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J. Biol. Chem., Vol. 282, Issue 15, 11030-11037, April 13, 2007

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Physicochemical and Biological Analysis of Synthetic Bacterial Lipopeptides

VALIDITY OF THE CONCEPT OF ENDOTOXIC CONFORMATION^*

Andra B. Schromm¹, Jörg Howe^¶, Artur J. Ulmer^||, Karl-Heinz Wiesmüller^**, Tobias Seyberth, Günther Jung, Manfred Rössle, Michel H. J. Koch, Thomas Gutsmann^¶, and Klaus Brandenburg^¶

From the Research Center Borstel, Leibniz Center for Medicine and Biosciences, Department of Immunochemistry and Biochemical Microbiology, Emmy Noether Group of Immunobiophysics, ^¶Division of Biophysics, ^||Division of Immunology, 23845 Borstel, Germany, ^**EMC Microcollections GmbH, 72070 Tübingen, Germany, Institute of Organic Chemistry, University of Tübingen, 72076 Tübingen, Germany, and European Molecular Biology Laboratory c/o DESY, Notkestrasse 85, 22603 Hamburg, Germany

The importance of the biological function and activity of lipoproteins from the outer or cytoplasmic membranes of Gram-positive and Gram-negative bacteria is being increasingly recognized. It is well established that they are like the endotoxins (lipopolysaccharide (LPS)), which are the main amphiphilic components of the outer membrane of Gram-negative bacteria, potent stimulants of the human innate immune system, and elicit a variety of proinflammatory immune responses. Investigations of synthetic lipopeptides corresponding to N-terminal partial structures of bacterial lipoproteins defined the chemical prerequisites for their biological activity and in particular the number and length of acyl chains and sequence of the peptide part. Here we present experimental data on the biophysical mechanisms underlying lipopeptide bioactivity. Investigation of selected synthetic diacylated and triacylated lipopeptides revealed that the geometry of these molecules (i.e. the molecular conformations and supramolecular aggregate structures) and the preference for membrane intercalation provide an explanation for the biological activities of the different lipopeptides. This refers in particular to the agonistic or antagonistic activity (i.e. their ability to induce cytokines in mononuclear cells or to block this activity, respectively). Biological activity of lipopeptides was hardly affected by the LPS-neutralizing antibiotic polymyxin B, and the biophysical interaction characteristics were found to be in sharp contrast to that of LPS with polymyxin B. The analytical data show that our concept of "endotoxic conformation," originally developed for LPS, can be applied also to the investigated lipopeptide and suggest that the molecular mechanisms of cell activation by amphiphilic molecules are governed by a general principle.

Received for publication, January 10, 2007 , and in revised form, February 15, 2007.

^* This work was funded by Deutsche Forschungsgemeinschaft Grants SCHR 621/2-2 and Ul 68/3-1, the European Commission (Antimicrobial Endotoxin Neutralizing Peptides to Combat Infectious Diseases), and the Federal Ministry of Education and Research Project Biochance 0312662. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 49-4537-188296; Fax: 49-4537-188632; E-mail: aschromm{at}fz-borstel.de.

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