title: E5531, a pure endotoxin antagonist of high potency.
abstract: Shock due to Gram-negative bacterial sepsis is a consequence of acute inflammatory response to lipopolysaccharide (LPS) or endotoxin released from bacteria. LPS is a major constituent of the outer membrane of Gram-negative bacteria, and its terminal disaccharide phospholipid (lipid A) portion contains the key structural features responsible for toxic activity. Based on the proposed structure of nontoxic Rhodobacter capsulatus lipid A, a fully stabilized endotoxin antagonist E5531 has been synthesized. In vitro, E5531 demonstrated potent antagonism of LPS-mediated cellular activation in a variety of systems. In vivo, E5531 protected mice from LPS-induced lethality and, in cooperation with an antibiotic, protected mice from a lethal infection of viable Escherichia coli.
authors.affiliation: Elsai Research Institute, Andover, MA 01810-2441, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Christ
authors.forename: O
authors.initials: O
authors.lastname: Asano
authors.forename: A L
authors.initials: AL
authors.lastname: Robidoux
authors.forename: M
authors.initials: M
authors.lastname: Perez
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: G R
authors.initials: GR
authors.lastname: Dubuc
authors.forename: W E
authors.initials: WE
authors.lastname: Gavin
authors.forename: L D
authors.initials: LD
authors.lastname: Hawkins
authors.forename: P D
authors.initials: PD
authors.lastname: McGuinness
authors.forename: M A
authors.initials: MA
authors.lastname: Mullarkey
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D015195:Drug Design; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D004927:Escherichia coli Infections / Q000276:immunology; D006090:Gram-Negative Bacteria / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D008050:Lipid A / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D009070:Moxalactam / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D016354:Rhodobacter capsulatus / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001500:BCG Vaccine; D016207:Cytokines; D004731:Endotoxins; D008050:Lipid A; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C092845:E 5531; D009070:Moxalactam