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Kinetin Riboside and Its ProTides Activate the Parkinson’s Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-03-28 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01897
Laura Osgerby 1 , Yu-Chiang Lai 2 , Peter J. Thornton 3 , Joseph Amalfitano 1 , Cécile S. Le Duff 1 , Iqra Jabeen 1 , Hachemi Kadri 3 , Ageo Miccoli 4 , James H. R. Tucker 1 , Miratul M. K. Muqit 2, 5 , Youcef Mehellou 4
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-03-28 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01897
Laura Osgerby 1 , Yu-Chiang Lai 2 , Peter J. Thornton 3 , Joseph Amalfitano 1 , Cécile S. Le Duff 1 , Iqra Jabeen 1 , Hachemi Kadri 3 , Ageo Miccoli 4 , James H. R. Tucker 1 , Miratul M. K. Muqit 2, 5 , Youcef Mehellou 4
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Since loss of function mutations of PINK1 lead to early onset Parkinson’s disease, there has been growing interest in the discovery of small molecules that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability, and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases.
中文翻译：
激动素核糖苷及其蛋白激活与帕金森病相关的PTEN诱导的假定激酶1（PINK1），与线粒体去极化无关。
由于PINK1功能突变的丧失导致帕金森氏病的早期发作，因此人们对发现能放大PINK1激酶活性的小分子的兴趣日益浓厚。我们在此报告了四种激动素核糖苷ProTides的设计，合成，血清稳定性和水解性。这些ProTides与激动素核糖体一起激活了独立于线粒体去极化的细胞中的PINK1。这突出了修饰的核苷及其磷酸盐前药作为神经退行性疾病治疗的潜力。
更新日期：2017-03-28
中文翻译：
激动素核糖苷及其蛋白激活与帕金森病相关的PTEN诱导的假定激酶1（PINK1），与线粒体去极化无关。
由于PINK1功能突变的丧失导致帕金森氏病的早期发作，因此人们对发现能放大PINK1激酶活性的小分子的兴趣日益浓厚。我们在此报告了四种激动素核糖苷ProTides的设计，合成，血清稳定性和水解性。这些ProTides与激动素核糖体一起激活了独立于线粒体去极化的细胞中的PINK1。这突出了修饰的核苷及其磷酸盐前药作为神经退行性疾病治疗的潜力。
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