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Volume 271, Number 45, Issue of November 8, 1996 pp. 28120-28127
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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High Affinity Endotoxin-binding and Neutralizing Peptides Based on the Crystal Structure of Recombinant Limulus Anti-lipopolysaccharide Factor

(Received for publication, March 4, 1996, and in revised form, August 7, 1996)

Christine Ried , Claudia Wahl ^§ , Thomas Miethke ^§ , Günter Wellnhofer , Christiane Landgraf ^¶ , Jens Schneider-Mergener ^¶ and Adolf Hoess ^§

From  MorphoSys GmbH, 80807 Munich, Germany, the ^§ Institute of Medical Microbiology and Hygiene, Technical University of Munich, 81675 Munich, Germany, and the ^¶ Institute of Medical Immunology, Humboldt University of Berlin, 10098 Berlin, Germany

Lipid A, the conserved portion of endotoxin or lipopolysaccharide, is the major mediator of septic shock, and therefore endotoxin-neutralizing molecules could have important clinical applications. The crystal structure of recombinant Limulus anti-lipopolysaccharide factor (rLALF) (Hoess, A., Watson, S., Siber, G. R., and Liddington, R. (1993) EMBO J. 12, 3351-3356), has been used to design synthetic peptides comprising different parts of the exposed amphipathic loop in the proposed endotoxin-binding domain of rLALF. We investigated the minimal requirements of rLALF for endotoxin and lipid A binding with linear 10-mer peptides. Only one linear peptide, corresponding to amino acids 36-45 of rLALF, was able to bind lipid A and endotoxin above background levels. Cyclic peptides, however, bind lipid A and endotoxin with high affinity, presumably by mimicking the three dimensional characteristics of the exposed hairpin loop. The cyclic peptide including amino acids 36-47, LALF-14, has a lipid A binding activity comparable to the high affinity endotoxin-binding peptide polymyxin B. LALF-14 has an improved serum half-life compared with its linear counterpart, and it is not toxic for cultured human monocytes or red blood cells. In mice, it blocks tumor necrosis factor- induction after endotoxin challenge. The characterization of the minimal endotoxin-binding domain of rLALF and, importantly, its structure provided a basis for designing small molecules that could have prophylactic and/or therapeutic properties in humans for the management of septic shock.

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