Redox‐Responsive Side Chain Structural Changes in a Seven‐Membered Cyclic α,α‐Disubstituted α‐Amino Acid with a Disulfide Bond Enable Reversible Conformational Changes in Peptides

We report the development of a redox-responsive system that induces reversible conformational changes in peptides through the design of a seven-membered cyclic α,α-disubstituted α-amino acid with a disulfide bond, 5-amino-1,2-dithiepane-5-carboxylic acid (Dtp). Upon reduction, the disulfide bond in Dtp was cleaved to form thiols, converting Dtp into (2-mercaptoethyl)homocysteine (Mhc), and this process was reversed by oxidation. Dtp-containing peptides predominantly adopted 3₁₀-helical conformation in solution, whereas Mhc-containing peptides exhibited a mixture of helical and other conformations. This redox-responsive mechanism allows for precise control over peptide secondary structures, making it a promising approach for designing functional helical peptides capable of acting molecular switches in response to intracellular reductive environments.