Department of Biochemistry and Organic Chemistry, Uppsala University, Uppsala, Sweden.
J Med Chem. 2009 Dec 24;52(24):8002-9. doi: 10.1021/jm901092h.
Alzheimer's disease (AD), an age related neurodegenerative disorder, threatens to become a major health-economic problem. Assembly of 40- or 42-residue amyloid beta-peptides (Abeta) into neurotoxic oligo-/polymeric beta-sheet structures is an important pathogenic feature in AD, thus, inhibition of this process has been explored to prevent or treat AD. The C-terminal part plays an important role in Abeta aggregation, but most Abeta aggregation inhibitors have targeted the central region around residues 16-23. Herein, we synthesized hexapeptides with varying extents of N-methylation based on residues 32-37 of Abeta, to target its C-terminal region. We measured the peptides' abilities to retard beta-sheet and fibril formation of Abeta and to reduce Abeta neurotoxicity. A penta-N-methylated peptide was more efficient than peptides with 0, 2, or 3 N-methyl groups. This penta-N-methylated peptide moreover increased life span and locomotor activity in Drosophila melanogaster flies overexpressing human Abeta(1-42).
阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，有可能成为一个主要的健康经济问题。40 或 42 个残基的淀粉样β肽（Abeta）组装成神经毒性寡聚/多聚β-折叠结构是 AD 的一个重要发病特征，因此，抑制该过程已被探索用于预防或治疗 AD。C 端部分在 Abeta 聚集中起重要作用，但大多数 Abeta 聚集抑制剂的靶标是残基 16-23 周围的中心区域。在此，我们根据 Abeta 的 32-37 位残基合成了具有不同程度 N-甲基化的六肽，以靶向其 C 端区域。我们测量了这些肽延迟 Abeta 的β-折叠和纤维形成以及降低 Abeta 神经毒性的能力。五甲基化肽比 0、2 或 3 个 N-甲基化肽更有效。此外，这种五甲基化肽还增加了过度表达人 Abeta(1-42)的黑腹果蝇的寿命和运动活性。
