Peptides that contain β-amino acids display stable secondary structures, such as helices and sheets, and are often referred to as foldamers. Cyclic β^2,3-amino acids (cβAAs), such as 2-aminocyclohexanecarboxylic acid (2-ACHC), are strong helix/turn inducers due to their restricted conformations. Here we report the ribosomal synthesis of foldamer peptides that contain multiple, up to ten, consecutive cβAAs via genetic code reprogramming. We also report the de novo discovery of macrocyclic cβAA-containing peptides capable of binding to a protein target. As a demonstration, potent binders with low-to-subnanomolar K_D values were identified for human factor XIIa (hFXIIa) and interferon-gamma receptor 1, from a library of their 10¹² members. One of the anti-hFXIIa macrocyclic peptides that exhibited a high inhibitory activity and serum stability was co-crystallized with hFXIIa. The X-ray structure revealed that it adopts an antiparallel β-sheet structure induced by a (1S,2S)-2-ACHC residue via the formation of two γ-turns. This work demonstrates the potential of this platform to explore the previously inaccessible sequence space of cβAA-containing peptides.

含有 β-氨基酸的肽显示出稳定的二级结构，例如螺旋和折叠，通常被称为折叠体。环状 β ^2,3 -氨基酸 (cβAAs)，例如 2-氨基环己烷羧酸 (2-ACHC)，由于其受限的构象，是强螺旋/转角诱导剂。在这里，我们通过遗传密码重编程报告了包含多个、多达 10 个连续 cβAAs 的折叠肽的核糖体合成。我们还报告了能够与蛋白质靶标结合的含有大环 cβAA 的肽的从头发现。作为证明，从它们的 10 ^{12库中鉴定出具有低至亚纳摩尔}K _D值的强效结合剂，用于人因子 XIIa (hFXIIa) 和干扰素-γ 受体 1成员。一种表现出高抑制活性和血清稳定性的抗 hFXIIa 大环肽与 hFXIIa 共结晶。X射线结构表明，它采用(1 S ,2 S )-2-ACHC残基通过形成两个γ-转角诱导的反平行β-折叠结构。这项工作证明了该平台具有探索以前无法访问的含 cβAA 肽序列空间的潜力。