Department of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Florence 50134, Italy.
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
J Med Chem. 2023 Jul 27;66(14):9519-9536. doi: 10.1021/acs.jmedchem.3c00182. Epub 2023 Jul 11.
Natural aminosterols are promising drug candidates against neurodegenerative diseases, like Alzheimer and Parkinson, and one relevant protective mechanism occurs via their binding to biological membranes and displacement or binding inhibition of amyloidogenic proteins and their cytotoxic oligomers. We compared three chemically different aminosterols, finding that they exhibited different (i) binding affinities, (ii) charge neutralizations, (iii) mechanical reinforcements, and (iv) key lipid redistributions within membranes of reconstituted liposomes. They also had different potencies (EC) in protecting cultured cell membranes against amyloid-β oligomers. A global fitting analysis led to an analytical equation describing quantitatively the protective effects of aminosterols as a function of their concentration and relevant membrane effects. The analysis correlates aminosterol-mediated protection with well-defined chemical moieties, including the polyamine group inducing a partial membrane-neutralizing effect (79 ± 7%) and the cholestane-like tail causing lipid redistribution and bilayer mechanical resistance (21 ± 7%), linking quantitatively their chemistry to their protective effects on biological membranes.
天然氨基甾醇是一种很有前途的治疗神经退行性疾病（如阿尔茨海默病和帕金森病）的药物候选物，其相关的保护机制之一是通过与生物膜结合，置换或抑制淀粉样蛋白和其细胞毒性寡聚物的结合抑制。我们比较了三种化学性质不同的氨基甾醇，发现它们表现出不同的（i）结合亲和力，（ii）电荷中和，（iii）机械增强，以及（iv）在重建脂质体的膜内关键脂质重分布。它们在保护培养的细胞膜免受淀粉样β寡聚物方面也具有不同的效力（EC）。全局拟合分析得出了一个解析方程，定量描述了氨基甾醇作为其浓度和相关膜效应的函数的保护作用。该分析将氨基甾醇介导的保护作用与明确定义的化学部分相关联，包括诱导部分膜中和效应的多胺基团（79±7%）和导致脂质重分布和双层机械阻力的胆甾烷样尾部（21±7%），将其化学性质与其对生物膜的保护作用定量联系起来。
