Pharmacological Validation of Trypanosoma brucei Phosphodiesterases as Novel Drug Targets
Pharmacological Validation of Trypanosoma brucei Phosphodiesterases as Novel Drug Targets
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DOI：
10.1093/infdis/jir857
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发表时间：
2012-07-15
影响因子：
6.4
通讯作者：
Seebeck, Thomas
中科院分区：
文献类型：
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作者：
de Koning, Harry P.;Gould, Matthew K.;Seebeck, Thomas
被忽视的传染病药物的开发经常使用寄生虫特异性酶作为靶标。我们在这里证明，具有高度保守的人类同源物的寄生虫酶可能代表一个有希望的新的潜在药物靶点库。人类致命昏睡病的病原体布鲁氏锥虫的环核苷酸特异性磷酸二酯酶（PDEs）对寄生虫至关重要。高度保守的人类同源物是公认的药物靶点。我们在这里描述什么是我们所知的第一个药理验证锥虫体PDEs作为药物靶点。一个专有化合物库的高通量筛选确定了许多有效的命中。其中一个化合物，四氢酞嗪酮化合物A (Cpd A)，进一步表征。它引起细胞内环磷酸腺苷（cAMP）的急剧增加。短期内细胞活力不受影响，但细胞增殖立即受到抑制，3天内细胞死亡。Cpd A阻止细胞分裂，导致多核、多鞭毛细胞最终溶解。这些观察结果在药理学上证实了高度保守的锥虫体PDEs是潜在的药物靶点。
The development of drugs for neglected infectious diseases often uses parasite-specific enzymes as targets. We here demonstrate that parasite enzymes with highly conserved human homologs may represent a promising reservoir of new potential drug targets. The cyclic nucleotide-specific phosphodiesterases (PDEs) of Trypanosoma brucei, causative agent of the fatal human sleeping sickness, are essential for the parasite. The highly conserved human homologs are well-established drug targets. We here describe what is to our knowledge the first pharmacological validation of trypanosomal PDEs as drug targets. High-throughput screening of a proprietary compound library identified a number of potent hits. One compound, the tetrahydrophthalazinone compound A (Cpd A), was further characterized. It causes a dramatic increase of intracellular cyclic adenosine monophosphate (cAMP). Short-term cell viability is not affected, but cell proliferation is inhibited immediately, and cell death occurs within 3 days. Cpd A prevents cytokinesis, resulting in multinucleated, multiflagellated cells that eventually lyse. These observations pharmacologically validate the highly conserved trypanosomal PDEs as potential drug targets.