Department of Pharmaceutical Manufacturing Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan; Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Bioorg Med Chem. 2013 Nov 1;21(21):6323-7. doi: 10.1016/j.bmc.2013.08.062. Epub 2013 Sep 7.
Inhibition of amyloid β peptide (Aβ) aggregation is a potential therapeutic approach to treat Alzheimer's disease. We report that an O-acyl isopeptide of Aβ1-42 (1) containing an ester bond at the Gly(25)-Ser(26) moiety inhibits Aβ1-42 fibril formation at equimolar ratio. Inhibitory activity was retained by an N-Me-β-Ala(26) derivative (2), in which the ester of 1 was replaced with N-methyl amide to improve chemical stability at physiological pH. Inhibition was verified by fluorescence anisotropy, Western blot, and atomic force microscopy. This report suggests a new class of Aβ aggregation inhibitor based on modification of Aβ1-42 at Gly(25)-Ser(26).
抑制淀粉样β肽（Aβ）聚集是治疗阿尔茨海默病的一种潜在治疗方法。我们报告说，Aβ1-42 的一个 O-酰基异肽（1）在 Gly（25）-Ser（26）部分含有酯键，以等摩尔比例抑制 Aβ1-42 纤维形成。含有 N-Me-β-Ala（26）取代基（2）的抑制剂保留了抑制活性，其中 1 的酯被 N-甲基酰胺取代，以提高生理 pH 值下的化学稳定性。通过荧光各向异性、Western blot 和原子力显微镜验证了抑制作用。本报告提出了一种基于 Aβ1-42 在 Gly（25）-Ser（26）处修饰的 Aβ 聚集抑制剂新类别。
