title: Biophysical mechanisms of the neutralization of endotoxins by lipopolyamines.
abstract: Endotoxins (lipopolysaccharides, LPS) are one of the strongest immunostimulators in nature, responsible for beneficial effects at low, and pathophysiological effects at high concentrations, the latter frequently leading to sepsis and septic shock associated with high mortality in critical care settings. There are no drugs specifically targeting the pathophysiology of sepsis, and new therapeutic agents are therefore urgently needed. The lipopolyamines are a novel class of small molecules designed to sequester and neutralize LPS. To understand the mechanisms underlying the binding and neutralization of LPS toxicity, we have performed detailed biophysical analyses of the interactions of LPS with candidate lipopolyamines which differ in their potencies of LPS neutralization. We examined gel-to-liquid crystalline phase behavior of LPS and of its supramolecular aggregate structures in the absence and presence of lipopolyamines, the ability of such compounds to incorporate into different membrane systems, and the thermodynamics of the LPS:lipopolyamine binding. We have found that the mechanisms which govern the inactivation process of LPS obey similar rules as found for other active endotoxin neutralizers such as certain antimicrobial peptides.
authors.affiliation: Department. of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA.
authors.forename: Diptesh
authors.initials: D
authors.lastname: Sil
authors.forename: Lena
authors.initials: L
authors.lastname: Heinbockel
authors.forename: Yani
authors.initials: Y
authors.lastname: Kaconis
authors.forename: Manfred
authors.initials: M
authors.lastname: Rössle
authors.forename: Patrick
authors.initials: P
authors.lastname: Garidel
authors.forename: Thomas
authors.initials: T
authors.lastname: Gutsmann
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
authors.forename: Klaus
authors.initials: K
authors.lastname: Brandenburg
keywords: Endotoxins; Inflammation.; Lipopolyamines; Lipopolysaccharide; Sepsis