Sculpting Secondary Structure of a Cyclic Peptide: Conformational Analysis of a Cyclic Hexapeptide Containing a Combination of l -Leu, d -Leu, and Aib Residues

• Published in: ACS omega 2023-11, Vol.8 (46), p.44106-44111
• Main Authors: Ito, Takahito, Yokoo, Hidetomo, Kato, Takuma, Doi, Mitsunobu, Demizu, Yosuke
• Format: Article
• Language: English
• ISSN: 2470-1343; 2470-1343
• DOI: 10.1021/acsomega.3c06397

We have previously reported that cyclo(l-Leu-d-Leu-Aib-l-Leu-d-Leu-Aib) (2), a cyclic hexapeptide consisting of heterochiral l-Leu and d-Leu (l-Leu-d-Leu) residues with achiral 2-aminoisobutyric acid (Aib) residues, forms a figure-8 conformation. In this study, we newly designed cyclo(l-Leu-d-Leu-Aib-d-Leu-l-Leu-Aib)+ (4), an epimer of 2, and examined the conformational differences between 2 and 4 by X-ray crystallographic analysis. Peptide 4 formed a planar cyclic conformation with an antiparallel β-sheet hydrogen-bonding pattern. This investigation demonstrates the potential to manipulate the molecular conformation of cyclic peptides by simply arranging the l- and d-amino acids and emphasizes that diverse conformations can be obtained by using cyclic peptides. Harnessing cyclic peptides as platforms for distinct molecular structures is a promising approach to expanding the chemical space for various applications.