Department of Neurology, David Geffen School of Medicine, University of California Los Angeles (UCLA), 635 Charles E. Young Drive S., Los Angeles, CA 90095, USA.
ChemMedChem. 2012 Mar 5;7(3):515-22. doi: 10.1002/cmdc.201100584. Epub 2012 Feb 3.
Neurotoxic Aβ42 oligomers are believed to be the main cause of Alzheimer's disease. Previously, we found that the C-terminal fragments (CTFs), Aβ(30-42) and Aβ(31-42) were the most potent inhibitors of Aβ42 oligomerization and toxicity in a series of Aβ(x-42) peptides (x=28-39). Therefore, we chose these peptides as leads for further development. These CTFs are short (12-13 amino acids) hydrophobic peptides with limited aqueous solubility. Our first attempt to attach hydrophilic groups to the N terminus resulted in toxic peptides. Therefore, we next incorporated N-methyl amino acids, which are known to increase the solubility of such peptides by disrupting the β-sheet formation. Focusing on Aβ(31-42), we used a two-step N-methyl amino acid substitution strategy to study the structural factors controlling inhibition of Aβ42-induced toxicity. First, each residue was substituted by N-Me-alanine (N-Me-A). In the next step, in positions where substitution produced a significant effect, we restored the original side chain. This strategy allowed exploring the role of both side chain structure and N-Me substitution in inhibitory activity. We found that the introduction of an N-Me amino acid was an effective way to increase both the aqueous solubility and the inhibitory activity of Aβ(31-42). In particular, N-Me amino acid substitution at position 9 or 11 increased the inhibitory activity relative to the parent peptide. The data suggest that inhibition of Aβ42 toxicity by short peptides is highly structure-specific, providing a basis for the design of new peptidomimetic inhibitors with improved activity, physicochemical properties, and metabolic stability.
神经毒性 Aβ42 寡聚物被认为是阿尔茨海默病的主要原因。此前，我们发现 C 端片段（CTFs），Aβ（30-42）和 Aβ（31-42）是一系列 Aβ（x-42）肽（x=28-39）中抑制 Aβ42 寡聚化和毒性的最有效抑制剂。因此，我们选择这些肽作为进一步开发的先导。这些 CTFs 是短（12-13 个氨基酸）疏水性肽，水溶性有限。我们最初尝试在 N 端连接亲水基团导致肽毒性。因此，我们接下来加入了 N-甲基氨基酸，已知通过破坏β-折叠形成来增加此类肽的溶解度。我们专注于 Aβ（31-42），使用两步 N-甲基氨基酸取代策略研究控制 Aβ42 诱导毒性抑制的结构因素。首先，每个残基都被 N-Me-丙氨酸（N-Me-A）取代。在下一步中，在取代产生显著影响的位置，我们恢复了原始侧链。这种策略允许探索侧链结构和 N-Me 取代在抑制活性中的作用。我们发现，引入 N-Me 氨基酸是提高 Aβ（31-42）水溶性和抑制活性的有效方法。特别是，在位置 9 或 11 引入 N-Me 氨基酸会增加相对于母体肽的抑制活性。数据表明，短肽对 Aβ42 毒性的抑制具有高度的结构特异性，为设计具有改善的活性、物理化学性质和代谢稳定性的新型肽模拟抑制剂提供了依据。
