A Genetically Encoded, Phage‐Displayed Cyclic‐Peptide Library

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.

Genetically Encoded Fragment-Based Discovery (GE-FBD) from Phage-Displayed Macrocyclic Libraries with Genetically-Encoded Unnatural Pharmacophores

“…These libraries when modified with DPD should yield shelf-stable, divergent macrocyclic precursors to GE-macrocyclic libraries with unnatural fragments. It is possible to produce GE-macrocyclic libraries with unnatural fragment by direct translation via unnatural amino acid mutagenesis [61][62][63] , metabolic suppression 64,65 and flexigyme technology 11,22 . However, the unique advantage of late stage chemical modifications is the ability to introduce large functionalities such as fluorophores, metal chelators (Fig.…”

Chemical Diversification of Simple Synthetic Antibodies

“…52,123 In this regard, the simple synthetic antibodies and characterization strategies elucidated in this work could facilitate sideby-side evaluations of multiple chemical modification strategies. Finally, while many routes to prepare chemically modified peptides in display formats are now available, 29,[35][36][124][125][126][127][128][129][130][131] very few analogous approaches for the chemical diversification of proteins have been described. 53,60 The efficient preparation and chemical diversification of antibodies on the yeast surface opens up new possibilities for discovering "drug-like" protein leads in high throughput.…”

Learning from the Past: Possible Urgent Prevention and Treatment Options for Severe Acute Respiratory Infections Caused by 2019-nCoV

“…Several research groups including ours have developed methods for building macrocyclic peptide libraries and apply them for the quick identification of macrocyclic peptide ligands for drug targets. [15][16][17][18][19][20] Applications of these libraries to search for potent ligands for the 2019-nCoV RBD or the two ACE2 engaging peptide regions will potentially lead to rapid discovery of anti-2019-nCoV macrocyclic peptides. Although our group has initiated this effort, the lengthy process of the drug discovery process will make it not possible to help patients in the current epidemic.…”