Abstract
Foldamers, which are folded oligomers with well-defined conformations, have been recently reported to have a good cell-penetrating ability. α,α-Disubstituted α-amino acids are one such promising tool for the design of peptide foldamers. Here, we prepared four types of L-arginine-rich nonapeptides containing L-leucine or α,α-disubstituted α-amino acids, and evaluated their secondary structures and cell-penetrating abilities in order to elucidate a correlation between them. Peptides containing α,α-disubstituted α-amino acids had similar resistance to protease digestion but showed different secondary structures. Intracellular uptake assays revealed that the helicity of peptides was important for their cell-penetrating abilities. These findings suggested that a peptide foldamer with a stable helical structure could be promising for the design of cell-penetrating peptides.
Highlights
Cell-penetrating peptides (CPPs) are promising tools for the delivery of membrane-impermeable compounds into living cells[1,2]
Preparation of peptides. 9-Fluorenylmethoxycarbonyl (Fmoc)-protected disubstituted α-amino acids (dAAs), Fmoc-(S,S)-Ac5cdOM-OH, was synthesized according to Fig. 2 from Cbz-(S,S)-Ac5cdOM-OMe, which was prepared from dimethyl L-(+)tartrate, as reported previously[28,29]
The hydrolysis of Cbz-(S,S)-Ac5cdOM-OMe under alkaline conditions followed by deprotection of the Cbz-protecting group by hydrogenolysis using H2 and 5% Pd/C gave crude dAA H-(S,S)Ac5cdOM-OH
Summary
Cell-penetrating peptides (CPPs) are promising tools for the delivery of membrane-impermeable compounds into living cells[1,2]. Β-Peptide foldamer was used for building a stable cationic amphipathic helix and showed high cell-penetrating ability[11]. The introduction of cyclic dAAs into Arg-rich peptides led to a marked conformational change from a random coil to a helical structure and elevated the stability of peptides against protease digestion[24,25]. No definitive evidence that the stable helical structure of peptide foldamers with dAAs, excluding amphipathic helical peptides[18,26,27], led to their high cell-penetrating abilities has been reported so far. The objective of this study was to investigate the effects of stable helical structures of peptide foldamers after the introduction of dAAs on their cell-penetrating abilities. In order to clarify any influence of dAA incorporation, Leu peptide, which was composed of only natural AAs, was prepared as a control
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