Abstract
Lipopolysaccharides (LPS), otherwise termed endotoxins, are an integral part of the outer leaflet of the outermembrane of Gram-negative bacteria. Lipopolysaccharides play a pivotal role in the pathogenesis of Septic Shock, a major cause of mortality in the critically ill patient, worldwide. The sequestration of circulatory endotoxin may be a viable therapeutic strategy for the prophylaxis and treatment of Gram-negative sepsis. We have earlier shown that the pharmacophore necessary for small molecules to bind LPS involves two protonatable cationic functions separated by about 15 Å, permitting the simultaneous interaction with the negatively charged phosphates on lipid A, the toxically active center of endotoxin. In this report, screening of a multi-thousand membered polyamine library through the combined use of computational and bioassay-guided screens resulted in the discovery of two novel classes of LPS-binding agents. These are represented by the 1) spermine sulfonamides and 2) C-aryl-substituted spermine analogs. We present the selection approach, screening results, computational multivariate analyses and initial structure-activity relationship evaluation herein.
Keywords: Endotoxin, lipopolysaccharide, sepsis, shock, fluorescence, high-throughput screening
Combinatorial Chemistry & High Throughput Screening
Title: Anti-Endotoxin Agents. 3. Rapid Identification of High-Affinity Lipopolysaccharide-Binding Compounds in a Substituted Polyamine Library
Volume: 9 Issue: 1
Author(s): Stewart J. Wood, Kelly A. Miller, Gerald H. Lushington, Mark R. Burns and Sunil A. David
Affiliation:
Keywords: Endotoxin, lipopolysaccharide, sepsis, shock, fluorescence, high-throughput screening
Abstract: Lipopolysaccharides (LPS), otherwise termed endotoxins, are an integral part of the outer leaflet of the outermembrane of Gram-negative bacteria. Lipopolysaccharides play a pivotal role in the pathogenesis of Septic Shock, a major cause of mortality in the critically ill patient, worldwide. The sequestration of circulatory endotoxin may be a viable therapeutic strategy for the prophylaxis and treatment of Gram-negative sepsis. We have earlier shown that the pharmacophore necessary for small molecules to bind LPS involves two protonatable cationic functions separated by about 15 Å, permitting the simultaneous interaction with the negatively charged phosphates on lipid A, the toxically active center of endotoxin. In this report, screening of a multi-thousand membered polyamine library through the combined use of computational and bioassay-guided screens resulted in the discovery of two novel classes of LPS-binding agents. These are represented by the 1) spermine sulfonamides and 2) C-aryl-substituted spermine analogs. We present the selection approach, screening results, computational multivariate analyses and initial structure-activity relationship evaluation herein.
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Cite this article as:
Wood J. Stewart, Miller A. Kelly, Lushington H. Gerald, Burns R. Mark and David A. Sunil, Anti-Endotoxin Agents. 3. Rapid Identification of High-Affinity Lipopolysaccharide-Binding Compounds in a Substituted Polyamine Library, Combinatorial Chemistry & High Throughput Screening 2006; 9 (1) . https://dx.doi.org/10.2174/138620706775213903
DOI https://dx.doi.org/10.2174/138620706775213903 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
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