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Publication Abstract from PubMed

Improving the binding affinity and/or stability of peptide ligands often requires testing of large numbers of variants to identify beneficial mutations. Herein we propose a type of mutation that promises a high success rate. In a bicyclic peptide inhibitor of the cancer-related protease urokinase-type plasminogen activator (uPA), we observed a glycine residue that has a positive varphi dihedral angle when bound to the target. We hypothesized that replacing it with a D-amino acid, which favors positive varphi angles, could enhance the binding affinity and/or proteolytic resistance. Mutation of this specific glycine to D-serine in the bicyclic peptide indeed improved inhibitory activity (1.75-fold) and stability (fourfold). X-ray-structure analysis of the inhibitors in complex with uPA showed that the peptide backbone conformation was conserved. Analysis of known cyclic peptide ligands showed that glycine is one of the most frequent amino acids, and that glycines with positive varphi angles are found in many protein-bound peptides. These results suggest that the glycine-to-D-amino acid mutagenesis strategy could be broadly applied.

Improving Binding Affinity and Stability of Peptide Ligands by Substituting Glycines with D-Amino Acids.,Chen S, Gfeller D, Buth SA, Michielin O, Leiman PG, Heinis C Chembiochem. 2013 Jul 4. doi: 10.1002/cbic.201300228. PMID:23828687^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.