Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

SUBMITTER: Guillaume J

PROVIDER: S-EPMC5487351 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

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

Guillaume Joren J Wang Jing J Janssens Jonas J Remesh Soumya G SG Risseeuw Martijn D P MDP Decruy Tine T Froeyen Mathy M Elewaut Dirk D Zajonc Dirk M DM Calenbergh Serge Van SV

Scientific reports 20170627 1

Invariant Natural Killer T-cells (iNKT-cells) are an attractive target for immune response modulation, as upon CD1d-mediated stimulation with KRN7000, a synthetic α-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 α-galactosylsphingamides, were evaluated for their capacity to stimulate iNKT-cells. W ...[more]

PMID: 28655912

Similar Datasets

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

Project description:A series of α-GalCer analogues containing an α-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 α-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

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

Project description: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 studies, that a hydrogen bonding interaction is involved between the ω-hydroxy group and a polar amino acid residue in the hydrophobic binding groove.

| S-EPMC4027640 | 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

Crystal structures of bovine CD1d reveal altered ?GalCer presentation and a restricted A' pocket unable to bind long-chain glycolipids.

Project description:NKT cells play important roles in immune surveillance. They rapidly respond to pathogens by detecting microbial glycolipids when presented by the non-classical MHC I homolog CD1d. Previously, ruminants were considered to lack NKT cells due to the lack of a functional CD1D gene. However, recent data suggest that cattle express CD1d with unknown function. In an attempt to characterize the function of bovine CD1d, we assessed the lipid binding properties of recombinant Bos taurus CD1d (boCD1d) in vitro. BoCD1d is able to bind glycosphingolipids (GSLs) with fatty acid chain lengths of C??, while GSLs with fatty acids of C?? do not bind. Crystal structures of boCD1d bound to a short-chain C??-di-sulfatide antigen, as well as short-chain C??-?GalCer revealed that the Á pocket of boCD1d is restricted in size compared to that of both mouse and human CD1d, explaining the inability of long chain GSL's to bind to boCD1d. Moreover, while di-sulfatide is presented similarly compared to the presentation of sulfatide by mouse CD1d, ?GalCer is presented differently at the cell surface, due to an amino acid Asp151Asn substitution that results in loss of intimate contacts between the ?GalCer headgroup and CD1d. The altered ?GalCer presentation by boCD1d also explains its lack of cross-activation of mouse iNKT cells and raises the interesting question of the nature and function of bovine lipid-reactive T cells.

| S-EPMC3479135 | biostudies-literature

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

Project description:Replacement of the amide moiety in the structure of α-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 α-GalCer analogues are reported. The novel α-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-γ and IL-4 cytokine expression in vitro compared to that of α-GalCer.

| S-EPMC4753537 | biostudies-literature

Divergent synthetic approach to 6''-modified ?-GalCer analogues.

Project description:A synthetic approach is presented for the synthesis of galacturonic acid and D-fucosyl modified KRN7000. The approach allows for late-stage functionalisation of both the sugar 6''-OH and the sphingosine amino groups, which enables convenient synthesis of promising 6''-modified KRN7000 analogues.

| S-EPMC3246390 | biostudies-literature

A Designed <i>α</i>-GalCer Analog Promotes Considerable Th1 Cytokine Response by Activating the CD1d-iNKT Axis and CD11b-Positive Monocytes/Macrophages.

Project description:Selective helper T cell 1 (Th1) priming agonists are a promising area of investigation for immunotherapeutic treatment of various diseases. α-galactosylceramide (α-GalCer, KRN7000), a well-studied Th1-polarizer, simultaneously induces helper T cell 2 (Th2)-type responses, which is a major drawback for its clinical applications. Based on surflex-docking computation, α-GalCer-diol, with added hydroxyl groups in the acyl chain, is designed and synthesized. Structural analyses reveal stronger affinity between α-GalCer-diol and cluster of differentiation 1d (CD1d), leading to enhanced antigen presentation by dendritic cells (DCs) and self-activation, as reflected by tight binding of the T-cell receptor (TCR)/KRN7000/CD1d ternary complex and elevated production of interleukin 12 (IL-12) and interferon-γ (IFN-γ). Consequently, invariant natural killer T cells (iNKTs) are activated and exhibit an improved Th1-type cytokine profile ex vivo and in vivo. Different from KRN7000, α-GalCer-diol markedly boosts the expansion of the CD11b+ subpopulation and enhances IFN-γ content in CD11b+ cells. These reinforced Th1-type responses collectively endow α-GalCer-diol more robust antitumor activity in a xenograft animal model using B16-F10 melanoma cells. Together, the data demonstrate a new mechanism through which α-GalCer-diol induces stronger Th1-type responses by stimulating CD11b+ leukocyte expansion and DC-conducted CD1d-restricted and TCR-mediated iNKT activation. Hence, this study may facilitate the development of novel Th1 priming agonists.

| S-EPMC7375225 | biostudies-literature

Alpha-S-GalCer: synthesis and evaluation for iNKT cell stimulation.

Project description:The synthesis and evaluation for iNKT stimulation of alpha-S-galactosylceramide is reported. Prepared by alkylation of a galactosylthiol, this analog of the potent immunostimulatory agent, KRN7000, did not stimulate iNKT cells either in vitro or in vivo.

| S-EPMC2628538 | biostudies-literature

New CD1d agonists: synthesis and biological activity of 6″-triazole-substituted α-galactosyl ceramides.

Project description:Huisgen [3+2] dipolar cycloaddition of 6″-azido-6″-deoxy-α-galactosyl ceramide 11 with a range of alkynes (or a benzyne precursor) yielded a series of triazole-containing α-galactosyl ceramide (α-GalCer) analogues in high yield. These α-GalCer analogues and the precursor azide 11 were tested for their ability to activate iNKT cells and stimulate IL-2 cytokine secretion in vitro, and IFN-γ and IL-4 cytokine secretion in vivo. Some of these analogues, specifically 11, 12b, 12f and 13, were more potent IL-2 stimulators than the prototypical CD1d agonist, α-GalCer 1. In terms of any cytokine bias, most of the triazole-containing analogues exhibited a small Th2 cytokine-biasing response relative to that shown by α-GalCer 1. In contrast, the cycloaddition precursor, namely azide 11, provided a small Th1 cytokine-biasing response.

| S-EPMC3401990 | 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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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