title: Design of a potent novel endotoxin antagonist.
abstract: BACKGROUND
  Bactericidal permeability increasing protein (BPI) binds to and neutralizes lipopolysaccharide (LPS, endotoxin). Small synthetic peptides based on the amino acid sequence of the LPS binding domain of BPI neutralize LPS, albeit inefficiently. Although the LPS binding domain of native BPI possesses a beta-turn secondary structure, this structure is not present in small derivative peptides. The purpose of this study was to determine whether the addition of a beta-turn to a BPI-derived peptide is associated with more potent endotoxin antagonism.
  
  
  METHODS
  We generated a hybrid peptide (BU3) on the basis of (1) a portion of the LPS binding domain from BPI and (2) amino acids known to initiate a beta-turn. BU3 folds with a beta-turn, and we tested its effects on LPS neutralization and LPS-induced tumor necrosis factor-alpha secretion, comparing it with BPI-derived peptide BG22 that lacks a beta-turn and to an irrelevant peptide (BG16).
  
  
  RESULTS
  Compared with BG22, BU3 demonstrated enhanced LPS neutralization and inhibition of LPS-induced tumor necrosis factor-alpha secretion in vitro and a similar diminution of endotoxemia and tumor necrosis factor-alpha secretion in a murine model of endotoxemia.
  
  
  CONCLUSIONS
  These data demonstrate the potential for enhancing the biologic activity of a BPI-derived peptide endotoxin antagonist via manipulation of its conformational structure.
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis 55455, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Uknis
authors.forename: K R
authors.initials: KR
authors.lastname: Wasiluk
authors.forename: R D
authors.initials: RD
authors.lastname: Acton
authors.forename: H G
authors.initials: HG
authors.lastname: Klaerner
authors.forename: P S
authors.initials: PS
authors.lastname: Dahlberg
authors.forename: E E
authors.initials: EE
authors.lastname: Ilyina
authors.forename: J R
authors.initials: JR
authors.lastname: Haseman
authors.forename: B H
authors.initials: BH
authors.lastname: Gray
authors.forename: K H
authors.initials: KH
authors.lastname: Mayo
authors.forename: D L
authors.initials: DL
authors.lastname: Dunn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D001665:Binding Sites; D001770:Blood Bactericidal Activity; D001798:Blood Proteins / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D019446:Endotoxemia / Q000517:prevention & control; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004926:Escherichia coli; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D004731:Endotoxins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C021623:bactericidal permeability increasing protein