Design of a potent novel endotoxin antagonist

Marc E. Uknis, Karen R. Wasiluk, Robert D. Acton, Hans G. Klaerner, Peter S. Dahlberg, Elena E. Ilyina, Judith R. Haseman, Beulah H. Gray, Kevin H. Mayo, David L. Dunn

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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 β-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 β-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 β-turn. BU3 folds with a β-turn, and we tested its effects on LPS neutralization and LPS-induced tumor necrosis factor-α secretion, comparing it with BPI-derived peptide BG22 that lacks a β-turn and to an irrelevant peptide (BG16). Results. Compared with BG22, BU3 demonstrated enhanced LPS neutralization and inhibition of LPS-induced tumor necrosis factor-α secretion in vitro and a similar diminution of endotoxemia and tumor necrosis factor-α 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.

Original languageEnglish (US)
Pages (from-to)380-385
Number of pages6
Issue number2
StatePublished - Aug 1997

Bibliographical note

Funding Information:
SEPSIS SYNDROME CONTINUES to be one of the leading causeso f mortality in critically ill patients, and gram-negative bacterial pathogens cause approximately one-third of cases.D espite intensive laboratory and clinical investigation, the mortality associated with gram-negative bacterial sepsisa nd shock remains -4O%, a statistic that has changed little in more than three decades.’ Lipopolysaccharide (LPS, endotoxin) is an integral component of the outer membrane of gram-negative bacteria and triggers activation of macrophages that, in turn, synthesize and secrete cytokines within the endogenous tissue milieu and systemic circulation. The resultant release of tumor necrosis factor-a (TNF-a) and other cytokines by macrophages is causally linked to the host inflammatory response and the subsequent development of septic shock.2 Supported by grant ROl GM32414 from the National Institutes of Health (D.L.D.) and a grant from the North Star Foundation (B.H.G.). Presented at the Fifty-eighth Annual Meeting of the Society of University Surgeons, Tampa, Fla., Feb. 13-15, 1997. Reprint requests: David L. Dunn, MD, PhD, Box 242 University of Minnesota, 420 Delaware St. SE, Minneapolis, MN 55455. Copyright 0 1997 by Mosby-Year Book, Inc.


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