IDENTIFICATION OF D-PEPTIDE LIGANDS THROUGH MIRROR-IMAGE PHAGE DISPLAY

Genetically encoded libraries of peptides and oligonucleotides are wel l suited for the identification of ligands for many macromolecules. A major drawback of these techniques is that the resultant ligands are s ubject to degradation by naturally occurring enzymes. Here, a method i s described that uses a biologically encoded library for the identific ation of D-peptide ligands, which should be resistant to proteolytic d egradation, In this approach, a protein is synthesized in the D-amino acid configuration and used to select peptides from a phage display li brary expressing random L-amino acid peptides, For reasons of symmetry , the mirror images of these phage-displayed peptides interact with th e target protein of the natural handedness, The value of this approach was demonstrated by the identification of a cyclic D-peptide that int eracts with the Src homology 3 domain of c-Src. Nuclear magnetic reson ance studies indicate that the binding site for this D-peptide partial ly overlaps the site for the physiological ligands of this domain.