Amyloid-β （Aβ） protein aggregation is the main hallmark of Alzheimer＇s disease （AD）. Inhibition of Aft fibrillation is thus a promising therapeutic approach to the prevention and treatment of AD. Recently, we d...Amyloid-β （Aβ） protein aggregation is the main hallmark of Alzheimer＇s disease （AD）. Inhibition of Aft fibrillation is thus a promising therapeutic approach to the prevention and treatment of AD. Recently, we designed a heptapeptide inhibitor, LVFFARK （LK7）. LK7 shows a promising inhibitory capability on Aft fibrillation, but is prone to self-assembling and displays high cytotoxicity, which would hinder its practical application. Herein, we modified LK7 by a head-to-tail cyclization and obtained a cyclic LK7 （cLK7）. cLK7 exhibits a different self-assembly behavior from LK7, and has higher stability against proteolysis than LK7 and little cytotoxicity to SH-SY5Y cells. Thermodynamic analysis revealed that both LK7 and cLK7 could bind to Aβ40 by electrostatic interactions, hydrogen bonding and hydrophobic interactions, but the binding affinity of cLK7 for Afl40 （KD = 4.96 μmol/L） is six times higher than that of LK7 （KD = 32.2 μmol/L）. The strong binding enables cLK7 to stabilize the secondary structure of Aβ40 and potently inhibit its nucleation, fibrillation and cytotoxicity at extensive concentration range, whereas LK7 could only moderately inhibit Aβ40 fibrillation and cytotoxicity at low concentrations. The findings indicate that the peptide cyclization is a promising approach to enhance the performance of peptide-based amyloid inhibitors.展开更多
文摘本文以76份青稞为研究对象,利用近红外光谱仪采集青稞4000~10000 cm-1波段光谱,并联合其水分、β-葡聚糖、直链淀粉、蛋白质实测含量数值,构建了基于近红外光谱技术的青稞特征营养成分含量快速检测模型。结果显示,SG卷积平滑(Savitzky Golay,SG)是水分、直链淀粉、β-葡聚糖含量的偏最小二乘法(Partial Least Squares,PLS)预测模型的最优光谱预处理方法,而SG卷积平滑+多元散射校正(Multiplicative Scatter Correction,MSC)是蛋白质含量的偏最小二乘法(PLS)预测模型的最优光谱预处理方法。为进一步提高青稞各成分含量预测模型的准确性,考察了竞争性自适应重加权法(Competitive Adaptive Reweighted Sampling,CARS)、连续投影算法(Successive Projections Algorithm,SPA)和变量组合集群分析混合迭代保留信息变量法(Variables Combination Population Analysis and Iterative Retained Information Variable,VCPA-IRIV)特征波长选择算法对模型预测结果的影响。结果表明,VCPA-IRIV处理可有效提高水分、直链淀粉、蛋白质含量预测模型的预测决定系数,降低预测均方根误差;CARS对β-葡聚糖含量预测模型优化效果显著。基于上述最优方法建立的青稞水分、β-葡聚糖、直链淀粉、蛋白质实测含量预测模型,其预测相关系数分别为0.9868、0.9808、0.9701、0.9879;预测均方根误差分别为0.2042、0.1846、0.8135、0.2095。综上,本研究建立的基于近红外光谱的青稞特征营养成分含量快速检测模型具有较高的准确性,对加工企业快速了解原料品质及高效筛选合格原料有一定指导意义。
文摘Amyloid-β （Aβ） protein aggregation is the main hallmark of Alzheimer＇s disease （AD）. Inhibition of Aft fibrillation is thus a promising therapeutic approach to the prevention and treatment of AD. Recently, we designed a heptapeptide inhibitor, LVFFARK （LK7）. LK7 shows a promising inhibitory capability on Aft fibrillation, but is prone to self-assembling and displays high cytotoxicity, which would hinder its practical application. Herein, we modified LK7 by a head-to-tail cyclization and obtained a cyclic LK7 （cLK7）. cLK7 exhibits a different self-assembly behavior from LK7, and has higher stability against proteolysis than LK7 and little cytotoxicity to SH-SY5Y cells. Thermodynamic analysis revealed that both LK7 and cLK7 could bind to Aβ40 by electrostatic interactions, hydrogen bonding and hydrophobic interactions, but the binding affinity of cLK7 for Afl40 （KD = 4.96 μmol/L） is six times higher than that of LK7 （KD = 32.2 μmol/L）. The strong binding enables cLK7 to stabilize the secondary structure of Aβ40 and potently inhibit its nucleation, fibrillation and cytotoxicity at extensive concentration range, whereas LK7 could only moderately inhibit Aβ40 fibrillation and cytotoxicity at low concentrations. The findings indicate that the peptide cyclization is a promising approach to enhance the performance of peptide-based amyloid inhibitors.
