title: Physicochemical and biological analysis of synthetic bacterial lipopeptides: validity of the concept of endotoxic conformation.
abstract: 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.
authors.affiliation: Research Center Borstel, Leibniz Center for Medicine and Biosciences, Department of Immunochemistry and Biochemical Microbiology, Emmy Noether Group of Immunobiophysics, Division of Biophysics, Borstel, Germany. aschromm@fz-borstel.de
authors.forename: Andra B
authors.initials: AB
authors.lastname: Schromm
authors.forename: Jörg
authors.initials: J
authors.lastname: Howe
authors.forename: Artur J
authors.initials: AJ
authors.lastname: Ulmer
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Wiesmüller
authors.forename: Tobias
authors.initials: T
authors.lastname: Seyberth
authors.forename: Günther
authors.initials: G
authors.lastname: Jung
authors.forename: Manfred
authors.initials: M
authors.lastname: Rössle
authors.forename: Michel H J
authors.initials: MH
authors.lastname: Koch
authors.forename: Thomas
authors.initials: T
authors.lastname: Gutsmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Brandenburg
mesh_terms: D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D011112:Polymyxin B / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D008070:Lipopolysaccharides; D008074:Lipoproteins; D010446:Peptide Fragments; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D011112:Polymyxin B