Spontaneous, co-translational peptide macrocyclization using p-cyanoacetylene-phenylalanine

Peptide macrocycles (PMCs) are increasingly popular for the development of inhibitors of protein-protein interactions (PPIs). Large libraries of PMCs are accessible using display technologies like mRNA display and phage display. These technologies require macrocyclization chemistries to be compatible with biological milieu, severely limiting the types of technologies available for cyclization. Here, we introduce the novel non-canonical amino acid (ncAA) p-cyanoacetylene-l-Phe (pCAF), which facilitates spontaneous, co-translational cyclization through Michael addition with cysteine under physiological conditions. This new, robust chemistry creates stable macrocycles of a wide variety of ring sizes including bicyclic structures.

Automated summary

Peptide macrocycles (PMCs) are popular for developing inhibitors of protein-protein interactions (PPIs). Large libraries of PMCs can be accessed using display technologies. The non-canonical amino acid pCAF enables spontaneous, co-translational cyclization under physiological conditions, creating stable macrocycles of various ring sizes.