ABSTRACT
Since the discovery in 1995 of α-galactosylceramide 1 (α-GalCer), also known as KRN7000,1 hundreds of compounds have been synthesized in order to activate invariant natural killer T (iNKT) cells. Such keen interest for this lymphocyte cell type is due to its ability to produce different cytokines that bias the immune response toward a Th1 or Th2 profile. Thus, an understanding of the immune polarization mechanism via iNKT activation may pave the way toward new therapeutics in various domains including cancer and infectious and autoimmune diseases. In this review, we propose an up-to-date analysis of iNKT activators associated with a structure-activity relationship (SAR) study aimed at complementing available reviews by highlighting molecular bases for a selective immune response.
Subject(s)
Galactosylceramides/pharmacology , Natural Killer T-Cells/immunology , Animals , Antigens, CD1d/immunology , Humans , Ligands , Lymphocyte Activation/immunology , Mice , Models, Molecular , Natural Killer T-Cells/drug effects , Rats , Structure-Activity Relationship , Th1 Cells/immunology , Th2 Cells/immunologyABSTRACT
Anthrax tetrasaccharide is an oligosaccharide expressed at the outermost surface of the Bacillus anthracis spores, featuring three rhamnoses and a rare sugar called anthrose. This motif has now been identified as a plausible component of future human vaccines against anthrax. We report herein the synthesis of a 2-O-demethylated-ß-D-anthropyranosyl-(1â3)-α-L-rhamnopyranose disaccharide analogue of this tetrasaccharide from a cyclic sulfate intermediate. This disaccharide conjugated to BSA induces an anti-native tetrasaccharide IgG antibody response when administered in BALB/c mice. Moreover, induced sera bound to native B. anthracis endospores. These results suggest that the disaccharide analogue, easily amenable for a synthetic scale-up, could be used in a glycoconjugate antigen formulation.
Subject(s)
Anthrax Vaccines/chemistry , Anthrax Vaccines/therapeutic use , Anthrax/prevention & control , Bacillus anthracis/immunology , Disaccharides/chemistry , Disaccharides/therapeutic use , Polysaccharides, Bacterial/analogs & derivatives , Animals , Anthrax/immunology , Anthrax/microbiology , Anthrax Vaccines/chemical synthesis , Anthrax Vaccines/immunology , Bacillus anthracis/chemistry , Cattle , Disaccharides/chemical synthesis , Disaccharides/immunology , Female , Glycoconjugates/chemical synthesis , Glycoconjugates/chemistry , Glycoconjugates/immunology , Glycoconjugates/therapeutic use , Humans , Immunization , Mice , Mice, Inbred BALB C , Polysaccharides, Bacterial/immunology , Serum Albumin, Bovine/chemical synthesis , Serum Albumin, Bovine/chemistry , Serum Albumin, Bovine/immunology , Serum Albumin, Bovine/therapeutic use , Spores, Bacterial/chemistry , Spores, Bacterial/immunologyABSTRACT
The synthesis of the anthrax tetrasaccharide, amenable for conjugation, has been envisaged by both [2+2] and [1+3] approaches from D-fucose and L-rhamnose. The successful route reported herein relies on a [1+3] strategy in which the 1,2-trans-glycosidic linkages have been secured using a participating group at the 2-position of the donors using conventional thio as well as trichloroacetimidate glycosylation chemistry. The exchange of the ester to benzyl protective groups on the rhamnosyl moiety was key to achieve the final assembly and functionalization of the tetrasaccharide.
Subject(s)
Amino Sugars/chemistry , Antigens, Bacterial/chemistry , Bacillus anthracis/chemistry , Deoxyglucose/analogs & derivatives , Fucose/chemistry , Oligosaccharides/chemical synthesis , Rhamnose/chemistry , Acetamides , Animals , Antigens, Bacterial/immunology , Bacillus anthracis/immunology , Chloroacetates , Deoxyglucose/chemistry , Esters , Glycosylation , Humans , Magnetic Resonance Spectroscopy , Methylation , Molecular Structure , Trichloroacetic Acid/chemistryABSTRACT
Anthrose is the upstream terminal unit of the tetrasaccharide side chain from a major glycoprotein of Bacillus anthracis exosporium and is part of important antigenic determinants. A novel entry to anthrose-containing antigens and precursors is described. The synthetic route, starting from D(+)-fucose, makes use of intermediates featuring a cyclic sulfite or sulfate function which serves successively as a protecting and a leaving group.
