Insights into the Impact of a Membrane-Anchoring Moiety on the Biological Activities of Bivalent Compounds As Potential Neuroprotectants for Alzheimer’s Disease,Journal of Medicinal Chemistry

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Insights into the Impact of a Membrane-Anchoring Moiety on the Biological Activities of Bivalent Compounds As Potential Neuroprotectants for Alzheimer’s Disease
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-05 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01284
Liu He , Yuqi Jiang , Kai Liu , Victoria Gomez-Murcia ₁ , Xiaopin Ma ₂ , Alejandro Torrecillas ₁ , Qun Chen , Xiongwei Zhu ₂ , Edward Lesnefsky , Juan C. Gomez-Fernandez ₁ , Bin Xu ₃ , Shijun Zhang

Affiliation

Bivalent compounds anchoring in different manners to the membrane were designed and biologically characterized to understand the contribution of the anchor moiety to their biological activity as neuroprotectants for Alzheimer’s disease. Our results established that the anchor moiety is essential, and we identified a preference for diosgenin, as evidenced by 17MD. Studies in primary neurons and mouse brain mitochondria also identified 17MD as exhibiting activity on neuritic outgrowth and the state 3 oxidative rate of glutamate while preserving the coupling capacity of the mitochondria. Significantly, our studies demonstrated that the integrated bivalent structure is essential to the observed biological activities. Further studies employing bivalent compounds as probes in a model membrane also revealed the influence of the anchor moiety on how they interact with the membrane. Collectively, our results suggest diosgenin to be an optimal anchor moiety, providing bivalent compounds with promising pharmacology that have potential applications for Alzheimer’s disease.

中文翻译：

膜固定部分对二价化合物作为阿尔茨海默氏病潜在神经保护剂的生物活性的影响的见解。

设计了以不同方式锚定到膜上的二价化合物，并对其生物学特性进行了表征，以了解锚定部分对它们作为阿尔茨海默氏病神经保护剂的生物学活性的贡献。我们的研究结果确定了锚固部分是必不可少的，并且我们确定了对薯gen皂素的偏好，如17MD所示。对原代神经元和小鼠脑线粒体的研究还确定了17MD表现出对神经生长的活性和谷氨酸的3态氧化速率，同时保持线粒体的偶联能力。重要的是，我们的研究表明整合的二价结构对于观察到的生物活性至关重要。在模型膜中使用二价化合物作为探针的进一步研究还揭示了锚部分对它们如何与膜相互作用的影响。总的来说，我们的结果表明薯os皂甙元是最佳的锚定基团，为具有潜在药理作用的二价化合物提供了潜在的治疗阿尔茨海默氏病的潜力。

更新日期：2018-01-05

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