How useful is ferrocene as a scaffold for the design of β-sheet foldamers?
How useful is ferrocene as a scaffold for the design of β-sheet foldamers?
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DOI：
10.1002/anie.200801460
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Kraatz, Heinz-Bernhard
中科院分区：
文献类型：
--
作者：
Chowdhury, Somenath;Schatte, Gabriele;Kraatz, Heinz-Bernhard
结构明确的合成肽折叠体的设计在某种程度上是出于研究蛋白质折叠机制[1]或生物化学过程[2]的目的，以产生具有潜在生物学应用的分子[3]或产生新材料。[4]采用b-片状构象的折叠体具有特别的魅力，并且作为模型系统在促进我们对疾病（包括阿尔茨海默氏病和亨廷顿氏病）的理解方面具有巨大的潜力。非天然支架对于获得具有确定的、稳定的b-片层样结构的折叠体特别重要。[5，6]二茂铁（Fc）已被研究为分子支架，支持连接到两个平行双环的两个podant肽链之间的b-折叠样相互作用。[7]氨基酸的1，n '-二取代的Fc-缀合物表现出独特的非蛋白质“交叉链”H-键合模式，其中形成10元H-键合环（方案1中的化合物1）。这一结果表明，简单的延伸可能导致具有延伸的b-片层样结构的折叠体。然而，如方案1中的化合物2所示，将两个取代基各自延伸一个氨基酸以形成二肽，显示了指向相反方向的两个额外的氨基酸，同时保持了近端氨基酸的H-键合模式。通过N-杂环修饰肽缀合物的两个C末端产生ag turn基序，其中肽链参与链内H-键合，[8]因此引起了对Fc支架支持延伸的b-折叠样结构的真实价值的严重关注。问题似乎是与共线排列的肽链和潜在的空间拥挤的Fc核心。通过环化迫使肽形成特定构象导致了H-键合模式，尽管不相同，但在H-键合环和肽二面角的形成方面与蛋白质b-片层中观察到的有一些相似之处。在分子间水平上，氢键相互作用将缔合物形成前所未有的超分子组装体。[9]这一成功的关键是使用甘氨酸（Gly）作为柔性氨基酸，其可以适应接近Fc核心的宽范围的二面角。基于这些结果，我们假设，如果选择Gly作为近端氨基酸，然后是具有高b-折叠倾向的氨基酸，例如缬氨酸（瓦尔）或异亮氨酸（Ile），[10]则可能形成支持两个侧肽取代基之间的延长的H-键合相互作用的无环Fc-肽折叠体（方案1中的3）。基于这些考虑，我们选择了序列Gly-Val-Cys（Cys=半胱氨酸）和Gly-Ile-Cys，并通过N-末端Gly残基将它们偶联至1，1 ′-Fc-二羧酸。在这里，我们的调查结果，这表明，这些折叠体表现出稳定的氢键相互作用与交替的b-片样构象的肽骨架。
The design of structurally well-defined synthetic peptide foldamers is motivated to some degree by the aim to study mechanisms of protein folding [1] or biochemical processes,[2] to generate molecules with potential biological applications,[3] or to generate novel materials.[4] Foldamers adopting b-sheetlike conformations have held a particular fascination and have tremendous potential as model systems in furthering our understanding of diseases, including Alzheimer s and Huntington s diseases. Non-natural scaffolds have been particularly important for obtaining foldamers with a defined, stable b-sheet-like structure.[5, 6] Ferrocene (Fc) has been investigated as a molecular scaffold that supports b-sheet-like interactions between two podant peptide chains that are linked to the two parallel cyclopentadienyl rings.[7] 1, n’-disubstituted Fc-conjugates of amino acids exhibit a distinct non-proteinic “cross-strand” H-bonding pattern, in which a 10-membered H-bonded ring is formed (compound 1 in Scheme 1). This result suggests that simple extension might result in a foldamer that possesses an extended b-sheet-like structure. However, extending the two substituents by one amino acid each to form a dipeptide, as illustrated by compound 2 in Scheme 1, shows the two additional amino acids pointing in opposite directions, while the H-bonding pattern of the proximal amino acids is maintained. Modification of the two C termini of the peptide conjugate by a N-heterocycle yields ag turn motif, in which the peptide strands are engaged in intrastrand H-bonding,[8] thus raising serious concerns of the true value of the Fc scaffold to support an extended b-sheet-like structure. The problem appears to be with the colinear alignment of the peptide chains and potential steric congestion about the Fc core. Forcing peptides into a specific conformation by cyclization has led to a H-bonding pattern that, although not identical, bears some resemblance to what is observed in proteinic b-sheets, in terms of the formation of H-bonded rings and peptide dihedral angles. On an intermolecular level, H-bonding interactions form associated conjugates into unprecedented supramolecular assemblies.[9] The key to this success was the use of glycine (Gly) as a flexible amino acid that can accommodate a wide range of dihedral angles proximal to the Fc core. Based on these results, we hypothesized that if Gly is chosen as proximal amino acid followed by an amino acid with high b-sheet propensity, such as valine (Val) or isoleucine (Ile),[10] it might be possible to form acyclic Fc-peptide foldamers that support extended H-bonding interactions between the two pendant peptide substitutents (3 in Scheme 1). Based on these considerations, we selected the sequences Gly-Val-Cys (Cys= cysteine) and Gly-Ile-Cys and coupled them to 1, 1’-Fc-dicarboxylic acid through the N-terminal Gly residues. Herein, the results of our investigations are presented, which demonstrate that these foldamers exhibit a stable H-bonding interaction with an alternating b-sheet-like conformation of the peptide backbone.