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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

Aggregate structures of LPS R595 in the presence of DS176 (A) and DS347 (B) in small-angle X-ray scattering (SAXS) experimentswith synchrotron radiation. The logarithm of the scattering intensity (logI) is plotted versus the scattering vector, s (=1/d, d, spacingsof the reflections).
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Figure 4: Aggregate structures of LPS R595 in the presence of DS176 (A) and DS347 (B) in small-angle X-ray scattering (SAXS) experimentswith synchrotron radiation. The logarithm of the scattering intensity (logI) is plotted versus the scattering vector, s (=1/d, d, spacingsof the reflections).

Mentions: The aggregate structure of LPS was monitored by using small-angle X-ray scattering (SAXS) with synchrotron radiation in the absence and presence of the LPAs. As LPS that from S. minnesota deep rough mutant R595 was taken, since this compound with its short sugar chain gives better resolved SAXS patterns than compounds with long sugar chains. SAXS patterns are shown for LPS R595 in the presence of DS176 (Fig. 4A) and of DS347 (Fig. 4B). For the LPS:DS176 system, SAXS patterns are indicative of only one broad intensity distribution between 0.1 and 0.35/nm, which corresponds to the existence of a LPS bilayer system, e.g, for a unilamellar structure which is frequently found for this endotoxin. Therefore, the addition of compound DS176 does not change the LPS aggregate structure significantly. In the presence of DS347, the patterns exhibit reflections at equidistant ratios. Thus, for example, at 40 °C there are 4 reflections with a main peak at 5.49 nm and further reflections at 2.72 nm = 5.49/2 nm, 1.81 nm = 5.49/3 nm, and 1.35 nm = 5.49/4 nm, which are clearly indicative for the existence of a multilamellar structure of the LPS assembly.


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)

Aggregate structures of LPS R595 in the presence of DS176 (A) and DS347 (B) in small-angle X-ray scattering (SAXS) experimentswith synchrotron radiation. The logarithm of the scattering intensity (logI) is plotted versus the scattering vector, s (=1/d, d, spacingsof the reflections).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Aggregate structures of LPS R595 in the presence of DS176 (A) and DS347 (B) in small-angle X-ray scattering (SAXS) experimentswith synchrotron radiation. The logarithm of the scattering intensity (logI) is plotted versus the scattering vector, s (=1/d, d, spacingsof the reflections).
Mentions: The aggregate structure of LPS was monitored by using small-angle X-ray scattering (SAXS) with synchrotron radiation in the absence and presence of the LPAs. As LPS that from S. minnesota deep rough mutant R595 was taken, since this compound with its short sugar chain gives better resolved SAXS patterns than compounds with long sugar chains. SAXS patterns are shown for LPS R595 in the presence of DS176 (Fig. 4A) and of DS347 (Fig. 4B). For the LPS:DS176 system, SAXS patterns are indicative of only one broad intensity distribution between 0.1 and 0.35/nm, which corresponds to the existence of a LPS bilayer system, e.g, for a unilamellar structure which is frequently found for this endotoxin. Therefore, the addition of compound DS176 does not change the LPS aggregate structure significantly. In the presence of DS347, the patterns exhibit reflections at equidistant ratios. Thus, for example, at 40 °C there are 4 reflections with a main peak at 5.49 nm and further reflections at 2.72 nm = 5.49/2 nm, 1.81 nm = 5.49/3 nm, and 1.35 nm = 5.49/4 nm, which are clearly indicative for the existence of a multilamellar structure of the LPS assembly.

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