Amphipathic cell-penetrating peptides based on the pep-1 sequence were synthesized by replacing the three hydrophilic glutamic acid residues with disubstituted, non-proteinogenic, hydrophobic amino acids. These substitutions facilitated maintenance of the peptides' secondary structure in a helical conformation, even in aqueous solution. Stability against enzymatic degradation was improved through the use of disubstituted amino acids. The resultant peptides exhibited high membrane permeability that remained relatively stable during prolonged incubation times. The results of this study indicate that the use of non-proteinogenic amino acids may be an effective approach to improve the cell membrane permeability for existing amphiphilic peptides.
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