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, *
1 Department. of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA
2 Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften, Borstel, Germany
3 European Molecular Biology Laboratory, Hamburg, Germany
4 Martin-Luther-Universität Halle-Wittenberg, Halle, Germany


Article Metrics

CrossRef Citations:
0
Total Statistics:

Full-Text HTML Views: 673
Abstract HTML Views: 474
PDF Downloads: 208
Total Views/Downloads: 1355
Unique Statistics:

Full-Text HTML Views: 412
Abstract HTML Views: 227
PDF Downloads: 130
Total Views/Downloads: 769



© Sil et al.; Licensee Bentham Open.

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.

* Address correspondence to this author at the Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften, Borstel, Germany; Tel: +49(0)4537-1882350; Fax: +49(04537-1886320; E-mail: kbrandenburg@fz-borstel.de


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.

Keywords: : Endotoxins, Lipopolysaccharide, Lipopolyamines, Sepsis, Inflammation.