Naturally derived peptide scaffolds as asymmetric ligands for catalysis

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.