Small Efficient Cell-penetrating Peptides Derived from Scorpion Toxin Maurocalcine*

Background: This study aimed at developing a new set of maurocalcine-derived cell-penetrating peptides from truncation. Results: Several truncated peptides were designed and evaluated for Cy5 dye cell penetration. Conclusion: All truncated peptides are competitive cell-penetrating peptides, many of them comparing favorably well with TAT. Significance: Maurocalcine-derived truncated cell-penetrating peptides differ in their properties, enlarging the potential fields of applications. Maurocalcine is the first demonstrated example of an animal toxin peptide with efficient cell penetration properties. Although it is a highly competitive cell-penetrating peptide (CPP), its relatively large size of 33 amino acids and the presence of three internal disulfide bridges may hamper its development for in vitro and in vivo applications. Here, we demonstrate that several efficient CPPs can be derived from maurocalcine by replacing Cys residues by isosteric 2-aminobutyric acid residues and sequence truncation down to peptides of up to 9 residues in length. A surprising finding is that all of the truncated maurocalcine analogues possessed cell penetration properties, indicating that the maurocalcine is a highly specialized CPP. Careful examination of the cell penetration properties of the truncated analogues indicates that several maurocalcine-derived peptides should be of great interest for cell delivery applications where peptide size matters.