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Characterization of the interactions of a polycationic, amphiphilic, terminally branched oligopeptide with lipid A and lipopolysaccharide from the deep rough mutant of Salmonella minnesota

Wellcome Trust Research Laboratory, Department of Gastrointestinal Sciences, Christian Medical College, Vellore, India, Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India, 1000 Wahl Hall East, 3901 Rainbow Blvd, Kansas City, KS 66160-7382, USA. sdavid{at}kumc.edu

S.K. Awasthi

Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India

A. Wiese

Forschungszentrum Borstel, Borstel, Germany

A.J. Ulmer

Forschungszentrum Borstel, Borstel, Germany

B. Lindner

Forschungszentrum Borstel, Borstel, Germany

K. Brandenburg

Forschungszentrum Borstel, Borstel, Germany

U. Seydel

Forschungszentrum Borstel, Borstel, Germany

E.Th. Rietschel

Forschungszentrum Borstel, Borstel, Germany

A. Sonesson

Department of Bioanalytical Chemistry, Astra Draco AB, Lund, Sweden

P. Balaram

Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India

The lipid A and lipopolysaccharide (LPS) binding and neutralizing activities of a synthetic, polycationic, amphiphilic peptide were studied. The branched peptide, designed as a functional analog of polymyxin B, has a six residue hydrophobic sequence, bearing at its N-terminus a penultimate lysine residue whose - and E-amino groups are coupled to two terminal lysine residues. In fluorescence spectroscopic studies designed to examine relative affinities of binding to the toxin, neutralization of surface charge and fluidization of the acyl domains, the peptide was active, closely resembling the effects of polymyxin B and its nonapeptide derivative; however, the synthetic peptide does not induce phase transitions in LPS aggregates as do polymyxin B and polymyxin B nonapeptide. The peptide was also comparable with polymyxin B in its ability to inhibit LPS-mediated IL-1 and IL-6 release from human peripheral blood mononuclear cells. The synthetic compound is devoid of antibacterial activities and did not induce conductance fluxes in LPS-containing asymmetric planar membranes. These results strengthen the premise that basicity and amphiphilicity are necessary and sufficient physical properties that ascribe endotoxin binding and neutralizing activities, and further suggest that antibacterial/membrane perturbant and LPS neutralizing activities are dissociable, which may be of value in designing LPS-sequestering agents of low toxicity.

Innate Immunity, Vol. 3, No. 5, 369-379 (1996)
DOI: 10.1177/096805199600300501


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