β-片形成抗血管生成Anginex的折叠α/β-肽类似物：结构和生物活性,Journal of the American Chemical Society

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β-片形成抗血管生成Anginex的折叠α/β-肽类似物：结构和生物活性
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2013-10-22 , DOI: 10.1021/ja408054f
Zsófia Hegedüs ₁ , Edit Wéber ₁ , Éva Kriston-Pál ₂ , Ildikó Makra ₂ , Ágnes Czibula ₂ , Éva Monostori ₂ , Tamás A. Martinek ₁

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β-折叠和α-肽序列设计的原理已经很好地确立，而含有同源氨基酸构建块的折叠模拟物的原理仍在研究中。为了揭示含有 β-氨基酸的折叠体的结构-功能关系，我们采用自上而下的方法研究了 anginex 的一系列 α/β-肽类似物，这是一种形成 β-折叠的抗血管生成肽。八种 anginex 类似物是通过系统的 α → β(3) 取代开发的，并通过使用 NMR 和 CD 光谱进行分析。折叠体保留了β-折叠趋势，但折叠倾向降低。β-片层的形成可以由胶束环境诱导，类似于母体肽的形成。当 α → β(3) 交换位于 β-折叠核心时，解构效应更高。β-折叠稳定性与取代模式的分析以及庞大的 β(3)V 和 β(3)I 残基的局部构象偏差表明，α-和 β-残基的 H 键偏好之间的不匹配发挥了重要作用。在结构破坏效应中的作用较小。温度相关的 CD 和 NMR 测量表明，α/β-肽的疏水稳定化程度降低。折叠聚体肽的生物活性分析表明，四种 anginex 衍生物剂量依赖性地抑制小鼠内皮细胞系的增殖。在这项工作中应用的 α → β(3) 替代策略可以成为构建具有降低聚集趋势和改善药代动力学特性的生物活性 β-折叠模拟物的有用方法。

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Foldameric α/β-Peptide Analogs of the β-Sheet-Forming Antiangiogenic Anginex: Structure and Bioactivity

The principles of β-sheet folding and design for α-peptidic sequences are well established, while those for sheet mimetics containing homologated amino acid building blocks are still under investigation. To reveal the structure-function relations of β-amino-acid-containing foldamers, we followed a top-down approach to study a series of α/β-peptidic analogs of anginex, a β-sheet-forming antiangiogenic peptide. Eight anginex analogs were developed by systematic α → β(3) substitutions and analyzed by using NMR and CD spectroscopy. The foldamers retained the β-sheet tendency, though with a decreased folding propensity. β-Sheet formation could be induced by a micellar environment, similarly to that of the parent peptide. The destructuring effect was higher when the α → β(3) exchange was located in the β-sheet core. Analysis of the β-sheet stability versus substitution pattern and the local conformational bias of the bulky β(3)V and β(3)I residues revealed that a mismatch between the H-bonding preferences of the α- and β-residues played a minor role in the structure-breaking effect. Temperature-dependent CD and NMR measurements showed that the hydrophobic stabilization was scaled-down for the α/β-peptides. Analysis of the biological activity of the foldamer peptides showed that four anginex derivatives dose-dependently inhibited the proliferation of a mouse endothelial cell line. The α → β(3) substitution strategy applied in this work can be a useful approach to the construction of bioactive β-sheet mimetics with a reduced aggregation tendency and improved pharmacokinetic properties.

更新日期：2013-10-22

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