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Pyrazolones Activate the Proteasome by Gating Mechanisms and Protect Neuronal Cells from β-Amyloid Toxicity.
ChemMedChem ( IF 3.6 ) Pub Date : 2019-12-17 , DOI: 10.1002/cmdc.201900612 Anna Maria Santoro 1 , Valeria Lanza 1 , Francesco Bellia 1 , Diego Sbardella 2, 3 , Grazia R Tundo 3 , Alessandra Cannizzo 4 , Giuseppe Grasso 4 , Mariaconcetta Arizzi 4 , Vincenzo G Nicoletti 5 , Stefano Alcaro 6 , Giosuè Costa 6 , Adriana Pietropaolo 6 , Gaetano Malgieri 7 , Gianluca D'Abrosca 7 , Roberto Fattorusso 7 , Sara García-Viñuales 1 , Ikhlas M M Ahmed 1 , Massimiliano Coletta 3 , Danilo Milardi 1
ChemMedChem ( IF 3.6 ) Pub Date : 2019-12-17 , DOI: 10.1002/cmdc.201900612 Anna Maria Santoro 1 , Valeria Lanza 1 , Francesco Bellia 1 , Diego Sbardella 2, 3 , Grazia R Tundo 3 , Alessandra Cannizzo 4 , Giuseppe Grasso 4 , Mariaconcetta Arizzi 4 , Vincenzo G Nicoletti 5 , Stefano Alcaro 6 , Giosuè Costa 6 , Adriana Pietropaolo 6 , Gaetano Malgieri 7 , Gianluca D'Abrosca 7 , Roberto Fattorusso 7 , Sara García-Viñuales 1 , Ikhlas M M Ahmed 1 , Massimiliano Coletta 3 , Danilo Milardi 1
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Proteasome malfunction parallels abnormal amyloid accumulation in Alzheimer's Disease (AD). Here we scrutinize a small library of pyrazolones by assaying their ability to enhance proteasome activity and protect neuronal cells from amyloid toxicity. Tube tests evidenced that aminopyrine and nifenazone behave as 20S proteasome activators. Enzyme assays carried out on an "open gate" mutant (α3ΔN) proteasome demonstrated that aminopyrine activates proteasome through binding the α-ring surfaces and influencing gating dynamics. Docking studies coupled with STD-NMR experiments showed that H-bonds and π-π stacking interactions between pyrazolones and the enzyme play a key role in bridging α1 to α2 and, alternatively, α5 to α6 subunits of the outer α-ring. Aminopyrine and nifenazone exhibit neurotrophic properties and protect differentiated human neuroblastoma SH-SY5Y cells from β-amyloid (Aβ) toxicity. ESI-MS studies confirmed that aminopyrine enhances Aβ degradation by proteasome in a dose-dependent manner. Our results suggest that some pyrazolones and, in particular, aminopyrine are promising compounds for the development of proteasome activators for AD treatment.
中文翻译：
吡唑啉酮通过门控机制激活蛋白酶体，并保护神经元细胞免受β-淀粉样蛋白的毒性。
蛋白酶体功能异常与阿尔茨海默氏病（AD）中异常的淀粉样蛋白积累相似。在这里，我们通过分析吡唑啉酮增强蛋白酶体活性和保护神经元细胞免受淀粉样蛋白毒性的能力，来审查一个小的吡唑啉酮文库。试管试验证明氨基比林和尼非那zone起20S蛋白酶体激活剂的作用。在“开门”突变体（α3ΔN）蛋白酶体上进行的酶分析表明，氨基比林通过结合α环表面和影响门控动力学来激活蛋白酶体。对接研究和STD-NMR实验表明，吡唑啉酮与酶之间的H键和π-π堆积相互作用在桥接外部α环的α1至α2以及α5至α6亚基方面起着关键作用。氨基比林和尼非那宗具有神经营养特性，可保护分化的人神经母细胞瘤SH-SY5Y细胞免受β-淀粉样蛋白（Aβ）的毒性。ESI-MS研究证实，氨基比林可以通过蛋白酶体以剂量依赖的方式增强Aβ的降解。我们的结果表明，某些吡唑啉酮，尤其是氨基比林是有望开发用于AD治疗的蛋白酶体激活剂的化合物。
更新日期：2019-12-18
中文翻译：
吡唑啉酮通过门控机制激活蛋白酶体，并保护神经元细胞免受β-淀粉样蛋白的毒性。
蛋白酶体功能异常与阿尔茨海默氏病（AD）中异常的淀粉样蛋白积累相似。在这里，我们通过分析吡唑啉酮增强蛋白酶体活性和保护神经元细胞免受淀粉样蛋白毒性的能力，来审查一个小的吡唑啉酮文库。试管试验证明氨基比林和尼非那zone起20S蛋白酶体激活剂的作用。在“开门”突变体（α3ΔN）蛋白酶体上进行的酶分析表明，氨基比林通过结合α环表面和影响门控动力学来激活蛋白酶体。对接研究和STD-NMR实验表明，吡唑啉酮与酶之间的H键和π-π堆积相互作用在桥接外部α环的α1至α2以及α5至α6亚基方面起着关键作用。氨基比林和尼非那宗具有神经营养特性，可保护分化的人神经母细胞瘤SH-SY5Y细胞免受β-淀粉样蛋白（Aβ）的毒性。ESI-MS研究证实，氨基比林可以通过蛋白酶体以剂量依赖的方式增强Aβ的降解。我们的结果表明，某些吡唑啉酮，尤其是氨基比林是有望开发用于AD治疗的蛋白酶体激活剂的化合物。
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