title: Identification of D-peptide ligands through mirror-image phage display.
abstract: Genetically encoded libraries of peptides and oligonucleotides are well suited for the identification of ligands for many macromolecules. A major drawback of these techniques is that the resultant ligands are subject to degradation by naturally occurring enzymes. Here, a method is described that uses a biologically encoded library for the identification of D-peptide ligands, which should be resistant to proteolytic degradation. In this approach, a protein is synthesized in the D-amino acid configuration and used to select peptides from a phage display library expressing random L-amino acid peptides. For reasons of symmetry, the mirror images of these phage-displayed peptides interact with the target protein of the natural handedness. The value of this approach was demonstrated by the identification of a cyclic D-peptide that interacts with the Src homology 3 domain of c- SRC. Nuclear magnetic resonance studies indicate that the binding site for this D-peptide partially overlaps the site for the physiological ligands of this domain.
authors.affiliation: Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge MA 02142, USA.
authors.forename: T N
authors.initials: TN
authors.lastname: Schumacher
authors.forename: L M
authors.initials: LM
authors.lastname: Mayr
authors.forename: D L
authors.initials: DL
authors.lastname: Minor
authors.forename: M A
authors.initials: MA
authors.lastname: Milhollen
authors.forename: M W
authors.initials: MW
authors.lastname: Burgess
authors.forename: P S
authors.initials: PS
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001435:Bacteriophages; D001483:Base Sequence; D001665:Binding Sites; D002645:Chickens; D003001:Cloning, Molecular; D015723:Gene Library; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D018909:src Homology Domains
chemical_list: D008024:Ligands; D010455:Peptides; D010456:Peptides, Cyclic; D016392:Proto-Oncogene Proteins pp60(c-src)