E5531, a pure endotoxin antagonist of high potency.
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.
Christ
W J
WJ
Elsai Research Institute, Andover, MA 01810-2441, USA.
Asano
O
O
Robidoux
A L
AL
Perez
M
M
Wang
Y
Y
Dubuc
G R
GR
Gavin
W E
WE
Hawkins
L D
LD
McGuinness
P D
PD
Mullarkey
M A
MA
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
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