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

Sunil A. David; Bethany Bechtel; Cariappa Annaiah; V. I. Mathan; P. Balaram

doi:10.1016/0005-2760(94)90250-X

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

Sunil A. David, Bethany Bechtel, Cariappa Annaiah, V. I. Mathan, P. Balaram

Medicinal Chemistry

Research output: Contribution to journal › Article › peer-review

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Abstract

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 μM), 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.

Original language	English (US)
Pages (from-to)	167-175
Number of pages	9
Journal	Biochimica et Biophysica Acta (BBA)/Lipids and Lipid Metabolism
Volume	1212
Issue number	2
DOIs	https://doi.org/10.1016/0005-2760(94)90250-X
State	Published - May 13 1994

Bibliographical note

Funding Information:
SD is a recipient of a Senior Research Fellowship from the Council for Scientific and Industrial Research, New Delhi. BB was a Fulbright Scholarship awardee.T he authorsa re grateful to Prof. Kastowsky for providingt he atomic coordinateso f the molecular modelo f core-glycolipidD, r. P.J. Munson for the ALL-FIT programs,M r. Ragothammaa nd Mr. Gowda for assistancew ith the NMR experiments,D r. Sowd-hamani,M r. S. Suresha nd Dr. B. Rajini for their help with DISCOVER, and Dr. George Babu for help with flow cytometry.

Keywords

Aminoquinoline
Biguanide
Endotoxin-antagonism
Fluorescence
Lipid A
Lipopolysaccharide
NMR
Pentamidine
Phenothiazine

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title = "Interaction of cationic amphiphilic drugs with lipid A: Implications for development of endotoxin antagonists",

abstract = "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 Kd: 0.12 μM), 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.",

keywords = "Aminoquinoline, Biguanide, Endotoxin-antagonism, Fluorescence, Lipid A, Lipopolysaccharide, NMR, Pentamidine, Phenothiazine",

author = "David, {Sunil A.} and Bethany Bechtel and Cariappa Annaiah and Mathan, {V. I.} and P. Balaram",

note = "Funding Information: SD is a recipient of a Senior Research Fellowship from the Council for Scientific and Industrial Research, New Delhi. BB was a Fulbright Scholarship awardee.T he authorsa re grateful to Prof. Kastowsky for providingt he atomic coordinateso f the molecular modelo f core-glycolipidD, r. P.J. Munson for the ALL-FIT programs,M r. Ragothammaa nd Mr. Gowda for assistancew ith the NMR experiments,D r. Sowd-hamani,M r. S. Suresha nd Dr. B. Rajini for their help with DISCOVER, and Dr. George Babu for help with flow cytometry.",

year = "1994",

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doi = "10.1016/0005-2760(94)90250-X",

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T1 - Interaction of cationic amphiphilic drugs with lipid A

T2 - Implications for development of endotoxin antagonists

AU - David, Sunil A.

AU - Bechtel, Bethany

AU - Annaiah, Cariappa

AU - Mathan, V. I.

AU - Balaram, P.

N1 - Funding Information: SD is a recipient of a Senior Research Fellowship from the Council for Scientific and Industrial Research, New Delhi. BB was a Fulbright Scholarship awardee.T he authorsa re grateful to Prof. Kastowsky for providingt he atomic coordinateso f the molecular modelo f core-glycolipidD, r. P.J. Munson for the ALL-FIT programs,M r. Ragothammaa nd Mr. Gowda for assistancew ith the NMR experiments,D r. Sowd-hamani,M r. S. Suresha nd Dr. B. Rajini for their help with DISCOVER, and Dr. George Babu for help with flow cytometry.

PY - 1994/5/13

Y1 - 1994/5/13

N2 - 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 Kd: 0.12 μM), 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.

AB - 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 Kd: 0.12 μM), 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.

KW - Aminoquinoline

KW - Biguanide

KW - Endotoxin-antagonism

KW - Fluorescence

KW - Lipid A

KW - Lipopolysaccharide

KW - NMR

KW - Pentamidine

KW - Phenothiazine

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JO - Biochimica et Biophysica Acta (BBA)/Lipids and Lipid Metabolism

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IS - 2

ER -

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

Abstract

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