Display Selection of a Hybrid Foldamer-Peptide Macrocycle

Abstract

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.

Chemo-ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines

“…Although widely employed, each of these methods suffers from at least one liability with respect to downstream applications and none provide added value: Disulfide bonds are reversible, while thioethers are flexible and, like click reaction products, prone to oxidation. Alternative macrocyclization strategies that generate stable and drug-like linkers are widely recognized as an unmet need 9,[22][23][24][25][26][27] . Chemistry that exploits the macrocyclization event to establish a known pharmacophore within the peptide backbone prior to biological display is a promising strategy towards this end 28 .…”