A Helix‐Stabilized Cell‐Penetrating Peptide as an Intracellular Delivery Tool

Two types of cationic cyclic α,α‐disubstituted α‐amino acids: ApiC 2 NH2(which possesses a lysine mimic side chain) and Api C2Gu (which possesses an arginine mimic side chain), were developed. These amino acids were incorporated into an arginine‐based peptide sequence [( l ‐Arg‐ l ‐Arg‐dAA) 3 : dAA=ApiC 2 NH2or Api C2Gu ], and the relationship between the secondary structures of the resulting peptides and their ability to pass through cell membranes was investigated. The peptide containing Api C2Gu formed a stable α‐helical structure and was more effective at penetrating cells than the nonhelical Arg nonapeptide (R 9 ). Furthermore, the peptide was able to deliver plasmid DNA into various types of cells in a highly efficient manner.