Biophysical Mechanisms of the Neutralization of Endotoxins by Lipopolyamines
Diptesh Sil1, Lena Heinbockel2, Yani Kaconis2, Manfred Rössle3, Patrick Garidel4, Thomas Gutsmann2, Sunil A David1, Klaus Brandenburg2, *
Identifiers and Pagination:Year: 2013
First Page: 82
Last Page: 93
Publisher Id: TOBIOCJ-7-82
Article History:Received Date: 17/7/2013
Revision Received Date: 30/7/2013
Acceptance Date: 8/8/2013
Electronic publication date: 30/9/2013
Collection year: 2013
open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
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.