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Biophysical mechanisms of the neutralization of endotoxins by lipopolyamines.

Sil D, Heinbockel L, Kaconis Y, Rössle M, Garidel P, Gutsmann T, David SA, Brandenburg K - Open Biochem J (2013)

Bottom Line: The lipopolyamines are a novel class of small molecules designed to sequester and neutralize LPS.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.

View Article: PubMed Central - PubMed

Affiliation: Department. of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Gel-to-liquid crystalline phase transition of the hydrocarbon chains of LPS R60 at different concentrations of DS176 (A) and DS347(B) by Fourier-transform infrared spectroscopy. The peak position of the symmetric vibration of the methylene groups νs(CH2) is plottedversus temperature. In the gel phase, the wavenumber values lie at 2850 cm-1, in the liquid crystalline phase they are shifted to 2852.5 to2853.0 cm-1.
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Figure 2: Gel-to-liquid crystalline phase transition of the hydrocarbon chains of LPS R60 at different concentrations of DS176 (A) and DS347(B) by Fourier-transform infrared spectroscopy. The peak position of the symmetric vibration of the methylene groups νs(CH2) is plottedversus temperature. In the gel phase, the wavenumber values lie at 2850 cm-1, in the liquid crystalline phase they are shifted to 2852.5 to2853.0 cm-1.

Mentions: Data of FTIR experiments are presented in Fig. (2) for LPS R60 in the absence and presence of DS176 (A) and DS347 (B). As can be seen, pure LPS shows a melting of the hydrocarbon chains at Tm= 36 °C, which decreases in the presence of the LPAs, with DS176 exhibiting a quite moderate decrease to 28 °C at [LPS]:[DS176] 1:2 (weight%), whereas DS347 causes at the highest concentration a complete disappearance of the phase transition. For both compounds, the presence of the LPAs leads to an increase in fluidity (increase in the wavenumber values), which, however, is much higher for DS347 than for compound DS176. The results for compounds DS96 and Yan673 (not shown) are indicative for an only slight decrease in the Tm of LPS, but a decrease in the wavenumbers, whereas Yan673 behaves similar to compound DS347, i.e., a strong increase in the wavenumber values in the entire temperature range. Thus, there is apparently no correlation of these data to their biological action as shown in Fig. (1).


Biophysical mechanisms of the neutralization of endotoxins by lipopolyamines.

Sil D, Heinbockel L, Kaconis Y, Rössle M, Garidel P, Gutsmann T, David SA, Brandenburg K - Open Biochem J (2013)

Gel-to-liquid crystalline phase transition of the hydrocarbon chains of LPS R60 at different concentrations of DS176 (A) and DS347(B) by Fourier-transform infrared spectroscopy. The peak position of the symmetric vibration of the methylene groups νs(CH2) is plottedversus temperature. In the gel phase, the wavenumber values lie at 2850 cm-1, in the liquid crystalline phase they are shifted to 2852.5 to2853.0 cm-1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3795406&req=5

Figure 2: Gel-to-liquid crystalline phase transition of the hydrocarbon chains of LPS R60 at different concentrations of DS176 (A) and DS347(B) by Fourier-transform infrared spectroscopy. The peak position of the symmetric vibration of the methylene groups νs(CH2) is plottedversus temperature. In the gel phase, the wavenumber values lie at 2850 cm-1, in the liquid crystalline phase they are shifted to 2852.5 to2853.0 cm-1.
Mentions: Data of FTIR experiments are presented in Fig. (2) for LPS R60 in the absence and presence of DS176 (A) and DS347 (B). As can be seen, pure LPS shows a melting of the hydrocarbon chains at Tm= 36 °C, which decreases in the presence of the LPAs, with DS176 exhibiting a quite moderate decrease to 28 °C at [LPS]:[DS176] 1:2 (weight%), whereas DS347 causes at the highest concentration a complete disappearance of the phase transition. For both compounds, the presence of the LPAs leads to an increase in fluidity (increase in the wavenumber values), which, however, is much higher for DS347 than for compound DS176. The results for compounds DS96 and Yan673 (not shown) are indicative for an only slight decrease in the Tm of LPS, but a decrease in the wavenumbers, whereas Yan673 behaves similar to compound DS347, i.e., a strong increase in the wavenumber values in the entire temperature range. Thus, there is apparently no correlation of these data to their biological action as shown in Fig. (1).

Bottom Line: The lipopolyamines are a novel class of small molecules designed to sequester and neutralize LPS.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.

View Article: PubMed Central - PubMed

Affiliation: Department. of Medicinal Chemistry, University of Kansas, Lawrence, KS, USA.

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.

No MeSH data available.


Related in: MedlinePlus