Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM CNR), Department of Biochemical Sciences , Sapienza University , P.le A. Moro 5 , 00185 Rome , Italy.
Department of Biochemical Sciences , Sapienza University , P.le A. Moro 5 , 00185 Rome , Italy.
Mol Pharm. 2018 Aug 6;15(8):3069-3078. doi: 10.1021/acs.molpharmaceut.8b00185. Epub 2018 Jun 27.
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.
利什曼病、恰加斯病和昏睡病影响着全世界数百万人的健康，并导致每年约有 5 万人死亡。这些疾病分别由利什曼原虫、克氏锥虫和布氏锥虫引起。这些寄生虫具有许多共同特征，包括基因保守性、蛋白质之间的高氨基酸同一性、糖体和动基体等亚细胞结构的存在以及基因组结构，这可能使药物开发具有家族特异性，而不是物种特异性，即基于对共同保守的寄生虫靶标的抑制。然而，迄今为止，尚未确定出最佳的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公司高通量筛选的 LeishBox，这是一组基于 180 万个化合物的 192 种最佳抗利什曼原虫化合物，用于鉴定已验证的利什曼原虫靶标——三磷酸鸟苷还原酶 (TR) 的特异性抑制剂，同时平行分析同源的人类酶——谷胱甘肽还原酶 (GR)。我们鉴定了三种特异性的高活性 TR 抑制剂，并对已解决的 TR 结构进行了对接，从而阐明了 TR 抑制的可能分子基础。由于动基体中的 TRs 高度保守，并且这些化合物抑制利什曼原虫、克氏锥虫和布氏锥虫的生长，因此鉴定共同的验证靶标可能会导致开发出有效的抗动基体药物。
