Biophysical mechanisms of endotoxin neutralization by cationic amphiphilic peptides.

Abstract:

:Bacterial endotoxins (lipopolysaccharides (LPS)) are strong elicitors of the human immune system by interacting with serum and membrane proteins such as lipopolysaccharide-binding protein (LBP) and CD14 with high specificity. At LPS concentrations as low as 0.3 ng/ml, such interactions may lead to severe pathophysiological effects, including sepsis and septic shock. One approach to inhibit an uncontrolled inflammatory reaction is the use of appropriate polycationic and amphiphilic antimicrobial peptides, here called synthetic anti-LPS peptides (SALPs). We designed various SALP structures and investigated their ability to inhibit LPS-induced cytokine secretion in vitro, their protective effect in a mouse model of sepsis, and their cytotoxicity in physiological human cells. Using a variety of biophysical techniques, we investigated selected SALPs with considerable differences in their biological responses to characterize and understand the mechanism of LPS inactivation by SALPs. Our investigations show that neutralization of LPS by peptides is associated with a fluidization of the LPS acyl chains, a strong exothermic Coulomb interaction between the two compounds, and a drastic change of the LPS aggregate type from cubic into multilamellar, with an increase in the aggregate sizes, inhibiting the binding of LBP and other mammalian proteins to the endotoxin. At the same time, peptide binding to phospholipids of human origin (e.g., phosphatidylcholine) does not cause essential structural changes, such as changes in membrane fluidity and bilayer structure. The absence of cytotoxicity is explained by the high specificity of the interaction of the peptides with LPS.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Kaconis Y,Kowalski I,Howe J,Brauser A,Richter W,Razquin-Olazarán I,Iñigo-Pestaña M,Garidel P,Rössle M,Martinez de Tejada G,Gutsmann T,Brandenburg K

doi

10.1016/j.bpj.2011.04.041

subject

Has Abstract

pub_date

2011-06-08 00:00:00

pages

2652-61

issue

11

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(11)00517-0

journal_volume

100

pub_type

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