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Interaction of cationic amphiphilic drugs with lipid A: Implications for development of endotoxin antagonists

Sunil, A and David, SA and Bethany, Bechtel and Cariappa, Annaiah and Mathan, VI and Balaram, P (1994) Interaction of cationic amphiphilic drugs with lipid A: Implications for development of endotoxin antagonists. In: Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1212 (2). pp. 167-175.

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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.

Item Type: Journal Article
Additional Information: Copy right of this article belongs to Elsevier Science.
Keywords: Lipopolysaccharide; Lipid A; Fluorescence; NMR; Phenothiazine; Aminoquinoline; Biguanide; Pentamidine; Endotoxin-antagonism
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Depositing User: Ms TV Yashodha
Date Deposited: 28 Apr 2010 06:52
Last Modified: 19 Sep 2010 06:00
URI: http://eprints.iisc.ac.in/id/eprint/27316

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