Manipulation of Conformational Changes in Cyclic Peptides Using a Molecular Switch

Compared to linear peptides, cyclic peptides have attracted much attention because of enhanced binding affinity, membrane permeability, and metabolic stability through constrained conformations. Recent studies revealed that some cyclic peptides can adopt multiple conformers, influencing their biological activity. However, strategies to control these interconversions remain underexplored. In this study, we introduced an ortho ‐disubstituted benzamide (DiBA) unit as a molecular switch in cyclic peptides, enabling the separation of conformers and selective interconversion between four conformers. The DiBA unit has C─N and C─C bonds that can be controlled by external stimuli. The method was successfully applied to cyclic peptides with different ring sizes and amino acid sequences, and selective interconversion between conformations was achieved by different stimuli such as light and heat. These results suggest that regulating biological activity through the controlled interconversion between multiple conformations of a cyclic peptide may be applicable as a method for modulating its biological activity.