Cell-Penetrating Helical Peptides Having l‑Arginines and Five-Membered Ring α,α-Disubstituted α‑Amino Acids

Abstract

Cell-penetrating peptides are powerful tools in the delivery of drugs, proteins, and nucleic acids into cells; therefore, focus has recently been placed on their development. In this study, we synthesized seven types of peptides possessing three l-arginines (l-Arg) and six l-leucines (l-Leu) and/or 1-aminocyclopentane-1-carboxylic acids (Ac₅c), and investigated their secondary structures and cell-penetrating abilities. The peptide composed of an equal number of l-Arg, l-Leu, and Ac₅c formed 3₁₀/α-helical structures in TFE solution and exhibited the highest cell-penetrating ability of all the peptides examined. Additional cellular uptake studies revealed that the incorporation of Ac₅c into peptides led to improved tolerability against serum. The results of the present study will help in the design of novel cell-penetrating peptides