Ribosomal synthesis and de novo discovery of bioactive foldamer peptides containing cyclic β-amino acids

Peptides that contain beta-amino acids display stable secondary structures, such as helices and sheets, and are often referred to as foldamers. Cyclic beta(2,3)-amino acids (c beta AAs), 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 c beta AAs via genetic code reprogramming. We also report the de novo discovery of macrocyclic c beta AA-containing peptides capable of binding to a protein target. As a demonstration, potent binders with low-to-subnanomolarK(D)values were identified for human factor XIIa (hFXIIa) and interferon-gamma receptor 1, from a library of their 10(12) 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 beta-sheet structure induced by a (1S,2S)-2-ACHC residue via the formation of two gamma-turns. This work demonstrates the potential of this platform to explore the previously inaccessible sequence space of c beta AA-containing peptides.