Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer's Disease.
Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer's Disease.
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DOI：
10.3233/jad-150618
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Arancio O
中科院分区：
文献类型：
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作者：
Fà M;Zhang H;Staniszewski A;Saeed F;Shen LW;Schiefer IT;Siklos MI;Tapadar S;Litosh VA;Libien J;Petukhov PA;Teich AF;Thatcher GR;Arancio O
阿尔茨海默病是与神经退行性过程相关的最重要的脑病理之一，与calpain介导的蛋白水解过度激活有关。先前的数据显示，钙蛋白酶抑制由淀粉样蛋白-β过量产生的异常突触可塑性和记忆具有令人信服的功效，淀粉样蛋白-β是该疾病的一个独特标志。此外，钙蛋白酶抑制剂在阿尔茨海默病中的有益作用是可以通过钙蛋白酶过度激活的发生来预测的，钙蛋白酶过度激活导致记忆相关通路的损伤，而异常钙流入可能独立于淀粉样蛋白-β升高。然而，目前可用的有效钙蛋白酶抑制剂分子缺乏足够的选择性。这项工作旨在表征一类新型环氧化合物基抑制剂的功效，与原型环氧化合物基通用calpain抑制剂E64相比，合成了对calpain 1的选择性和效力更高的抑制剂。功能和初步毒理学研究都证明了新型选择性钙蛋白酶抑制剂NYC438和NYC488的有效性、效力和安全性。
Alzheimer’s disease, one of the most important brain pathologies associated with neurodegenerative processes, is related to overactivation of calpain-mediated proteolysis. Previous data showed a compelling efficacy of calpain inhibition against abnormal synaptic plasticity and memory produced by the excess of amyloid-β, a distinctive marker of the disease. Moreover, a beneficial effect of calpain inhibitors in Alzheimer’s disease is predictable by the occurrence of calpain hyperactivation leading to impairment of memory-related pathways following abnormal calcium influxes that might ensue independently of amyloid-β elevation. However, molecules currently available as effective calpain inhibitors lack adequate selectivity. This work is aimed at characterizing the efficacy of a novel class of epoxide-based inhibitors, synthesized to display improved selectivity and potency towards calpain 1 compared to the prototype epoxide-based generic calpain inhibitor E64. Both functional and preliminary toxicological investigations proved the efficacy, potency, and safety of the novel and selective calpain inhibitors NYC438 and NYC488 as possible therapeutics against the disease.