Lipopolysaccharide sequestrants: Structural correlates of activity and toxicity in novel acylhomospermines
Lipopolysaccharide sequestrants: Structural correlates of activity and toxicity in novel acylhomospermines
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DOI：
10.1021/jm049449j
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发表时间：
2005-04-07
影响因子：
7.3
通讯作者：
David, SA
中科院分区：
文献类型：
--
作者：
Miller, KA;Kumar, EVKS;David, SA
脂多糖（LPS），也称为“内毒素”，是革兰氏阴性菌的外膜成分。脂多糖在“感染性休克”的发病机制中起关键作用，这是危重病人死亡的主要原因。目前还不存在通过靶向脂多糖来限制下游全身炎症过程的治疗选择。我们已经定义了小分子特异性结合和中和LPS所必需的药效团，并使用败血症的动物模型表明，小分子隔离循环LPS是一种可行的治疗策略。本文对一系列酰基化精胺同源化合物与LPS的相互作用进行了表征。对单酰基化合物而言，有效隔离LPS的最佳酰基链长为C-16。这些化合物中最有希望的是4e，它与LPS结合的ED50为1.37 μ M.小鼠J774A.1细胞中的一氧化氮产生以及人血液中的tnf - α，在浓度低于毒性剂量的数量级时，4e以剂量依赖的方式抑制。给d -半乳糖胺致敏小鼠以超致死剂量LPS刺激，给予4e可显著保护小鼠免于致死。有效的抗内毒素活性，低毒性和易于合成使这类化合物具有潜在的重要治疗价值的候选内毒素隔离剂。
Lipopolysaccharides (LPS), otherwise termed "endotoxins", are outer membrane constituents of Gram-negative bacteria. Lipopolysaccharides play a key role in the pathogenesis of "septic shock", a major cause of mortality in the critically ill patient. Therapeutic options aimed at limiting downstream systemic inflammatory processes by targeting lipopolysaccharide do not exist at the present time. We have defined the pharmacophore necessary for small molecules to specifically bind and neutralize LPS and, using animal models of sepsis, have shown that the sequestration of circulatory LPS by small molecules is a therapeutically viable strategy. In this paper, the interactions of a series of acylated homologated spermine compounds with LPS have been characterized. The optimal acyl chain length for effective sequestration of LPS was identified to be C-16 for the monoacyl compounds. The most promising of these compounds, 4e, binds LPS with an ED50 of 1.37 mu M. Nitric oxide production in murine J774A.1 cells, as well as TNF-alpha in human blood, is inhibited in a dose-dependent manner by 4e at concentrations orders of magnitude lower than toxic doses. Administration of 4e to D-galactosamine-sensitized mice challenged with supralethal doses of LPS provided significant protection against lethality. Potent antiendotoxic activity, low toxicity, and ease of synthesis render this class of compounds candidate endotoxin-sequestering agents of potential significant therapeutic value.