Biophysical mechanisms of the neutralization of endotoxins by lipopolyamines.
Biophysical mechanisms of the neutralization of endotoxins by lipopolyamines.
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DOI：
10.2174/1874091x01307010082
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Brandenburg K
中科院分区：
文献类型：
--
作者：
Sil D;Heinbockel L;Kaconis Y;Rössle M;Garidel P;Gutsmann T;David SA;Brandenburg K
内毒素（脂多糖，LPS）是自然界中最强的免疫刺激剂之一，在低浓度时产生有益作用，在高浓度时产生病理生理作用，后者经常导致败血症和败血性休克，并与重症监护环境中的高死亡率相关。目前还没有专门针对脓毒症病理生理学的药物，因此迫切需要新的治疗药物。脂多胺是一类新型小分子，旨在隔离和中和 LPS。为了了解 LPS 毒性结合和中和的机制，我们对 LPS 与候选脂多胺的相互作用进行了详细的生物物理分析，这些候选脂多胺的 LPS 中和效力不同。我们研究了在脂多胺不存在和存在的情况下LPS及其超分子聚集体结构的凝胶-液晶相行为、此类化合物掺入不同膜系统的能力以及LPS：脂多胺结合的热力学。我们发现，控制 LPS 失活过程的机制遵循与其他活性内毒素中和剂（例如某些抗菌肽）相似的规则。
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.