ABSTRACT
Here, we report ribosomal construction of thioether-macrocyclic α/ß3-peptide libraries in which ß-homoglycine, ß-homoalanine, ß-homophenylglycine, and ß-homoglutamine are introduced by genetic code reprogramming. The libraries were applied to the RaPID (Random nonstandard Peptides Integrated Discovery) selection against human EGFR to obtain PPI (protein-protein interaction) inhibitors. The resulting peptides contained up to five ß3-amino acid (ß3AA) residues and exhibited outstanding binding affinity, PPI inhibitory activity, and proteolytic stability, which were attributed to the ß3AAs included in the peptides. This showcase work has demonstrated that the use of such ß3AAs enhances the drug-like properties of peptides, providing a unique platform for the discovery of de novo macrocycles against a protein of interest.
Subject(s)
Peptide Library , Peptides , Amino Acids/chemistry , ErbB Receptors/metabolism , Humans , Peptides/chemistry , Peptides, Cyclic/chemistry , Sulfides/chemistryABSTRACT
d/l-Hybrid peptides are an attractive class of molecular modality because they are able to exhibit high proteolytic stability and unique structural diversity which cannot be accessed by those consisting of only proteinogenic l-amino acids. Despite such an expectation, it has not been possible to devise de novo d/l-hybrid peptides capable of disrupting the function of a protein target(s) due to the lack of an effective method that reliably constructs a highly diverse library and screens active species. Here we report for the first time construction of a library consisting of 1012 members of macrocyclic d/l-hybrid peptides containing five kinds of d-amino acids and performance of the RaPID selection against human EGFR as a showcase to uncover PPI (protein-protein interaction) inhibitors.
