Mirror-image protein and peptide drug discovery through mirror-image phage display

Mirror-image proteins and peptides composed of D-amino acids are garnering increasing attention as diagnostic agents and drug candidates due to their higher stability and lower immunogenicity compared with their L-amino acid counterparts. The often-used strategy to discover mirror-image protein and peptide ligands of a native protein is the mirror-image phage display technique, in which the D-enantiomeric form of the L-target is used as the bait in phage display screening. Advancements in chemical protein synthesis have greatly facilitated the production of these D-protein targets, which are unattainable through recombinant expression technologies. This review spotlights recent developments in mirror-image protein and peptide drugs, focusing on the state-of-the-art synthetic methodologies that have been employed to acquire D-protein targets as well as the basic workflow and recent progress of mirror-image phage display and its applications to drug discovery.