Lysine–spermine conjugates: hydrophobic polyamine amides as potent lipopolysaccharide sequestrants

Lipopolysaccharides (LPS), otherwise termed ‘endotoxins’, are outer-membrane constituents of Gram-negative bacteria. Lipopolysaccharides play a key role in the pathogenesis of ‘Septic Shock’, a major cause of mortality in the critically ill patient. Therapeutic options aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide do not exist at the present time. We have defined the pharmacophore necessary for small molecules to specifically bind and neutralize LPS and, using animal models of sepsis, have shown that the sequestration of circulatory LPS by small molecules is a therapeutically viable strategy. In this paper, the interactions of a focused library of lysine–spermine conjugates with lipopolysaccharide (LPS) have been characterized. Lysine–spermine conjugates with the ε-amino terminus of the lysinyl moiety derivatized with long-chain aliphatic hydrophobic substituents in acyl or alkyl linkage bind and neutralize bacterial lipopolysaccharides, and may be of use in the prevention or treatment of endotoxic shock states.

Lysine–spermine conjugates with a long-chain aliphatic (C16–C20) substituent at R1 bind and neutralize bacterial lipopolysaccharides. These compounds reduce lethality in a murine model of lipopolysaccharide-induced shock, and may serve as novel leads for developing novel anti-lipopolysaccharide agents for the therapy of Gram-negative sepsis.Figure optionsDownload as PowerPoint slide