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 γ-AApeptides. In the library, we utilized the coding peptide tags synthesized with Dde-protected α-amino acids, which were orthogonal to solid phase synthesis of γ-AApeptides. Employing the thioether linkage, the desired macrocyclic γ-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.

中文翻译：

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针对EphA2的一珠两化合物硫醚桥连大环γ-AA肽筛选库

识别可识别肽或蛋白质的分子配体的识别很重要，但在化学生物学和生物医学领域提出了根本性的挑战。环状拟肽文库的开发是稀缺的，因此很少有针对蛋白质靶标的环状拟肽配体的发现。在本文中，我们报告了基于一类新型的大环拟肽γ-AA肽的前所未有的一珠两化合物（OBTC）组合文库。在该文库中，我们利用了由Dde保护的α-氨基酸合成的编码肽标签，这些标签与γ-AA肽的固相合成正交。利用硫醚键，发现所需的大环γ-AA肽对于配体鉴定是有效的。K _d = 81 nM）和有效拮抗的EphA2介导的信号转导。大环拟肽文库的这种新方法可能会导致生物大分子表面识别和功能调节的新型平台。