INTERACTION OF CATIONIC AMPHIPHILIC DRUGS WITH LIPID-A - IMPLICATIONS FOR DEVELOPMENT OF ENDOTOXIN ANTAGONISTS

被引:43
作者
DAVID, SA
BECHTEL, B
ANNAIAH, C
MATHAN, VI
BALARAM, P
机构
[1] CHRISTIAN MED COLL & HOSP,WELLCOME TRUST RES LAB,VELLORE 632004,TAMIL NADU,INDIA
[2] CHRISTIAN MED COLL & HOSP,DEPT GASTROINTESTINAL SCI,VELLORE 632004,TAMIL NADU,INDIA
[3] INDIAN INST SCI,MOLEC BIOPHYS UNIT,BANGALORE 560012,KARNATAKA,INDIA
[4] SCHIEFFELIN LEPROSY RES & TRAINING CTR,KARIGIRI 632106,INDIA
来源
BIOCHIMICA ET BIOPHYSICA ACTA-LIPIDS AND LIPID METABOLISM | 1994年 / 1212卷 / 02期
关键词
LIPOPOLYSACCHARIDE; LIPID A; FLUORESCENCE; NMR; PHENOTHIAZINE; AMINOQUINOLINE; BIGUANIDE; PENTAMIDINE; ENDOTOXIN-ANTAGONISM;
D O I
10.1016/0005-2760(94)90250-X
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:167 / 175
页数:9
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