Journal
NATURE CHEMISTRY
Volume 12, Issue 11, Pages 1081-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41557-020-0525-1
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Funding
- Japan Society for the Promotion of Science (JSPS) [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
- JST CREST of Molecular Technologies [JPMJCR12L2]
- 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) [JP19am0101090]
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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.
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