1 Department of Pharmacy, Faculty of Pharmaceutical Sciences, Københavns Universitet2 Department of Drug Design and Pharmacology, Faculty of Pharmaceutical Sciences, Københavns Universitet3 Natural Products and Peptides, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet4 Forskningsområdet, Sundhedsvidenskab5 Biologics, Department of Pharmacy, Faculty of Health and Medical Sciences, Københavns Universitet6 Department of Pharmacy, Faculty of Pharmaceutical Sciences, Københavns Universitet7 Natural Products and Peptides, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet8 Biologics, Department of Pharmacy, Faculty of Health and Medical Sciences, Københavns Universitet
effect of sequence and secondary structure
Cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs) show great potential as drug delivery vectors and new antibiotic drug entities, respectively. The current study deals with the properties of a variety of peptide analogs derived from the well-known CPP penetratin as well as octaarginine and different Tat sequences. The effects of peptide length, guanidinium content, and sequence of non-cationic residues were assessed in mammalian and bacterial cells. The arginine (Arg) content in the penetratin analogs was found to influence eukaryotic cell uptake efficiency, antimicrobial activity towards both Gram-positive and Gram-negative bacteria as well as eukaryotic cell viability. All examined analogs retained the ability to cross eukaryotic membranes giving rise to a distribution within the vacuolar apparatus. Interestingly, a series of shuffled analogs of penetratin with the cationic residues in conserved positions, attain the same a-helical conformation as native penetratin in the presence of cholesterol-containing liposomes, while conformational differences were observed in the presence of highly anionic liposomes. While the antibacterial effect of the two groups of peptides was similar, the eukaryotic cellular uptake of the shuffled analogs was noticeably lower than for native penetratin. Moreover, a point substitution of Met to Leu in native penetratin had no influence on eukaryotic cellular uptake and antimicrobial effect, and only a minor effect on cytotoxicity, in contrast to the fact that the same substitution in the shuffled analog gave rise to reduced eukaryotic cellular uptake while increasing the antibacterial effect and cytotoxicity.
B B a - Biomembranes, 2013, Vol 1828, Issue 2, p. 223-232