Protein ligand design: from phage display to synthetic protein epitope mimetics in human antibody Fc-binding peptidomimetics.
Phage display is a powerful method for selecting peptides with novel binding functions. Synthetic peptidomimetic chemistry is a powerful tool for creating structural diversity in ligands as a means to establish structure-activity relationships. Here we illustrate a method of bridging these two methodologies, by starting with a disulfide bridged phage display peptide which binds a human antibody Fc fragment (Delano et al. Science 2000, 287, 1279) and creating a backbone cyclic beta-hairpin peptidomimetic with 80-fold higher affinity for the Fc domain. The peptidomimetic is shown to adopt a well-defined beta-hairpin conformation in aqueous solution, with a bulge in one beta-strand, as seen in the crystal structure of the phage peptide bound to the Fc domain. The higher binding affinity of the peptidomimetic presumably reflects the effect of constraining the free ligand into the conformation required for binding, thus highlighting in this example the influence that ligand flexibility has on the binding energy. Since phage display peptides against a wide variety of different proteins are now accessible, this approach to synthetic ligand design might be applied to many other medicinally and biotechnologically interesting target proteins.
Dias
Ricardo L A
RL
Institute of Organic Chemistry, University of Zurich, USA.
Fasan
Rudi
R
Moehle
Kerstin
K
Renard
Annabelle
A
Obrecht
Daniel
D
Robinson
John A
JA
D040761:Biomimetic Materials / Q000737:chemistry; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007128:Immunoglobulin Fragments / Q000737:chemistry* / Q000276:immunology*; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000276:immunology*; D017510:Protein Folding; D013205:Staphylococcal Protein A / Q000737:chemistry / Q000276:immunology
D000939:Epitopes; D007128:Immunoglobulin Fragments; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D013205:Staphylococcal Protein A