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Inhibition of LPS binding on human monocytes by phosphonooxyethyl analogs of lipid A

Department of Immunology and Cell Biology, Institut fur Experimentelle Biologie und Medizin, Borstel, Germany, Department of Immunochemistry and Biochemical Microbiology, Forschungsinstitut Borstel, Institut für Experimentelle Biologie und Medizin, Borstel, Germany, Department of Chemistry, Osaka University, Faculty of Science, Osaka, Japan, Daiichi Pharmaceutical Co. Ltd, Tokyo, Japan

H. Brade

Department of Immunology and Cell Biology, Institut fur Experimentelle Biologie und Medizin, Borstel, Germany, Department of Immunochemistry and Biochemical Microbiology, Forschungsinstitut Borstel, Institut für Experimentelle Biologie und Medizin, Borstel, Germany, Department of Chemistry, Osaka University, Faculty of Science, Osaka, Japan, Daiichi Pharmaceutical Co. Ltd, Tokyo, Japan

S. Kusumoto

Department of Immunology and Cell Biology, Institut fur Experimentelle Biologie und Medizin, Borstel, Germany, Department of Immunochemistry and Biochemical Microbiology, Forschungsinstitut Borstel, Institut für Experimentelle Biologie und Medizin, Borstel, Germany, Department of Chemistry, Osaka University, Faculty of Science, Osaka, Japan, Daiichi Pharmaceutical Co. Ltd, Tokyo, Japan

T. Kusama

Department of Immunology and Cell Biology, Institut fur Experimentelle Biologie und Medizin, Borstel, Germany, Department of Immunochemistry and Biochemical Microbiology, Forschungsinstitut Borstel, Institut für Experimentelle Biologie und Medizin, Borstel, Germany, Department of Chemistry, Osaka University, Faculty of Science, Osaka, Japan, Daiichi Pharmaceutical Co. Ltd, Tokyo, Japan

E. Th. Rietschel

Department of Immunology and Cell Biology, Institut fur Experimentelle Biologie und Medizin, Borstel, Germany, Department of Immunochemistry and Biochemical Microbiology, Forschungsinstitut Borstel, Institut für Experimentelle Biologie und Medizin, Borstel, Germany, Department of Chemistry, Osaka University, Faculty of Science, Osaka, Japan, Daiichi Pharmaceutical Co. Ltd, Tokyo, Japan

H.-D. Flad

Department of Immunology and Cell Biology, Institut fur Experimentelle Biologie und Medizin, Borstel, Germany, Department of Immunochemistry and Biochemical Microbiology, Forschungsinstitut Borstel, Institut für Experimentelle Biologie und Medizin, Borstel, Germany, Department of Chemistry, Osaka University, Faculty of Science, Osaka, Japan, Daiichi Pharmaceutical Co. Ltd, Tokyo, Japan

A.J. Ulmer

Department of Immunology and Cell Biology, Institut fur Experimentelle Biologie und Medizin, Borstel, Germany, Department of Immunochemistry and Biochemical Microbiology, Forschungsinstitut Borstel, Institut für Experimentelle Biologie und Medizin, Borstel, Germany, Department of Chemistry, Osaka University, Faculty of Science, Osaka, Japan, Daiichi Pharmaceutical Co. Ltd, Tokyo, Japan

We investigated the inhibition of LPS binding on human monocytes by synthetic analogs of lipid A. A common characteristic of the analyzed structures is a -(or β-) phosphonooxyethyl group in position 1 of the GlcN I of the lipid A backbone. Compounds PE-1, PE-2 and PE-3 are analogs of synthetic Escherichia coli lipid A whereas PE-4 represents an analog of tetraacyl precursor Ia (synthetic compound 406). By determining the ability of these preparations to inhibit the binding of FITC-labeled LPS (E. coli 0111:B4) on human monocytes the relationship between their structure and cellular binding affinity was evaluated. The results showed a structure-dependent hierarchy of inhibition capacity. Thus, compound PE-1 inhibited the binding of FITC-LPS only slightly more than PE-2. However, compound PE-3, possessing β-configurated GlcN I, exhibited a drastically decreased inhibition capability. Best inhibition was obtained with compound PE-4. It was furthermore shown by a Lineweaver-Burk plot that the inhibition of LPS binding was due to competition of FITC-LPS and PE-4 for the same binding structure. The synthesis of stable 1-phosphonooxyethyl analogs of precursor Ia with high affinity for LPS receptor structures but lacking cytokine-inducing capacity (like PE-4) may be of relevance for their function as potent antagonists of LPS in therapy of endotoxic shock and sepsis.

Journal of Endotoxin Research, Vol. 1, No. 1, 14-20 (1994)
DOI: 10.1177/096805199400100104


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