ABSTRACT
The synthesis of a series of novel analogues of lipid A, the active principle of lipopolysaccharide, is reported. In these compounds, the 1-O-phosphono and (R)-3-hydroxytetradecanoyl moieties of native Salmonella minnesota R595 lipid A have been replaced with hydrogen and the length of the normal fatty acyl residues has been systematically varied. Normal fatty acid chain length in the 3-O-desacyl monophosphoryl lipid A (MLA) series is shown to be a critical determinant of iNOS gene expression in activated mouse macrophages and the induction of proinflammatory cytokines in human peripheral monocytes. Examination of pyrogenicity in rabbits and lethal toxicity in D-galactosamine-treated mice shows that toxic effects in the MLA series can be ameliorated by modifying fatty acid chain length. When used as an adjuvant for tetanus toxoid vaccines, certain MLA derivatives enhance the production of tetanus toxoid-specific antibodies in mice.
Subject(s)
Adjuvants, Immunologic/chemical synthesis , Lipid A/analogs & derivatives , Lipid A/chemical synthesis , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/toxicity , Animals , Cytokines/metabolism , Female , Fever/chemically induced , Humans , Immunoglobulin G/biosynthesis , In Vitro Techniques , Lethal Dose 50 , Lipid A/chemistry , Lipid A/pharmacology , Macrophages/drug effects , Macrophages/enzymology , Mice , Monocytes/drug effects , Monocytes/metabolism , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Rabbits , Salmonella/chemistry , Structure-Activity Relationship , Tetanus Toxoid , VaccinationABSTRACT
A novel series of acylated omega-aminoalkyl 2-amino-2-deoxy-4-phosphono-beta-D-glucopyranosides (aminoalkyl glucosaminide 4-phosphates) was synthesized and screened for immunostimulant activity. Several of these compounds enhance the production of tetanus toxoid-specific antibodies in mice and augment vaccine-induced cytotoxic T cells against EG.7-ova target cells.
