Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis.
Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis.
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DOI：
10.1074/jbc.m115.700385
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发表时间：
2016-02-26
期刊：
影响因子：
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通讯作者：
Selwood DL
中科院分区：
文献类型：
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作者：
Warne J;Pryce G;Hill JM;Shi X;Lennerås F;Puentes F;Kip M;Hilditch L;Walker P;Simone MI;Chan AW;Towers GJ;Coker AR;Duchen MR;Szabadkai G;Baker D;Selwood DL
线粒体渗透性转换孔是神经退行性疾病如多发性硬化症和脑和心脏缺血-再灌注损伤的公认药物靶标。肽基脯氨酰异构酶，亲环素D（CypD，PPIF），是一个积极的调节器的孔，和遗传下调或敲除改善疾病模型的结果。目前的肽基脯氨酰异构酶抑制剂在紧密保守的亲环蛋白旁系同源物之间没有显示出选择性，并表现出显著的脱靶效应、免疫抑制和毒性。因此，我们设计并合成了一种新的神经靶向CypD抑制剂，JW 47，使用喹啉阳离子栓系到环孢素。X射线分析用于验证设计概念，生物学评价显示CypD的选择性细胞抑制和与环孢素相比具有降低的细胞毒性的渗透性转换孔。在多发性硬化症神经变性的实验性自身免疫性脑脊髓炎疾病模型中，JW 47表现出对轴突的显著保护作用，并以最小的免疫抑制改善了运动评估。这些研究结果表明，选择性CypD抑制可能代表MS的可行治疗策略，并确定喹啉作为体内使用的线粒体靶向基团。
The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.