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

This report presents evidence for the interactions of several classes of cationic amphiphilic drugs including the phenothiazines, aminoquino lines, biguanides, and aromatic diamidines, with lipid A, the endotoxi c principle of lipopolysaccharides. The interactions of the drugs were quantitatively assessed by fluorescence methods. The affinities of th e drugs for lipid A parallel their endotoxin-antagonistic effects in t he Limulus gelation assay. Dicationic compounds bind lipid A with grea ter affinity; the affinity of such molecules increases exponentially a s a function of the distance between the basic moieties. The bis-amidi ne drug - pentamidine - examined in greater detail, binds lipid A with high affinity (apparent K-d: 0.12 mu M), and LPS, probably due to sim ultaneous 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 atte nuated toxicity in biological assays. These results have implications in the development of therapeutic strategies against endotoxin-related disease states.