title: Chicken cathelicidin-2-derived peptides with enhanced immunomodulatory and antibacterial activities against biological warfare agents.
abstract: Host defence peptides (HDPs) are considered to be excellent candidates for the development of novel therapeutic agents. Recently, it was demonstrated that the peptide C1-15, an N-terminal segment of chicken HDP cathelicidin-2, exhibits potent antibacterial activity while lacking cytotoxicity towards eukaryotic cells. In the present study, we report that C1-15 is active against bacteria such as Bacillus anthracis and Yersinia pestis that may potentially be used by bioterrorists. Substitution of single and multiple phenylalanine (Phe) residues to tryptophan (Trp) in C1-15 resulted in variants with improved antibacterial activity against B. anthracis and Y. pestis as well as decreased salt sensitivity. In addition, these peptides exhibited enhanced neutralisation of lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs). The antibacterial and LPS-neutralising activities of these C1-15-derived peptides are exerted at concentrations far below the concentrations that are toxic to human PBMCs. Taken together, we show that Phe-->Trp substitutions in C1-15 variants enhances the antibacterial and LPS-neutralising activities against pathogenic bacteria, including those that may potentially be used as biological warfare agents.
authors.affiliation: TNO Defence, Security and Safety, Rijswijk, The Netherlands.
authors.forename: E Margo
authors.initials: EM
authors.lastname: Molhoek
authors.forename: Albert
authors.initials: A
authors.lastname: van Dijk
authors.forename: Edwin J A
authors.initials: EJ
authors.lastname: Veldhuizen
authors.forename: Helma
authors.initials: H
authors.lastname: Dijk-Knijnenburg
authors.forename: Roos H
authors.initials: RH
authors.lastname: Mars-Groenendijk
authors.forename: Linda C L
authors.initials: LC
authors.lastname: Boele
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Kaman-van Zanten
authors.forename: Henk P
authors.initials: HP
authors.lastname: Haagsman
authors.forename: Floris J
authors.initials: FJ
authors.lastname: Bikker
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000633:toxicity; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000494:pharmacology* / Q000633:toxicity; D001408:Bacillus anthracis / Q000187:drug effects*; D054045:Biological Warfare Agents; D002645:Chickens; D015169:Colony Count, Microbial; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics / Q000494:pharmacology* / Q000633:toxicity; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D050296:Microbial Viability / Q000187:drug effects; D014734:Vibrio cholerae / Q000187:drug effects; D015010:Yersinia pestis / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D054045:Biological Warfare Agents; C504855:CMAP27 protein, chicken; D016207:Cytokines; D007155:Immunologic Factors; D008070:Lipopolysaccharides