Browse
Submit Data
Databases
API
Help

Dataset Information

12 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Design and Evaluation of ?-Hydroxy Fatty Acids Containing ?-GalCer Analogues for CD1d-Mediated NKT Cell Activation.

ABSTRACT: CD1d molecules recognize glycolipid antigens with straight chain fatty acid moieties. Although most of the residues in the CD1d binding groove are hydrophobic, some of the amino acids can form hydrogen bonds. Consequently, we have designed ?-hydroxy fatty acid-containing glycolipid derivatives of the prototypical CD1d ligand ?-GalCer. The potency of the ?-hydroxy analogues of the proper length is comparable to that of ?-GalCer. We propose, based on the biological results and molecular modeling studies, that a hydrogen bonding interaction is involved between the ?-hydroxy group and a polar amino acid residue in the hydrophobic binding groove.

SUBMITTER: Lim C

PROVIDER: S-EPMC4027640 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Design and Evaluation of ω-Hydroxy Fatty Acids Containing α-GalCer Analogues for CD1d-Mediated NKT Cell Activation.

Lim Chaemin C Kim Jae Hyun JH Baek Dong Jae DJ Lee Joo-Youn JY Cho Minjae M Lee Yoon-Sook YS Kang Chang-Yuil CY Chung Doo Hyun DH Cho Won-Jae WJ Kim Sanghee S

ACS medicinal chemistry letters 20140204 4

CD1d molecules recognize glycolipid antigens with straight chain fatty acid moieties. Although most of the residues in the CD1d binding groove are hydrophobic, some of the amino acids can form hydrogen bonds. Consequently, we have designed ω-hydroxy fatty acid-containing glycolipid derivatives of the prototypical CD1d ligand α-GalCer. The potency of the ω-hydroxy analogues of the proper length is comparable to that of α-GalCer. We propose, based on the biological results and molecular modeling s ...[more]

PMID: 24900836

Similar Datasets

Galactosylsphingamides: new ?-GalCer analogues to probe the F'-pocket of CD1d.

Project description:Invariant Natural Killer T-cells (iNKT-cells) are an attractive target for immune response modulation, as upon CD1d-mediated stimulation with KRN7000, a synthetic ?-galactosylceramide, they produce a vast amount of cytokines. Here we present a synthesis that allows swift modification of the phytosphingosine side chain by amidation of an advanced methyl ester precursor. The resulting KRN7000 derivatives, termed ?-galactosylsphingamides, were evaluated for their capacity to stimulate iNKT-cells. While introduction of the amide-motif in the phytosphingosine chain is tolerated for CD1d binding and TCR recognition, the studied ?-galactosylsphingamides showed compromised antigenic properties.

| S-EPMC5487351 | biostudies-literature

Design, Synthesis, and Immunological Evaluation of Benzyloxyalkyl-Substituted 1,2,3-Triazolyl ?-GalCer Analogues.

Project description:Replacement of the amide moiety in the structure of ?-GalCer with a 1,2,3-triazole linker is known to elicit a response skewed toward Th2 immunity, and glycolipids containing an aromatic ring in the terminus of their acyl or phytosphingosine structural component exhibit an enhanced Th1 immune response. In the current study, synthesis and immunological screening of a focused library of benzyloxyalkyl-substituted 1,2,3-triazolyl ?-GalCer analogues are reported. The novel ?-GalCer analogues activate invariant natural killer T (iNKT) cells via CD1d mediated presentation, which was confirmed by in vitro tests performed on iNKT hybridomas incubated with CD1d proteins. When tested on isolated murine splenocytes, the T1204B and T1206B compounds stimulated higher levels of both IFN-? and IL-4 cytokine expression in vitro compared to that of ?-GalCer.

| S-EPMC4753537 | biostudies-literature

Development of ?-GalCer Analogues with an ?-Fluorocarbonyl Moiety as Th2-Selective Ligands of CD1d.

Project description:A series of ?-GalCer analogues containing an ?-fluorocarbonyl moiety at the terminal position of the acyl chain were designed for targeting polar residues in the hydrophobic cavity of CD1d using a structure-based approach. The acyl chain length was efficiently adjusted by an asymmetric alkyne-alkyne cross coupling strategy, and the newly synthesized ?-GalCer analogues showed the high Th2-selective activity of iNKT cells. The biased activity of ligands could be caused by the hydrogen-bonding interaction between ligands and CD1d according to the Th2-selective cytokine secretion and molecular docking studies.

| S-EPMC6511957 | biostudies-literature

Synthesis and evaluation of amino-modified alpha-GalCer analogues.

Project description:Alpha-GalCer analogues featuring a phytoceramide 3- and 4-amino group have been synthesized. A Mitsunobu reaction involving phthalimide was employed for the introduction of the amino groups at the 3- and 4-positions of suitable phytosphingosine-derived precursors. The influence of these modifications on the interaction with the T-cell receptor of NKT cells was investigated, as well as the capacity of the amino-modified analogues to induce a cytokine response after in vivo administration.

| S-EPMC2903208 | biostudies-literature

The 3-Deoxy Analogue of ?-GalCer: Disclosing the Role of the 4-Hydroxyl Group for CD1d-Mediated NKT Cell Activation.

Project description:KRN7000, or ?-GalCer, is a potent agonist for natural killer T (NKT) cells. The 3-hydroxyl group of its phytosphingosine moiety is important for activating NKT cells, whereas its 4-hydroxyl group is perceived to be less crucial. To experimentally determine the role of the 4-hydroxyl group, we synthesized the 3-deoxy analogue of ?-GalCer. It was found that 3-deoxy-?-GalCer induced potent cytokine responses from NKT cells, comparable to those of both ?-GalCer and 4-deoxy-?-GalCer. This result and our docking studies suggest that the effects of an absence of the 3-hydroxyl group are compensated by the presence of a hydroxyl group at the C-4 position. Thus, we conclude that the 4-hydroxyl group of ?-GalCer is as important to the mechanism of action as the 3-hydroxyl group and that the two hydroxyl groups could play individual and cooperative roles in orienting the glycolipid into the proper position in CD1d to be recognized by the T cell receptor of NKT cells.

| S-EPMC4018141 | biostudies-literature

Chemical synthesis and biological evaluation of ?-hydroxy polyunsaturated fatty acids.

Project description:?-Hydroxy polyunsaturated fatty acids (PUFAs), natural metabolites from arachidonic acid (ARA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were prepared via convergent synthesis approach using two key steps: Cu-mediated CC bond formation to construct methylene skipped poly-ynes and a partial alkyne hydrogenation where the presence of excess 2-methyl-2-butene as an additive that is proven to be critical for the success of partial reduction of the poly-ynes to the corresponding cis-alkenes without over-hydrogenation. The potential biological function of ?-hydroxy PUFAs in pain was evaluated in naive rats. Following intraplantar injection, 20-hydroxyeicosatetraenoic acid (20-HETE, ?-hydroxy ARA) generated an acute decrease in paw withdrawal thresholds in a mechanical nociceptive assay indicating pain, but no change was observed from rats which received either 20-hydroxyeicosapentaenoic acid (20-HEPE, ?-hydroxy EPA) or 22-hydroxydocosahexaenoic acid (22-HDoHE, ?-hydroxy DHA). We also found that both 20-HEPE and 22-HDoHE are more potent than 20-HETE to activate murine transient receptor potential vanilloid receptor1 (mTRPV1).

| S-EPMC5584617 | biostudies-literature

Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant.

Project description:The glycolipid alpha-galactosylceramide (alpha-GalCer) has been shown to bind CD1d molecules to activate invariant natural killer T (iNKT) cells, and subsequently induce activation of various immune-competent cells, including dendritic cells, thereby providing a significant adjuvant effect for various vaccines. However, in phase I clinical trials, alpha-GalCer was shown to display only marginal biological activity. In our search for a glycolipid that can exert more potent stimulatory activity against iNKT cells and dendritic cells and produce an adjuvant effect superior to alpha-GalCer, we performed step-wise screening assays on a focused library of 25 alpha-GalCer analogues. Assays included quantification of the magnitude of stimulatory activity against human iNKT cells in vitro, binding affinity to human and murine CD1d molecules, and binding affinity to the invariant t cell receptor of human iNKT cells. Through this rigorous and iterative screening process, we have identified a lead candidate glycolipid, 7DW8-5, that exhibits a superior adjuvant effect than alpha-GalCer on HIV and malaria vaccines in mice.

| S-EPMC2919905 | biostudies-other

RNASeq of Developing Arabidopsis Seeds Producing Hydroxy-Fatty Acids

Project description:Arabidopsis seeds expressing the castor fatty acid hydroxylase accumulate hydroxylated fatty acids up to 17% of total fatty acids in seed triacylglycerols, however total seed oil is also reduced up to 50%. Investigations into the cause of the reduced oil phenotype through in vivo [14C]acteate and [3H]2O metabolic labeling of developing seeds surprisingly revealed that the rate of de novo fatty acid synthesis within the transgenic seeds was approximately half that of control seeds. Addition of castor phospholipid:diacylglycerol acyltransferase (PDAT) increased hydroxylated fatty acid content of the seed oil, increased the rate of fatty acid synthesis, and mostly restored seed oil levels. RNAseq analysis indicated no changes in expression of fatty acid synthesis genes in hydroxylase-expressing plants. Transcript profiles of Arabidopsis developing seeds of three lines, at three stages of development were generated by deep sequencing, in triplicate, using Illumina.

2014-01-10 | E-GEOD-53952 | biostudies-arrayexpress

RNASeq of Developing Arabidopsis Seeds Producing Hydroxy-Fatty Acids

2014-01-10 | GSE53952 | GEO

NKT TCR recognition of CD1d-?-C-galactosylceramide.

Project description:NKT cells respond to a variety of CD1d-restricted glycolipid Ags that are structurally related to the prototypic Ag ?-galactosylceramide (?-GalCer). A modified analog of ?-GalCer with a carbon-based glycosidic linkage (?-C-GalCer) has generated great interest because of its apparent ability to promote prolonged, Th1-biased immune responses. In this study, we report the activation of spleen NKT cells to ?-C-GalCer, and related C-glycoside ligands, is weaker than that of ?-GalCer. Furthermore, the V?8.2 and V?7 NKT TCR affinity for CD1d-?-C-GalCer, and some related analogs, is ?10-fold lower than that for the NKT TCR-CD1d-?-GalCer interaction. Nevertheless, the crystal structure of the V?8.2 NKT TCR-CD1d-?-C-GalCer complex is similar to that of the corresponding NKT TCR-CD1d-?-GalCer complex, although subtle differences at the interface provide a basis for understanding the lower affinity of the NKT TCR-CD1d-?-C-GalCer interaction. Our findings support the concept that for CD1d-restricted NKT cells, altered glycolipid ligands can promote markedly different responses while adopting similar TCR-docking topologies.

| S-EPMC3710193 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data