title: Structural polymorphism and endotoxic activity of synthetic phospholipid-like amphiphiles.
abstract: The physicochemical characteristics and in vitro biological activity of various synthetic hexaacyl phospholipid dimers were compared with the respective behavior of bacterial endotoxins (lipopolysaccharide, LPS). The structural variations of the synthetic amphiphiles include different stereochemical (R,S) configurations about their ester- and amide-linkages for the acyl chains and differences in the length of the serine backbone spacer. The temperature of the gel to liquid crystalline phase transition of the acyl chains (T(c)) lies between 10 and 15 degrees C for the compounds with the shortest backbone and decreases rapidly for the compounds with longer backbones. The phase transition enthalpies (8-16 kJ x mol(-1)) are considerably lower than those of lipid A from hexaacyl endotoxins (28-35 kJ x mol(-1)). In contrast, the dependence of T(c) on Mg(2+) and water content shows a behavior typical for endotoxins: a significant increase with increasing Mg(2+) and decreasing water concentrations. The aggregate structure is sensitively dependent not only on the length of the backbone spacer but also on the different stereochemical variations. It can be directly correlated with the biological activity of the compounds. Thus, as with natural lipid A, the capacity to induce cytokine production in mononuclear cells is directly related to the affinity to form nonlamellar cubic or inverted hexagonal H(II) aggregate structures. Together with the data on the transport and intercalation of the dimers into phospholipid liposomes mediated by the lipopolysaccharide-binding protein (LBP), our conformational concept of endotoxicity and cell activation can be applied to these non-LPS structures: endotoxically active compounds incorporate into membranes of immune cells and cause conformational changes at the site of signaling proteins such as Toll-like receptors or K(+)-channels due to their conical molecular shape.
authors.affiliation: Forschungszentrum Borstel, Leibniz-Institut für Medizin und Biowissenschaften, Parkallee 10, D-23845 Borstel, Germany. Kbranden@fz-borstel.de
authors.forename: K
authors.initials: K
authors.lastname: Brandenburg
authors.forename: L
authors.initials: L
authors.lastname: Hawkins
authors.forename: P
authors.initials: P
authors.lastname: Garidel
authors.forename: J
authors.initials: J
authors.lastname: Andrä
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: H
authors.initials: H
authors.lastname: Heine
authors.forename: M H J
authors.initials: MH
authors.lastname: Koch
authors.forename: U
authors.initials: U
authors.lastname: Seydel
mesh_terms: D000818:Animals; D016466:CHO Cells; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D003460:Crystallization; D016207:Cytokines / Q000096:biosynthesis; D019281:Dimerization; D031541:Fluorescence Resonance Energy Transfer; D005782:Gels; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000819:agonists / Q000737:chemistry* / Q000633:toxicity*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008968:Molecular Conformation; D010743:Phospholipids / Q000138:chemical synthesis* / Q000633:toxicity*; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D017550:Spectroscopy, Fourier Transform Infrared; D051193:Toll-Like Receptors; D014961:X-Ray Diffraction
chemical_list: D016207:Cytokines; C475978:ER 803022; C475979:ER 805046; D005782:Gels; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010743:Phospholipids; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2; D051193:Toll-Like Receptors