Septic Shock is a major cause of death in medical and surgical intensive care units in the United States. Endotoxin, a lipopolysaccharide (LPS) from gram-negative bacteria has been implicated in the pathogenesis of this syndrome. Inhibition or neutralization of the toxin may be useful in the treatment of septic shock. A family of endotoxin-binding proteins have been identified in a number of mammals (rabbit, humans) from a variety of sources (neutrophils, endothelial cells, and liver). These proteins bind tightly to endotoxin and alter its biologic activity. Sequencing of these proteins has shown that the LPS site has >70% homology regardless of the source of the protein and that short peptide sequences from the active site retains LPS-binding activity. In this investigation we plan to synthesize a number of LPS-binding peptides based on these known structures. Each peptide will be tested for both the enhancement and neutralization of endotoxin basic structure-function relationships. In vivo studies in mice will be conducted with the most active peptides to look for protection from endotoxin challenge. These experiments will help define the potential in vivo actions of the naturally occurring proteins from which these peptides are derived and may lead to the development of a new group of anti-endotoxin agents useful in the treatment of septic shock. So far 16 peptides have been synthesized and studied in vitro. Methods have now been developed to synthesize a series of new structures that have proved to be very difficult to make.
