Challenge to overcome current limitations of cell-penetrating peptides.

The penetration of biological membranes is a prime obstacle for the delivery of pharmaceutical drugs. Cell-penetrating peptide (CPP) is an efficient vehicle that can deliver various cargos across the biological membranes. Since the discovery, CPPs have been rigorously studied to unveil the underlying penetrating mechanism as well as to exploit CPPs for various biomedical applications. This review will focus on the various strategies to overcome current limitations regarding stability, selectivity, and efficacy of CPPs.

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 cis- trans 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 cis-Ab-LK peptide showed remarkable increase of cell penetration compared to the destabilized trans-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.

Azobenzene-based chloride transporters with light-controllable activities.

Synthetic chloride transporters containing two urea groups linked through a diazobenzene spacer have been prepared and the trans-to-cis isomerization by light stimulation results in dramatic changes in the chloride transport activities across lipid and cell membranes.