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

Jonas Janssens, 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
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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

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MLA
Janssens, Jonas, et al. “4"-O-Alkylated α-Galactosylceramide Analogues as INKT-Cell Antigens : Synthetic, Biological, and Structural Studies.” CHEMMEDCHEM, vol. 14, no. 1, 2019, pp. 147–68, doi:10.1002/cmdc.201800649.
APA
Janssens, J., Bitra, A., Wang, J., Decruy, T., Venken, K., Van der Eycken, J., … Van Calenbergh, S. (2019). 4"-O-Alkylated α-galactosylceramide analogues as iNKT-cell antigens : synthetic, biological, and structural studies. CHEMMEDCHEM, 14(1), 147–168. https://doi.org/10.1002/cmdc.201800649
Chicago author-date
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): 147–68. https://doi.org/10.1002/cmdc.201800649.
Chicago author-date (all authors)
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. doi:10.1002/cmdc.201800649.
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.
IEEE
[1]
J. Janssens et al., “4"-O-Alkylated α-galactosylceramide analogues as iNKT-cell antigens : synthetic, biological, and structural studies,” CHEMMEDCHEM, vol. 14, no. 1, pp. 147–168, 2019.
@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"-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.}},
  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}},
  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}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{147--168}},
  title        = {{4''-O-Alkylated α-galactosylceramide analogues as iNKT-cell antigens : synthetic, biological, and structural studies}},
  url          = {{http://doi.org/10.1002/cmdc.201800649}},
  volume       = {{14}},
  year         = {{2019}},
}
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