**2. History and origin of CPPs**

The CPPs are initially discovered in 1965 when it was observed that histones and cationic polyamines such as polylysine stimulate the uptake of albumin by tumor cells in culture. It was shown that the conjugation of polylysine to albumin and other proteins enhances their transport into cells. Moreover, a comparison study of different homopolymers of cationic amino acids demonstrates that medium-length polymers of arginine enter cells more effective than similarlength polymers composed of lysine, ornithine, or histidine [11]. In 1988, it was discovered that the human immunodeficiency virus type 1 (HIV-1) encoded trans-acting activator of transcription (Tat) peptide which also translocates cell membranes and gains intracellular mammalian cells [12, 13]. Covalently the conjugation of Tat peptide to proteins or fluorescent markers allowed these molecules to gain into the cell. A few years later, another discovery was followed when polycationic peptide of natural (VP22 and AntP) and synthetic origin (transportan) was used for the delivery of genes, proteins, small exogenous peptide, or even nanoparticles. Furthermore, it was demonstrated that small domains in these peptides are often responsible for cellular entry [14]. Thus, these translocation sequences could be shortened to a few amino acids in comparison with the first Tat peptide, without affecting cell penetration efficiency [13]. Since that time, the list of synthetic CPPs has increased sharply, and the number continues to rise (**Table 1**). In the last decade, another peptide was described named maurocalcine (MCa), a 33 amino acid residue peptide that has been isolated from the venom of the Tunisian chactid scorpion *Scorpio maurus palmatus.* It folds according to an "inhibitor cystine knot" (ICK) motif and contains three disulfide bridges connected by the following pattern: C1–C4, C2–C5, and C3– C6 [15]. MCa acts on ryanodine receptors resulting in pharmacological activation. These receptors are calcium channels located in the membrane of the endoplasmic reticulum. They control Ca2+ release from internal stores and therefore a large number of cell functions [16, 17].

This peptide possesses vector properties when coupled to fluorescent streptavidin. This complex was shown to enter various cell types within minutes and in all cell types tested, a common feature of CPPs. A variety of mutants of MCa were then designed in order to unravel the most active residues for its pharmacological and penetration activities (**Figure 1**) [18, 19].
