Synthesis and immunobiological activity of an original series of acyclic lipid a mimics based on a pseudodipeptide backbone.
Ndelta-L-Homoserinyl-D-ornithinol pseudodipeptides N-acylated with typical Escherichia coli lipid A fatty acid residues and mono-O- or bis-O-phosphorylated have been prepared and their properties investigated. The derivatives carrying two phosphate groups were found to be inducers of NO production. In addition, while they were unable to induce significantly the production of interleukin-6 (IL-6) by human PBMC cells, these compounds behaved also as potent antagonists of LPS-induced IL-6 production in the same human cells system. In conclusion, the molecules described here are the first members of an original class of immunobiologically active lipid A mimics based on an acyclic pseudodipeptide backbone carrying only the essential functionalities of the parent lipid A structure (OM-174). As the products exhibit very low endotoxicity and pyrogenicity, this class of lipid A mimics therefore opens a new generation of immunoadjuvants that possibly could reach clinical applications.
Martin
Olivier R
OR
Institut de Chimie Organique et Analytique, Université d'Orléans, BP 6759, 45067 Orléans, France. Olivier.Martin@univ-orleans.fr
Zhou
Wei
W
Wu
Xinfu
X
Front-Deschamps
Sophie
S
Moutel
Stéphane
S
Schindl
Katharina
K
Jeandet
Patricia
P
Zbaeren
Claude
C
Bauer
Jacques A
JA
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004151:Dipeptides / Q000737:chemistry*; D004926:Escherichia coli; D005227:Fatty Acids / Q000737:chemistry*; D006714:Homoserine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008050:Lipid A / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D009569:Nitric Oxide / Q000096:biosynthesis; D010755:Organophosphates / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000093242:Interleukin-6 Inhibitors
D000276:Adjuvants, Immunologic; D004151:Dipeptides; D005227:Fatty Acids; D006714:Homoserine; D015850:Interleukin-6; D008050:Lipid A; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D010755:Organophosphates; D000093242:Interleukin-6 Inhibitors