Photoswitching of Cell Penetration of Amphipathic Peptides by Control of α‑Helical Conformation

We stapled an amphipathic peptide mainly consisting of leucine (L) and lysine (K) by an azobenzene (Ab) linker for photocontrol of the secondary structure. The <i>cis</i>–<i>trans</i> isomerization of the Ab moieties could stabilize and destabilize the α-helical conformation of the LK peptide along with dramatic change of associated peptide structures in a reversible manner by UV–vis irradiation. The cell-penetrating activities of the LK peptide can be readily regulated by the photocontrol, as the stabilized <i>cis</i>-Ab-LK peptide showed remarkable increase of cell penetration compared to the destabilized <i>trans</i>-Ab-LK peptide. The photoswitchable cell-penetrating peptides would provide important structural information for cell permeability as well as an effective targeting strategy for peptide-based pharmaceuticals with spatiotemporal specificity