Efficient -Helix Induction in a Linear Peptide Chain by N-Capping with a ridged-tricyclic Diproline Analogue
Efficient -Helix Induction in a Linear Peptide Chain by N-Capping with a ridged-tricyclic Diproline Analogue
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DOI：
10.1002/anie.201302014
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发表时间：
2013-09-02
影响因子：
16.6
通讯作者：
Schmalz, Hans-Guenther
中科院分区：
文献类型：
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作者：
Hack, Verena;Reuter, Cedric;Schmalz, Hans-Guenther
形成α螺旋基序的短氨基酸序列的识别代表了许多蛋白质-蛋白质相互作用（PPI）中的重要事件，并且此类基序的错误折叠通常与疾病相关，包括癌症和HIV。[1-3]因此，寻找稳定或模拟相关二级结构的合成化合物，同时将关键相互作用残基正确呈现到识别蛋白质表面构成了巨大的挑战。[4]由于定义感兴趣的 PPI 的关键结构特性及其对 PPI 自由能的贡献大多未知，因此通过使用具有明确（稳定）二级结构的修饰线性肽来识别这些特性将很有吸引力。然而，线性肽的构象稳定是一项复杂的任务，并且开发了几种策略来解决这个问题。例如，可以通过 i 和 i+ 4 个残基侧链之间的化学键来增强螺旋倾向。 [5]另一个概念使用非天然寡聚物，例如采用螺旋构象的类肽 [6] 或 ß-肽 [7]。由于主要由残基 i、i+ 3 和/或 i+ 4 和 i+ 7 的侧链构建的表面对于 α 螺旋识别很重要，因此将功能残基定向在空间定义位置（类似于氨基酸侧链）的构象限制支架是有前途的短 α 螺旋肽的模拟物。 [8] Kemp 和同事提出了一个优雅的概念，他们设计了位于肽 N 末端的构象限制的二脯氨酸模板。 [9]通过预先定向前四个氢键，他们实现了有利于 α 螺旋二级结构的偏差。然而，由于所用支架的双构象行为，其中两个脯氨酸单元通过柔性硫代亚甲基单元桥接，并且两个构象异构体（在溶液中相等）中只有一个表现出所需的螺旋诱导特性，因此效果并不特别明显。 [10]在分子模型的支持下，我们设想支架 ProM-5 [11](1)，即通过亚乙基桥制成刚性的 Pro-Pro 类似物，应该表现出比 Kemp [9, 10] 提出的 α-螺旋诱导 N-cap 更好的特性，因为它应该表现出或多或少的单构象行为（图 1）。
The recognition of short amino acid sequences forming an αhelical motif represents an important event in many protein–protein interactions (PPI), and misfolding of such motifs is often associated with diseases, including cancer and HIV.[1–3] Accordingly, the search for synthetic compounds stabilizing or mimicking the relevant secondary structure while properly presenting the key interaction residues to the recognizing protein surface constitutes a great challenge.[4] As the key structural properties defining the PPI of interest and their contribution to the free energy of the PPI are mostly not known, it would be attractive to identify these properties by using modified linear peptides with a defined (stabilized) secondary structure. However, conformational stabilization of a linear peptide is a complex task and several strategies were developed to address this problem. For instance, the helical propensity can be enhanced by means of a chemical linkage between the side chains of i and i+ 4 residues.[5] Another concept uses unnatural oligomers such as peptoids [6] or ß-peptides [7] adopting a helical conformation. Since mostly the surface built by the side chains of the residues i, i+ 3 and/or i+ 4, and i+ 7 is important for α-helix recognition, conformationally restricted scaffolds that orient functional residues in spatially defined positions (resembling the amino acid side chains) are promising mimics of short α-helical peptides.[8] An elegant concept was introduced by Kemp and co-workers who devised conformationally restricted diproline templates positioned at the N-terminus of a peptide.[9] By preorienting the first four hydrogen bonds they achieved a bias in favor of the α-helical secondary structure. However, the effects were not particularly pronounced owing to the biconformational behavior of the used scaffold in which the two proline units were bridged by a flexible thiomethylene unit and only one of two conformers (equally populated in solution) exhibited the desired helix-inducing properties.[10] Supported by molecular modeling, we envisioned that the scaffold ProM-5 [11](1), that is, a Pro-Pro analogue made rigid by means of an ethylidene bridge, should display better properties than the α-helix-inducing N-cap presented by Kemp [9, 10] because it should exhibit a more or less monoconformational behavior (Figure 1).