One-Bead Two-Compound Thioether Bridged Macrocyclic gamma-AApeptide Screening Library against EphA2

摘要

Identification of molecular ligands that recognize peptides or proteins is significant but poses a fundamental challenge in chemical biology and biomedical sciences. Development of cyclic peptidomimetic library is scarce, and thus discovery of cyclic peptidomimetic ligands for protein targets is rare. Herein we report the unprecedented one-bead-two -compound (OBTC) combinatorial library based on a novel class of the macrocyclic peptidomimetics gamma-AApeptides. In the library, we utilized the coding peptide tags synthesized with Dde-protected alpha-amino acids, which were orthogonal to solid phase synthesis of gamma-AApeptides. Employing the thioether linkage, the desired macrocyclic gamma-AApeptides were found to be effective for ligand identification. Screening the library against the receptor tyrosine kinase EphA2 led to the discovery of one lead compound that tightly bound to EphA2 (K-d = 81 nM) and potently antagonized EphA2-mediated signaling. This new approach of macrocyclic peptidomimetic library may lead to a novel platform for biomacromolecular surface recognition and function modulation.