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 release d from bacteria. LPS is a major constituent of the outer membrane of G ram-negative bacteria, and its terminal disaccharide phospholipid (lip id A) portion contains the key structural features responsible for tox ic activity. Based on the proposed structure of nontoxic Rhodobacter c apsulatus lipid A, a fully stabilized endotoxin antagonist E5531 has b een 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 Escherich ia coli.