Anti-endotoxin agents. 3. Rapid identification of high-affinity lipopolysaccharide-binding compounds in a substituted polyamine library

Stewart J. Wood, Kelly A. Miller, Gerald H. Lushington, Mark R. Burns, Sunil A. David

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are an integral part of the outer leaflet of the outer-membrane 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.

Original languageEnglish (US)
Pages (from-to)27-36
Number of pages10
JournalCombinatorial Chemistry and High Throughput Screening
Volume9
Issue number1
DOIs
StatePublished - Jan 2006

Keywords

  • Endotoxin
  • Fluorescence
  • High-throughput screening
  • Lipopolysaccharide
  • Sepsis
  • Shock

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