Display Selection of a Hybrid Foldamer-Peptide Macrocycle

A helical aromatic foldamer was identified that undergoes tRNA acylation by a flexizyme and ribosomal peptide initiation with yields sufficiently high to perform an mRNA display selection of macrocyclic foldamer-peptide hybrids. A hybrid macrocyle binder to the C-lobe of the E6AP HECT domain was selected that showed highly converged peptide residues. A crystal structure and molecular dynamics simulations revealed that both the peptide and foldamer are helical in an intriguing reciprocal stapling fashion. The strong residue convergence could be rationalized based on their involvement in specific interactions. The foldamer stabilizes the peptide helix through stapling and through contacts with key residues. It appears to also contribute to protein binding by direct protein interactions. The results altogether highlight possible benefits in inserting an aromatic foldamer into a peptide macrocycle for the purpose of protein recognition.