INTERACTION OF CATIONIC AMPHIPHILIC DRUGS WITH LIPID-A - IMPLICATIONS FOR DEVELOPMENT OF ENDOTOXIN ANTAGONISTS
INTERACTION OF CATIONIC AMPHIPHILIC DRUGS WITH LIPID-A - IMPLICATIONS FOR DEVELOPMENT OF ENDOTOXIN ANTAGONISTS
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DOI：
10.1016/0005-2760(94)90250-x
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发表时间：
1994-05-13
期刊：
影响因子：
--
通讯作者：
BALARAM, P
中科院分区：
文献类型：
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作者：
DAVID, SA;BECHTEL, B;BALARAM, P
本报告提供了几类阳离子两亲性药物，包括吩噻嗪、氨基喹啉、双胍和芳香二胺与脂类A(脂多糖的内毒素原理)相互作用的证据。用荧光法对药物间的相互作用进行了定量评价。这些药物的亲和力与它们的内毒素拮抗作用在凝胶试验中是相似的。双阳离子化合物以更大的亲和力结合脂类A；这种分子的亲和力随基本部分之间的距离呈指数增加。更详细的研究表明，双嘧啶类药物与脂类A和脂多糖结合的亲和力很高(表观K-d：0.12µM)，这可能是由于末端的酰胺基与脂类A上的阴离子磷酸盐同时相互作用所致。戊脒对内毒素的隔离降低了它与细胞结合的倾向，并且在生物检测中显示出减弱的毒性。这些结果对制定对内毒素相关疾病状态的治疗策略具有重要意义。
This report presents evidence for the interactions of several classes of cationic amphiphilic drugs including the phenothiazines, aminoquinolines, biguanides, and aromatic diamidines, with lipid A, the endotoxic principle of lipopolysaccharides. The interactions of the drugs were quantitatively assessed by fluorescence methods. The affinities of the drugs for lipid A parallel their endotoxin-antagonistic effects in the Limulus gelation assay. Dicationic compounds bind lipid A with greater affinity; the affinity of such molecules increases exponentially as a function of the distance between the basic moieties. The bis-amidine drug - pentamidine - examined in greater detail, binds lipid A with high affinity (apparent K-d: 0.12 mu M), and LPS, probably due to simultaneous interactions of the terminal amidine groups with the anionic phosphates on lipid A. The sequestration of endotoxin by pentamidine reduces its propensity to bind to cells, and the complex exhibits attenuated toxicity in biological assays. These results have implications in the development of therapeutic strategies against endotoxin-related disease states.