The Construction of a Genetically Encoded, Phage-Displayed Cyclic-Peptide Library.

Due to the great potentials of cyclic peptides as therapeutic agents, several phage-displayed peptide libraries in which cyclization is achieved by the covalent linkage of cysteines have been previously demonstrated to identify cyclic-peptide ligands for therapeutic targets. While problems remain in these cysteine conjugation strategies, we have invented a phage display technique in which its displayed peptides are cyclized through a proximity-driven Michael addition reaction between a cysteine and an amber-codon-encoded Nε-acryloyl-lysine (AcrK). Using a randomized 6-mer library in which peptides were cyclized at two ends through a cysteine-AcrK linker, we demonstrated the successful selection of a potent ligand, CycH8a, for histone deacetylase 8 (HDAC8). We believe this approach will find broad applications in drug discovery.