11 research outputs found
Convergent Synthesis of Digalactosyl Diacylglycerols
Efficient convergent chemical syntheses
of digalactosyl diacylglycerols
(DGDGs), which have both a galactose–galactose α(1→6)-linkage
and a galactose–glycerol β-linkage along with a diacylglycerol
containing various kinds of fatty acids, have been accomplished. In
order to achieve a concise synthesis, we chose to use allylic protective
groups as permanent protective groups. We have also achieved α-
and β-selective glycosylations for the respective linkages with
high yields as the key steps
Chemical Synthesis of d-<i>glycero</i>-d-<i>manno</i>-Heptose 1,7-Bisphosphate and Evaluation of Its Ability to Modulate NF-κB Activation
d-<i>glycero</i>-d-<i>manno</i>-Heptose 1,7-bisphosphate
(HBP) is the precursor for heptose residues
found in Gram-negative bacterial membrane surface glycoproteins and
glycolipids. HBP β-anomer was recently reported to be a pathogen-associated
molecular pattern (PAMP) that regulates TIFA-dependent immunity. Herein,
we report the chemical synthesis of HBP α- and β-anomers,
which highlights a C-7 carbon homologation via the Corey–Chaykovsky
reaction, and the introduction of a phosphate group at the anomeric
position using the Mitsunobu reaction. Furthermore, NF-κB reporter
assaying revealed that HBP β-anomer activates the NF-κB
signaling pathway
Isolated Polar Amino Acid Residues Modulate Lipid Binding in the Large Hydrophobic Cavity of CD1d
The
CD1d protein is a nonpolymorphic MHC class I-like protein that
controls the activation of natural killer T (NKT) cells through the
presentation of self- and foreign-lipid ligands, glycolipids, or phospholipids,
leading to the secretion of various cytokines. The CD1d contains a
large hydrophobic lipid binding pocket: the A′ pocket of CD1d,
which recognizes hydrophobic moieties of the ligands, such as long
fatty acyl chains. Although lipid–protein interactions typically
rely on hydrophobic interactions between lipid chains and the hydrophobic
sites of proteins, we showed that the small polar regions located
deep inside the hydrophobic A′ pocket could be used for the
modulation of the lipid binding. A series of the ligands, α-galactosyl
ceramide (α-GalCer) derivatives containing polar groups in the
acyl chain, was synthesized, and the structure–activity relationship
studies demonstrated that simple modification from a methylene to
an amide group in the long fatty acyl chain, when introduced at optimal
positions, enhanced the CD1d recognition of the glycolipid ligands.
Formation of hydrogen bonds between the amide group and the polar
residues was supported by molecular dynamics (MD) simulations and
WaterMap calculations. The computational studies suggest that localized
hydrating water molecules may play an important role in the ligand
recognition. Here, the results showed that confined polar residues
in the large hydrophobic lipid binding pockets of the proteins could
be potential targets to modulate the affinity for its ligands
Synthetic analogs of an Entamoeba histolytica glycolipid designed to combat intracellular Leishmania infection
Intracellular pathogens belonging to the genus Leishmania have developed effective strategies that enable them to survive within host immune cells. Immunostimulatory compounds that counteract such immunological escape mechanisms represent promising treatment options for diseases. Here, we demonstrate that a lipopeptidephosphoglycan (LPPG) isolated from the membrane of a protozoan parasite, Entamoeba histolytica (Eh), shows considerable immunostimulatory effects targeted against Leishmania (L.) major, a representative species responsible for cutaneous leishmaniasis (CL). Treatment led to a marked reduction in the number of intracellular Leishmania parasites in vitro, and ameliorated CL in a mouse model. We next designed and synthesized analogs of the phosphatidylinositol anchors harbored by EhLPPG; two of these analogs reproduced the anti-leishmanial activity of the native compound by inducing production of pro-inflammatory cytokines. The use of such compounds, either alone or as a supportive option, might improve the currently unsatisfactory treatment of CL and other diseases caused by pathogen-manipulated immune responses
Association of soluble T cell immunoglobulin domain and mucin-3 (sTIM-3) and mac-2 binding protein glycosylation isomer (M2BPGi) in patients with autoimmune hepatitis.
BackgroundAutoimmune hepatitis (AIH) is a disorder of unknown etiology in which immune-mediated liver injury progress to cirrhosis or hepatocellular carcinoma (HCC). The aim of the present study was to determine whether circulating soluble TIM3 (sTIM3) is elevated in patients with AIH patients and whether sTIM-3 levels are associated with clinical parameters of AIH.MethodsWe enrolled 123 Japanese patients with AIH who were identified from the National Hospital Organization-AIH-liver-network database, as well as 32 patients with chronic hepatitis C (CHC), 30 patients with primary biliary cholangitis (PBC) and healthy control subjects. Serum sTIM-3 concentrations were quantified by ELISA.ResultsSerum levels of sTIM-3 were significantly higher in AIH patients (median 4865 pg/ml; [interquartile range (IQR); 3122-7471]) compared to those in CHC (1026 pg/ml [IQR: 806-1283] pConclusionsCirculating sTIM-3 levels were elevated in AIH patients and are associated with AIH disease activity and AIH-related liver damage. These findings indicate that serum sTIM-3 correlated with disease status of AIH and could be useful biomarkers to detect autoimmune-mediated liver injury. Our data suggest a possible link between the TIM-3/GAL-9 pathway and AIH severity or phenotype, and further investigations of the TIM-3 pathway and AIH pathophysiology is warranted