洞察膜锚定部分对二价化合物生物活性的影响，这些化合物可能是阿尔茨海默病的神经保护剂。
Insights into the Impact of a Membrane-Anchoring Moiety on the Biological Activities of Bivalent Compounds As Potential Neuroprotectants for Alzheimer's Disease.
机构信息
Department of Biochemistry and Molecular Biology, Faculty of Veterinary, University of Murcia , Murcia, 30080, Spain.
Department of Pathology, Case Western Reserve University , Cleveland, Ohio 44106, United States.
出版信息
J Med Chem. 2018 Feb 8;61(3):777-790. doi: 10.1021/acs.jmedchem.7b01284. Epub 2018 Jan 5.
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.
设计了以不同方式锚定在膜上的双价化合物，并对其进行了生物学表征，以了解锚定部分对它们作为阿尔茨海默病神经保护剂的生物活性的贡献。我们的结果证实了锚定部分是必不可少的，并且我们确定了甾体皂苷元作为优选，这一点可以通过 17MD 得到证明。在原代神经元和小鼠脑线粒体中的研究也表明 17MD 可以促进神经突生长和谷氨酸的状态 3 氧化率，同时保持线粒体的偶联能力。重要的是，我们的研究表明，整合的双价结构对于观察到的生物学活性是必不可少的。进一步在模型膜中使用双价化合物作为探针的研究也揭示了锚定部分对它们与膜相互作用方式的影响。总的来说，我们的研究结果表明甾体皂苷元是一种理想的锚定部分，为双价化合物提供了有前途的药理学特性，可能对阿尔茨海默病有应用前景。
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