Septischer Schock: Molekulare Pathophysiologie und therapeutische Ansaetze. Teilprojekt B1: Isolierung und strukturelle Charakterisierung von Endotoxin-Antagonisten Ein Beitrag zur Untersuchung der Struktur-Funktionsweise von Lipoid A/LPS Strukturen mit antagonistischem Potential. Schlussbericht

Abstract

A new method has been developed to isolate and investigate lipid A and lipid A-part structures resulting in high purity (>95%) and excellent yield (35-40%). A preparation protocol has been elaborated to prepare polar and charged glycolipids suitable for mass spectrometric analysis (MALDI-TOF). In addition, non-invasive NMR-spectroscopy has been used and investigated in several organic and aqueous solution, allowing the lipid A-preparation to be investigated, thus giving access to study identical preparations by both ways chemically and biologically. This approach has to the best of our knowledge not been described so far. A new endotoxin-antagonist has been described for the first time, and its structure was completely elucidated and biologically characterised with respect to induce or inhibit proinflammatory cytokines in human monocytes (hMNC). The antagonist was identified as a tetraacylated lipid A part-structure expressing identical antagonistic activty as compared to the well characterised synthetic compound 406. The physicochemical properties of this new antagonist are in agreement with the model postulating that bioactivity of LPS (or lipid A) is related not directly to its primary structure, but rather to its physicochemical and supramolecular properties ('endotoxic conformation'). (orig.)SIGLEAvailable from TIB Hannover: F99B46 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman