Advanced search
1 file | 2.20 MB

4''-O-Alkylated α-galactosylceramide analogues as iNKT-cell antigens : synthetic, biological, and structural studies

Jonas Janssens (UGent) , Aruna Bitra, Jing Wang, Tine Decruy (UGent) , Koen Venken (UGent) , Johan Van der Eycken (UGent) , Dirk Elewaut (UGent) , Dirk Zajonc (UGent) and Serge Van Calenbergh (UGent)
(2019) CHEMMEDCHEM. 14(1). p.147-168
Author
Organization
Abstract
Invariant natural killer T-cells (iNKT) are a glycolipid-responsive subset of T-lymphocytes that fulfill a pivotal role in the immune system. The archetypical synthetic glycolipid, alpha-galactosylceramide (alpha-GalCer), whose molecular framework is inspired by a group of amphiphilic natural products, remains the most studied antigen for iNKT-cells. Nonetheless, the potential of alpha-GalCer as an immunostimulating agent is compromised by the fact that this glycolipid elicits simultaneous secretion of Th1- and Th2-cytokines. This has incited medicinal chemistry efforts to identify analogues that are able to perturb the Th1/Th2 balance. In this work, we present the synthesis of an extensive set of 4"-O-alkylated alpha-GalCer analogues, which were evaluated in vivo for their cytokine induction. We have found that conversion of the 4"-OH group to ether moieties decreases the immunogenic potential in mice relative to alpha-GalCer. Yet, the benzyl-modified glycolipids are able to produce a distinct pro-inflammatory immune response. The crystal structures suggest an extra hydrophobic interaction between the benzyl moiety and the alpha 2-helix of CD1d.
Keywords
GALCER ANALOGS, STIMULATING PROPERTIES, HUMAN CD1D, NKT CELLS, RECOGNITION, RECEPTOR, GALACTOGLYCOSPHINGOLIPIDS, GLYCOLIPIDS, ACTIVATION, ANTITUMOR, glycolipid antigens, iNKT-cell activation, KRN7000, alpha-galactosylceramide, alpha-GalCer analogues

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 2.20 MB

Citation

Please use this url to cite or link to this publication:

Chicago
Janssens, Jonas, Aruna Bitra, Jing Wang, Tine Decruy, Koen Venken, Johan Van der Eycken, Dirk Elewaut, Dirk Zajonc, and Serge Van Calenbergh. 2019. “4"-O-Alkylated Α-galactosylceramide Analogues as iNKT-cell Antigens : Synthetic, Biological, and Structural Studies.” Chemmedchem 14 (1): 147–168.
APA
Janssens, Jonas, Bitra, A., Wang, J., Decruy, T., Venken, K., Van der Eycken, J., Elewaut, D., et al. (2019). 4"-O-Alkylated α-galactosylceramide analogues as iNKT-cell antigens : synthetic, biological, and structural studies. CHEMMEDCHEM, 14(1), 147–168.
Vancouver
1.
Janssens J, Bitra A, Wang J, Decruy T, Venken K, Van der Eycken J, et al. 4"-O-Alkylated α-galactosylceramide analogues as iNKT-cell antigens : synthetic, biological, and structural studies. CHEMMEDCHEM. 2019;14(1):147–68.
MLA
Janssens, Jonas et al. “4"-O-Alkylated Α-galactosylceramide Analogues as iNKT-cell Antigens : Synthetic, Biological, and Structural Studies.” CHEMMEDCHEM 14.1 (2019): 147–168. Print.
@article{8599847,
  abstract     = {Invariant natural killer T-cells (iNKT) are a glycolipid-responsive subset of T-lymphocytes that fulfill a pivotal role in the immune system. The archetypical synthetic glycolipid, alpha-galactosylceramide (alpha-GalCer), whose molecular framework is inspired by a group of amphiphilic natural products, remains the most studied antigen for iNKT-cells. Nonetheless, the potential of alpha-GalCer as an immunostimulating agent is compromised by the fact that this glycolipid elicits simultaneous secretion of Th1- and Th2-cytokines. This has incited medicinal chemistry efforts to identify analogues that are able to perturb the Th1/Th2 balance. In this work, we present the synthesis of an extensive set of 4{\textacutedbl}-O-alkylated alpha-GalCer analogues, which were evaluated in vivo for their cytokine induction. We have found that conversion of the 4{\textacutedbl}-OH group to ether moieties decreases the immunogenic potential in mice relative to alpha-GalCer. Yet, the benzyl-modified glycolipids are able to produce a distinct pro-inflammatory immune response. The crystal structures suggest an extra hydrophobic interaction between the benzyl moiety and the alpha 2-helix of CD1d.},
  author       = {Janssens, Jonas and Bitra, Aruna and Wang, Jing and Decruy, Tine and Venken, Koen and Van der Eycken, Johan and Elewaut, Dirk and Zajonc, Dirk and Van Calenbergh, Serge},
  issn         = {1860-7179},
  journal      = {CHEMMEDCHEM},
  language     = {eng},
  number       = {1},
  pages        = {147--168},
  title        = {4''-O-Alkylated \ensuremath{\alpha}-galactosylceramide analogues as iNKT-cell antigens : synthetic, biological, and structural studies},
  url          = {http://dx.doi.org/10.1002/cmdc.201800649},
  volume       = {14},
  year         = {2019},
}

Altmetric
View in Altmetric
Web of Science
Times cited: