title: New antiseptic peptides to protect against endotoxin-mediated shock.
abstract: Systemic bacterial infections are associated with high mortality. The access of bacteria or constituents thereof to systemic circulation induces the massive release of immunomodulatory mediators, ultimately causing tissue hypoperfusion and multiple-organ failure despite adequate antibiotic treatment. Lipid A, the "endotoxic principle" of bacterial lipopolysaccharide (LPS), is one of the major bacterial immunostimuli. Here we demonstrate the biological efficacy of rationally designed new synthetic antilipopolysaccharide peptides (SALPs) based on the Limulus anti-LPS factor for systemic application. We show efficient inhibition of LPS-induced cytokine release and protection from lethal septic shock in vivo, whereas cytotoxicity was not observed under physiologically relevant conditions and concentrations. The molecular mechanism of LPS neutralization was elucidated by biophysical techniques. The lipid A part of LPS is converted from its "endotoxic conformation," the cubic aggregate structure, into an inactive multilamellar structure, and the binding affinity of the peptide to LPS exceeds those of known LPS-binding proteins, such as LPS-binding protein (LBP). Our results thus delineate a novel therapeutic strategy for the clinical management of patients with septic shock.
authors.affiliation: Forschungszentrum Borstel, Division of Biophysics, Parkallee 10, D-23845 Borstel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gutsmann
authors.forename: Iosu
authors.initials: I
authors.lastname: Razquin-Olazarán
authors.forename: Ina
authors.initials: I
authors.lastname: Kowalski
authors.forename: Yani
authors.initials: Y
authors.lastname: Kaconis
authors.forename: Jörg
authors.initials: J
authors.lastname: Howe
authors.forename: Rainer
authors.initials: R
authors.lastname: Bartels
authors.forename: Mathias
authors.initials: M
authors.lastname: Hornef
authors.forename: Tobias
authors.initials: T
authors.lastname: Schürholz
authors.forename: Manfred
authors.initials: M
authors.lastname: Rössle
authors.forename: Susana
authors.initials: S
authors.lastname: Sanchez-Gómez
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moriyon
authors.forename: Guillermo
authors.initials: G
authors.lastname: Martinez de Tejada
authors.forename: Klaus
authors.initials: K
authors.lastname: Brandenburg
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D001419:Bacteria / Q000187:drug effects; D002151:Calorimetry; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000737:chemistry / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D012772:Shock, Septic / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*
chemical_list: D000890:Anti-Infective Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D010455:Peptides