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。金属酶的反应性受第一配位球中的金属中心和给体原子的支配，与小型合成催化剂的反应性相同。酶的高效和选择性离不开复杂的蛋白质结构，对生物催化剂进行合理的结构-活性研究通常不是直截了当的。原则上，可以采用合成一种更简单的保留有序空间组织的肽。与酶相比，肽是基本的实体，它们很容易合成，可以在不损失结构复杂性的情况下精确调整立体电子性质。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微型蛋白质来容纳金属中心。选定的氨基酸将被合适的配位氨基酸取代，这些配位氨基酸能够结合金属并显示催化活性。为此，将合成两种从蜂毒微小蛋白——维生素a中提取的多肽。与维生素a相比，这两种肽都具有相似的α -螺旋序列，它们的链被设计成在理想的方形平面金属配合物的四个角上展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）。这些支架可以作为不同晚期过渡金属的配体，如Pd（II）、Pt（II）和Cu(II)，它们可以通过组氨酸的咪唑环或半胱氨酸中的硫基结合。由此产生的肽-金属配合物将代表潜在的不对称转化催化剂，如转移氢化，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.