Peptides Composed of Alternating L- and D-Amino Acids Inhibit Amyloidogenesis in Three Distinct Amyloid Systems Independent of Sequence.
Peptides Composed of Alternating L- and D-Amino Acids Inhibit Amyloidogenesis in Three Distinct Amyloid Systems Independent of Sequence.
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DOI：
10.1016/j.jmb.2016.03.013
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发表时间：
2016-06-05
影响因子：
5.6
通讯作者：
Daggett V
中科院分区：
文献类型：
--
作者：
Kellock J;Hopping G;Caughey B;Daggett V
现在有大量证据表明可溶性低聚物是淀粉样蛋白疾病的主要毒性因子。识别不同和无关淀粉样蛋白种类的毒性可溶性寡聚体形式的抗体的开发表明淀粉样蛋白形成期间的共同构象中间体。我们以前观察到一种新的二级结构元件，我们称之为α-折叠，在分子动力学模拟各种淀粉样蛋白，我们假设，有毒构象是由α-折叠结构。因此，α-折叠可能代表淀粉样蛋白生成的错误折叠中间体的构象特征和肽抑制剂的潜在独特结合靶点。最近，我们报道了一种新的发夹肽（α1或AP 90）的设计和表征，该发夹肽具有稳定的α折叠结构，并抑制β-淀粉样肽Aβ42和甲状腺素运载蛋白的聚集。AP 90是一个23个残基的发夹肽，具有交替的D-和L-氨基酸，具有有利于α-折叠形成的构象倾向和设计的转角。在这项研究中，我们对AP 90进行了反向工程，以确定其哪些设计特征最能赋予α-折叠稳定性和抑制活性。我们目前的实验表征（CD和FTIR）的7肽，旨在实现这一目标。此外，我们测量了它们抑制三种不相关淀粉样物质聚集的能力：Aβ42、甲状腺素运载蛋白和人胰岛胰淀素多肽。我们发现，发夹肽具有交替的L-和D-氨基酸，独立于序列，足以赋予α-折叠结构和抑制聚集。此外，我们发现α-折叠结构稳定性和抑制活性之间存在相关性。
There is now substantial evidence that soluble oligomers are primary toxic agents in amyloid diseases. Development of an antibody recognizing the toxic soluble oligomeric forms of different and unrelated amyloid species suggests a common conformational intermediate during amyloidogenesis. We previously observed common occurrence of a novel secondary structure element, which we call α-sheet, in molecular dynamics simulations of various amyloidogenic proteins, and we hypothesized that the toxic conformer is comprised of α-sheet structure. As such, α-sheet may represent a conformational signature of the misfolded intermediates of amyloidogenesis and a potential unique binding target for peptide inhibitors. Recently, we reported the design and characterization of a novel hairpin peptide (α1 or AP90) that adopts stable α-sheet structure and inhibits the aggregation of the β-Amyloid Peptide Aβ42, and transthyretin. AP90 is a 23-residue hairpin peptide featuring alternating D- and L- amino acids with favorable conformational propensities for α-sheet formation, and a designed turn. For this study, we reverse engineered AP90 to identify which of its design features is most responsible for conferring α-sheet stability and inhibitory activity. We present experimental characterization (CD and FTIR) of 7 peptides designed to accomplish this. In addition, we measured their ability to inhibit aggregation in three unrelated amyloid species: Aβ42, transthyretin, and human islet amylin polypeptide. We found that a hairpin peptide featuring alternating L- and D-amino acids, independent of sequence, is sufficient for conferring α-sheet structure and inhibition of aggregation. Additionally, we show a correlation between α-sheet structural stability and inhibitory activity.