title: Inducing toxicity by introducing a leucine-zipper-like motif in frog antimicrobial peptide, magainin 2.
abstract: Cytotoxicity, a major obstacle in therapeutic application of antimicrobial peptides, is controlled by leucine-zipper-like sequences in melittin and other naturally occurring antimicrobial peptides. Magainin 2 shows significantly lower cytotoxicity than many naturally occurring antimicrobial peptides and lacks this structural element. To investigate the consequences of introducing a leucine zipper sequence in magainin 2, a novel analogue (Mag-mut) was designed by rearranging only the positions of its hydrophobic amino acids to include this structural element. Both magainin 2 and Mag-mut showed appreciable similarities in their secondary structures in the presence of negatively charged lipid vesicles, in localizing and permeabilizing the selected bacteria and exhibiting bactericidal activities. However, Mag-mut bound and localized strongly on to the mammalian cells tested and exhibited significantly higher cytotoxicity than magainin 2. Only Mag-mut, but not magainin 2, permeabilized human red blood cells and zwitterionic lipid vesicles. In contrast with magainin 2, Mag-mut self-assembled in an aqueous environment and bound co-operatively on to zwitterionic lipid vesicles. The peptides formed pores of different sizes on to a selected mammalian cell. The results of the present study indicate an important role of the leucine zipper sequence in the cytotoxicity of Mag-mut and demonstrate that its introduction into a non-toxic peptide, without altering the amino acid composition, can render cytotoxicity.
authors: Molecular and Structural Biology Division, Central Drug Research Institute, CSIR, Lucknow 226001, India.
authors: Brijesh Kumar
authors: BK
authors: Pandey
authors: Saurabh
authors: S
authors: Srivastava
authors: Manish
authors: M
authors: Singh
authors: Jimut Kanti
authors: JK
authors: Ghosh
mesh_terms: D016475:3T3 Cells; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D016350:Leucine Zippers; D054806:Magainins / Q000737:chemistry* / Q000633:toxicity; D051379:Mice; D008826:Microbial Sensitivity Tests; D017433:Protein Structure, Secondary; D029867:Xenopus Proteins / Q000737:chemistry* / Q000633:toxicity
chemical_list: D054806:Magainins; D029867:Xenopus Proteins; C053301:magainin 2 peptide, Xenopus