Tuning the properties of a novel short cell-penetrating peptide by intramolecular cyclization with a triazole bridge

Cell-penetrating peptides (CPPs) present a versatile alternative to viral gene delivery vectors, addressing the still challenging task to suitably transport the desired gene to the target cell. In this work, the rational design of triazole-bridged CPPs and their detailed investigation concerning peptide/lipid interactions, using also NMR-based structure calculations, are reported. Cyclic versus linear: cyclic triazole-bridged cell-penetrating peptides are optimally arranged within the membrane, thus at the same time inducing suitable DNA complexation and successful peptide membrane insertion.