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 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 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.
Original language | English |
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Pages (from-to) | 15904-15909 |
Number of pages | 6 |
Journal | Angewandte Chemie - International Edition |
Volume | 58 |
Issue number | 44 |
DOIs | |
State | Published - 28 Oct 2019 |
Keywords
- HDAC8
- N-acryloyl-lysine
- cyclic peptides
- phage display
- proximity-driven cyclization