Peptides that contain β-amino acids display stable secondary structures, such as helices and sheets, and are often referred to as foldamers. Cyclic β2,3-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 KD 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.
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We thank H. Peacock for proofreading the manuscript. This work was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (B) (18H02080); Japan Science and Technology Agency (JST) PRESTO of Molecular Technology and Creation of New Functions (JPMJPR14K3); JST CREST Rising Star Award of Molecular Technology to T.K.; JST CREST of Molecular Technologies (JPMJCR12L2) and Japan Agency for Medical Research and Development (AMED), Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research) under JP19am0101090 to H.S.
The authors declare no competing interests.
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Katoh, T., Sengoku, T., Hirata, K. et al. Ribosomal synthesis and de novo discovery of bioactive foldamer peptides containing cyclic β-amino acids. Nat. Chem. 12, 1081–1088 (2020). https://doi.org/10.1038/s41557-020-0525-1
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