Synthesis of beta-(1-->4)-oligo-D-mannuronic acid neoglycolipids.
ABSTRACT Mammalian Toll-like receptors (TLRs) play important roles in host immune defense. The activation of TLR and down-stream signaling pathways have great impact on human physiology. Chemically diverse microbial products as well as synthetic ligands serve as agonists for these receptors. Recently, synthetic TLR ligands are being exploited as useful therapeutic agents for a variety of diseases including infections, inflammatory diseases, and cancers. Alginate polymers and oligosaccharides are strong immune stimulants mediated by TLR2/4, but synthesis of alginate oligomers is rarely studied. Reported here are the design and chemical synthesis of two beta-(1-->4)-di- and beta-(1-->4)-tri-d-mannuronic acid neoglycolipids 1 and 2 as potential TLR ligands. By using 4,6-di-O-benzylidene-protected 1-thio mannoside 7 as a glycosyl donor, the diastereoselective beta-d-mannosylation protocol provides the beta-(1-->4)-d-mannobiose and beta-(1-->4)-d-mannotriose derivatives, which upon regioselective oxidation with TEMPO/BAIB oxidation system yield the corresponding beta-(1-->4)-d-mannuronic acid containing neoglycolipids 1 and 2.
Article: Poly(anhydride) nanoparticles act as active Th1 adjuvants through Toll-like receptor exploitation.[show abstract] [hide abstract]
ABSTRACT: The mechanisms that underlie the potent Th1-adjuvant capacity of poly(methyl vinyl ether-co-maleic anhydride) nanoparticles (NPs) were investigated. Traditionally, polymer NPs have been considered delivery systems that promote a closer interaction between antigen and antigen-presenting cells (APCs). Our results revealed that poly(anhydride) NPs also act as agonists of various Toll-like receptors (TLRs) (TLR2, -4, and -5), triggering a Th1-profile cytokine release (gamma interferon [IFN-gamma], 478 pg/ml versus 39.6 pg/ml from negative control; interleukin-12 [IL-12], 40 pg/ml versus 7.2 pg/ml from negative control) and, after incubation with dendritic cells, inducing a 2.5- to 3.5-fold increase of CD54 and CD86 costimulatory molecule expression. Furthermore, in vivo studies suggest that NPs actively elicit a CD8(+) T-cell response. Immunization with empty NPs resulted in a significant delay in the mean survival date (from day 7 until day 23 postchallenge) and a protection level of 30% after challenge against a lethal dose of Salmonella enterica serovar Enteritidis. Taken together, our results provide a better understanding of how NPs act as active Th1 adjuvants in immunoprophylaxis and immunotherapy through TLR exploitation.Clinical and vaccine immunology: CVI 09/2010; 17(9):1356-62. · 2.37 Impact Factor