title: Bovine and human lactoferricin peptides: chimeras and new cyclic analogs.
abstract: Lactoferrin (LF) is an important antimicrobial and immune regulatory protein present in neutrophils and most exocrine secretions of mammals. The antimicrobial activity of LF has been related to the presence of an antimicrobial peptide sequence, called lactoferricin (LFcin), located in the N-terminal region of the protein. The antimicrobial activity of bovine LFcin is considerably stronger than the human version. In this work, chimera peptides combining segments of bovine and human LFcin were generated in order to study their antimicrobial activity and mechanism of action. In addition, the relevance of the conserved disulfide bridge and the resulting cyclic structure of both LFcins were analyzed by using "click chemistry" and sortase A-catalyzed cyclization of the peptides. The N-terminal region of bovine LFcin (residues 17-25 of bovine LF) proved to be very important for the antimicrobial activity of the chimera peptides against E. coli, when combined with the C-terminal region of human LFcin. Similarly the cyclic bovine LFcin analogs generated by "click chemistry" and sortase A preserved the antimicrobial activity of the original peptide, showing the significance of these two techniques in the design of cyclic antimicrobial peptides. The mechanism of action of bovine LFcin and its active derived peptides was strongly correlated with membrane leakage in E. coli and up to some extent with the ability to induce vesicle aggregation. This mechanism was also preserved under conditions of high ionic strength (150 mM NaCl) illustrating the importance of these peptides in a more physiologically relevant system.
authors.affiliation: Department of Biological Sciences, Biochemistry Research Group, University of Calgary, 2500 University Dr. NW, Calgary, AB, T2N 1N4, Canada.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Arias
authors.forename: Lindsey J
authors.initials: LJ
authors.lastname: McDonald
authors.forename: Evan F
authors.initials: EF
authors.lastname: Haney
authors.forename: Kamran
authors.initials: K
authors.lastname: Nazmi
authors.forename: Jan G M
authors.initials: JG
authors.lastname: Bolscher
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Vogel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D002417:Cattle; D002463:Cell Membrane Permeability / Q000187:drug effects; D057930:Click Chemistry; D004926:Escherichia coli / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D007781:Lactoferrin / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D013045:Species Specificity; D053835:Unilamellar Liposomes / Q000737:chemistry
chemical_list: D023181:Antimicrobial Cationic Peptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011993:Recombinant Fusion Proteins; D053835:Unilamellar Liposomes; C082171:lactoferricin B; D007781:Lactoferrin