title: The role of polar and facial amphipathic character in determining lipopolysaccharide-binding properties in synthetic cationic peptides.
abstract: Two series of peptides, designated K and NK were synthesized and tested for lipid A binding and neutralizing properties. K2, which has an 11-residue amphiphilic core, and a branched N-terminus bearing two branched lysinyl residues does not bind lipid A, while NK2, also with an 11-residue amphiphilic core comprised entirely of non-ionizable residues, and a similarly branched, cationic N-terminus, binds lipid A very weakly. Both peptides do not inhibit lipopolysaccharide (LPS) activity in the Limulus assay, nor do they inhibit LPS-induced TNF-alpha and NO production in J774 cells. These results are entirely unlike a homologous peptide with an exclusively hydrophobic core whose LPS-binding and neutralizing properties are very similar to that of polymyxin B [David SA, Awasthi SK, Wiese A et al. Characterization of the interactions of a polycationic, amphiphilic, terminally branched oligopeptide with lipid A and lipopolysaccharide from the deep rough mutant of Salmonella minnesota. J Endotoxin Res 1996; 3: 369-379]. These data suggest that a clear segregation of charged and apolar domains is crucial in molecules designed for purposes of LPS sequestration and that head-tail (polar) orientation of the cationic/hydrophobic regions is preferable to molecules with mixed or facial cationic/amphipathic character.
authors.affiliation: Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City 66160, USA. sdavid@kumc.edu
authors.forename: S A
authors.initials: SA
authors.lastname: David
authors.forename: S K
authors.initials: SK
authors.lastname: Awasthi
authors.forename: P
authors.initials: P
authors.lastname: Balaram
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D008033:Limulus Test; D008050:Lipid A / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism; D010452:Peptide Biosynthesis; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
chemical_list: D008050:Lipid A; D008070:Lipopolysaccharides; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide