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The role of polar and facial amphipathic character in determining lipopolysaccharide-binding properties in synthetic cationic peptides

Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA, sdavid{at}kumc.edu

Satish K. Awasthi

Institute of Medical Biochemistry and Genetics, The Panum Institute, Copenhagen, Denmark

P. Balaram

Institute of Medical Biochemistry and Genetics, The Panum Institute, Copenhagen, Denmark

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- 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.

Journal of Endotoxin Research, Vol. 6, No. 3, 249-256 (2000)
DOI: 10.1177/09680519000060030601


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