title: Antimicrobial and conformational studies of the active and inactive analogues of the protegrin-1 peptide.
abstract: The natural antimicrobial cationic peptide protegrin-1 displays a broad spectrum of antimicrobial activity and rapidly kills pathogens by interacting with their cell membrane. We investigated the structure-activity relationships of three protegrin-1 analogues: IB-367 (RGGLCYCRGRFCVCVGR-NH(2)), BM-1 (RGLCYCRGRFCVCVG-NH(2)) and BM-2 (RGLCYRPRFVCVG-NH(2)). Our antimicrobial and antifungal activity studies of these peptides showed that BM-1 was much more active than IB-367 against Gram-positive bacteria and fungi, whereas BM-2 was inactive. The BM-1 peptide showed fourfold reduced haemolysis relative to IB-367, an additional advantage of this peptide. In addition, BM-1 was about 15% cheaper than IB-367 to synthesize. The absence of two cysteine residues in the BM-2 sequence could be the main reason for its unstable conformation and antimicrobial inactivity. The solution structures of these peptides were determined in dimethyl sulphoxide using two-dimensional NMR and restrained molecular dynamics calculations. IB-367 and BM-1 formed short, antiparallel, beta-hairpin structures connected by a type II' beta-turn. The shorter, inactive BM-2 analogue exhibited major and minor conformations (predominantly unordered) in the NMR spectra and was much more flexible.
authors.affiliation: Faculty of Chemistry, University of Gdańsk, Poland.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Rodziewicz-Motowidło
authors.forename: Beata
authors.initials: B
authors.lastname: Mickiewicz
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Greber
authors.forename: Emilia
authors.initials: E
authors.lastname: Sikorska
authors.forename: Lukasz
authors.initials: L
authors.lastname: Szultka
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Kamysz
authors.forename: Wojciech
authors.initials: W
authors.lastname: Kamysz
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D005658:Fungi / Q000187:drug effects*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009842:Oligopeptides; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D009842:Oligopeptides; C547500:RGLCYCRGRFCVCVG-NH(2); C496527:arginyl-arginyl-arginyl-phenylalanyl-tryptophyl-tryptophyl-phenylalanyl-arginyl-aginyl-argininamide; C094880:protegrin-1; C119872:antimicrobial peptide IB-367