Genetically Encoded Libraries of Constrained Peptides

Many therapeutic peptides can still be improved with respect to target specificity, target affinity, resistance to peptidases/proteases, physical stability, and capacity to pass through membranes required for oral delivery. Several modifications can improve the peptides’ properties, in particular those that impose (a) conformational constraint(s). Screening of constrained peptides and the identification of hits is greatly facilitated by the generation of genetically encoded libraries. Recent breakthrough bacterial, phage, and yeast display screening systems of ribosomally synthesized post‐translationally constrained peptides, particularly those of lanthipeptides, are earning special attention. Here we provide an overview of display systems for constrained, genetically encoded peptides and indicate prospects of constrained peptide‐displaying phage and bacterial systems as such in vivo. Structural diversity and chemical space: Displayed peptides can be constrained either intracellularly by post‐translational modification (PTM) or extracellularly. Constrained peptides with optimal target specificity can be efficiently selected from nucleic‐acid‐encoded libraries through the use of, for instance, mRNA, phage, bacterial, and yeast display.