Towards a rational development of anti-endotoxin agents: novel approaches to sequestration of bacterial endotoxins with small molecules.
Endotoxins, or lipopolysaccharides (LPS), present on the surface of Gram-negative bacteria, play a key role in the pathogenesis of septic shock, a common clinical problem and a leading cause of mortality in critically ill patients, for which no specific therapeutic modalities are available at the present time. The toxic moiety of LPS is a glycolipid called 'lipid A', which is composed of a bisphosphorylated diglucosamine backbone bearing up to seven acyl chains in ester and amide linkages. Lipid A is structurally highly conserved in Gram-negative bacteria, and is therefore an attractive target for developing anti-endotoxin molecules designed to sequester, and thereby neutralize, the deleterious effects of endotoxins. The anionic and amphipathic nature of lipid A enables the interaction of a wide variety of cationic amphiphiles with the toxin. This review describes the systematic evaluation of several structural classes of cationic amphiphiles, both peptides and non-peptidic small molecules, in the broader context of recent efforts aimed at developing novel anti-endotoxin strategies. The derivation of a pharmacophore for LPS recognition has led to the identification of novel, nontoxic, structurally simple small molecules, the lipopolyamines. The lipopolyamines bind and neutralize LPS in in vitro experiments as well as in animal models of endotoxicity, and thus present novel and exciting leads for rational, structure-based development of LPS-sequestering agents of potential clinical value.
David
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SA
Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA. sdavid@ku.edu
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000906:Antibodies / Q000627:therapeutic use; D001665:Binding Sites; D015195:Drug Design; D004731:Endotoxins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism*; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011113:Polymyxins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D000906:Antibodies; D004731:Endotoxins; D008070:Lipopolysaccharides; D010455:Peptides; D011113:Polymyxins; D011506:Proteins