Comparison of the effects of perfluoroalkyl and alkyl groups on cellular uptake in short peptides

Abstract

The differences in the effects of perfluoroalkyl (R_F) and alkyl (R_H) groups on the cellular uptake of short peptides were evaluated. A facile synthetic method was established to produce Fmoc-protected amino acids bearing R_F and R_H groups on their side chains. The synthesized Fmoc-protected amino acids were successfully incorporated into peptides using solid-phase peptide synthesis. Peptides with an R_F group exhibited higher cellular uptake efficiency compared to peptides with an R_H group of the same side-chain length. Intriguingly, the cytotoxicity of the AF₆₄₇-R_F-tripeptide (R_F = C₈F₁₇) was lower than that of the AF₆₄₇-R_H-tripeptide (R_H = C₁₂H₂₅), despite similar cellular uptake efficiencies. An evaluation of the binding affinity of the peptides to liposome membranes suggested that the higher lipophobicity of the R_F group, compared to the R_H group, contributed to the lower cytotoxicity observed in the peptide with the R_F group. These findings indicate that the introduction of an R_F group into peptides has considerable potential for developing drug-delivery carriers with enhanced uptake efficiency and low cytotoxicity.