌药化合物，用于鉴定经过验证的利什曼原虫的特定抑制剂目标是锥虫硫磷还原酶（TR），同时平行分析同源的人类酶谷胱甘肽还原酶（GR）。我们确定了三种特定的高效TR抑制剂，并在TR解析的结构上进行了对接，从而阐明了TR抑制的推测分子基础。由于从动质体的TR非常保守，以及这些化合物抑制生长利什曼原虫，克氏锥虫和布氏锥虫，共用验证对象的识别可能导致的强效antikinetoplastid药物的开发。

更新日期：2018-06-13

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