A Genetically Encoded, Phage‐Displayed Cyclic‐Peptide Library. Issue 44 (9th September 2019) - Wang, Xiaoshan Shayna
Abstract: Superior to linear peptides in biological activities, cyclic peptides are considered to have great potential as therapeutic agents. To identify cyclic‐peptide ligands for therapeutic targets, phage‐displayed peptide libraries in which cyclization is achieved by the covalent conjugation of cysteines have been widely used. To resolve drawbacks related to cysteine conjugation, 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 N ϵ ‐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 potent ligands for TEV protease and HDAC8. All selected cyclic peptide ligands showed 4‐ to 6‐fold stronger affinity to their protein targets than their linear counterparts. We believe this approach will find broad applications in drug discovery. Abstract : Using amber‐codon suppression, N ϵ ‐acryloyl‐lysine was genetically encoded in a phage‐displayed peptide library for cyclization with a pre‐installed cysteine. Selection from this phage‐display library afforded cyclic peptides that bind TEV protease and histone deacetylase, HDAC8, much more strongly than their linear counterparts.