title: Antimicrobial activity of peptides derived from human ß-amyloid precursor protein.
abstract: Antimicrobial peptides are important effector molecules of the innate immune system. Here, we describe that peptides derived from the heparin-binding disulfide-constrained loop region of human ß-amyloid precursor protein are antimicrobial. The peptides investigated were linear and cyclic forms of NWCKRGRKQCKTHPH (NWC15) as well as the cyclic form comprising the C-terminal hydrophobic amino acid extension FVIPY (NWCKRGRKQCKTHPHFVIPY; NWC20c). Compared with the benchmark antimicrobial peptide LL-37, these peptides efficiently killed the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive Staphylococcus aureus and Bacillus subtilis, and the fungi Candida albicans and Candida parapsilosis. Correspondingly, fluorescence and electron microscopy demonstrated that the peptides caused defects in bacterial membranes. Analogously, the peptides permeabilised negatively charged liposomes. Despite their bactericidal effect, the peptides displayed very limited hemolytic activities within the concentration range investigated and exerted very small membrane permeabilising effects on human epithelial cells. The efficiency of the peptides with respect to bacterial killing and liposome membrane leakage was in the order NWC20c > NWC15c > NWC15l, which also correlated to the adsorption density for these peptides at the model lipid membrane. Thus, whereas the cationic sequence is a minimum determinant for antimicrobial action, a constrained loop-structure as well as a hydrophobic extension further contributes to membrane permeabilising activity of this region of amyloid precursor protein.
authors.affiliation: Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Biomedical Center, Tornavägen 10, SE-221 84, Lund, Sweden.
authors.forename: Praveen
authors.initials: P
authors.lastname: Papareddy
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Björn
authors.initials: B
authors.lastname: Walse
authors.forename: Artur
authors.initials: A
authors.lastname: Schmidtchen
authors.forename: Martin
authors.initials: M
authors.lastname: Malmsten
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic
chemical_list: D016564:Amyloid beta-Protein Precursor; D023181:Antimicrobial Cationic Peptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic