Naturally derived peptide scaffolds as asymmetric ligands for catalysis

生物催化在现代有机合成和化学物质制造中起着不可或缺的作用。金属酶的反应性由第一配位层中的金属中心和供体原子控制，与小的合成催化剂相同。酶的高效率和高选择性依赖于复杂的蛋白质结构，而对生物催化剂进行合理的结构-活性研究通常并不简单。原则上，可以采用保留有序空间组织的更简单肽的合成。与酶相比，肽是基本实体，并且它们可以容易地合成，从而能够在不损失结构复杂性的情况下精确调节立体电子性质。在这个项目中，我们希望探索人工金属酶的设计，通过工程结构定义的天然迷你蛋白质，以适应金属中心。选择的氨基酸将被能够结合金属并显示催化活性的合适配位氨基酸取代。两个肽衍生自蜂毒蛋白，蜂毒小蛋白，将合成用于此目的。与apamin相比，这两种肽都具有相似的α-螺旋序列，并且它们的链被设计为显示所有四个天然半胱氨酸残基（4-Cys）或两个半胱氨酸和两个组氨酸（2-His-2Cys），这些支架可以用作不同后过渡金属如Pd（II）和Pt（II）以及Cu（II）的配体，其可以通过组氨酸的咪唑环或半胱氨酸中的巯基结合。由此产生的肽金属络合物将代表潜在的催化剂，如转移氢化不对称转化作为最小的人工金属酶。

Biocatalysis plays an integral role within modern organic synthesis and chemical substances manufacturing. Reactivity of metalloenzymes is governed by the metal center and donor atoms in the first coordination sphere, in the same way as for small synthetic catalysts. Enzymes' great efficiency and selectivity relies on inextricably complex protein structures and a rational structure-activity study of a biocatalyst is usually not straightforward. In principle the synthesis of a simpler peptide which retains an ordered spatial organization, could be adopted. Peptides are elementary entities compared to enzymes, and they can easily be synthesized, enabling precise tuning of stereoelectronic properties without losing structural complexity. In this project we wish to explore the design of artificial metallo-enzymes by engineering structurally defined natural mini-proteins to accommodate a metal centre. Selected amino acids will be replaced with suitable coordinating amino acids which are capable of binding metals and display catalytic activity. Two peptides derived from apamin, a bee venom mini-protein, will be synthesized for this purpose. The peptides both feature a similar alpha-helix sequence compared to apamin, and their chains have been designed to exhibit either all four native cysteine residues (4-Cys) or two cysteines and two histidines (2-His-2Cys) at the four corners of an ideal square planar metal complex.These scaffolds could be used as ligands for different late transition metals like Pd(II) and Pt(II), and Cu(II), that could be bound via the imidazole ring of histidines or the thiol group in cysteines. The resulting peptide-metal complexes would represent potential catalysts for asymmetric transformations like transfer hydrogenation acting as minimal artificial metalloenzymes.