Structure-activity relationship studies of Bz amide-containing α-GalCer derivatives as natural killer T cell modulators
| Autor: | Junichiro Kishi, Shinsuke Inuki, Natsumi Hirata, Yukari Fujimoto, Emi Kashiwabara, Daisuke Yoshidome, Osamu Ichihara |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Ceramide
Stereochemistry Clinical Biochemistry Pharmaceutical Science chemical and pharmacologic phenomena Galactosylceramides Molecular Dynamics Simulation Ligands 01 natural sciences Biochemistry chemistry.chemical_compound Mice Structure-Activity Relationship Glycolipid Drug Discovery Moiety Structure–activity relationship Animals Molecular Biology Cells Cultured Binding Sites biology 010405 organic chemistry Organic Chemistry T-cell receptor hemic and immune systems Benzene Natural killer T cell Ligand (biochemistry) Amides 0104 chemical sciences Protein Structure Tertiary carbohydrates (lipids) 010404 medicinal & biomolecular chemistry chemistry CD1D biology.protein Molecular Medicine Cytokines Natural Killer T-Cells lipids (amino acids peptides and proteins) Antigens CD1d |
| Zdroj: | Bioorganicmedicinal chemistry letters. 29(8) |
| ISSN: | 1464-3405 |
| Popis: | Abstract CD1d is a non-polymorphic antigen-presenting glycoprotein that recognizes glycolipids as ligands. Ligands bind to the hydrophobic grooves of CD1d, and the resulting ligand-CD1d complexes activate natural killer T (NKT) cells by means of T cell receptor recognition, leading to the secretion of various cytokines. However, details of the ligand recognition mechanism of a large hydrophobic ligand binding pocket and the relationship between cytokine induction and ligand structure are unclear. We report the synthesis of α-GalCer derivatives containing a Bz amide group having various substituting groups in the ceramide moiety, and the analysis of the structure-activity relationships. The assays reveal that the Bz amide-containing CD1d ligands function as NKT cell modulators displaying Th2 cytokine biasing responses. Furthermore, molecular dynamics simulation studies suggest that the phenyl groups can interact with the aromatic amino acid residues in the lipid binding pocket of CD1d. |
| Databáze: | OpenAIRE |
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