Introduction of aromatic group on 4'-OH of α-GalCer manipulated NKT cell cytokine production

Bioorg Med Chem. 2011 Apr 15;19(8):2767-76. doi: 10.1016/j.bmc.2010.11.061. Epub 2010 Dec 2.

Abstract

The glycosphingolipid α-GalCer has been found to influence mammalian immune system significantly through the natural killer T cells. Unfortunately, the pre-clinical and clinical studies revealed several critical disadvantages that prevented the therapeutic application of α-GalCer in treating cancer and other diseases. Recently, the detailed illustration of the CD1d/α-GalCer/NKT TCR complex crystal structural, together with other latest structural and biological understanding on glycolipid ligands and NKT cells, provided a new platform for developing novel glycolipid ligands with optimized therapeutic effects. Here, we designed a series of novel aromatic group substituted α-GalCer analogues. The biological activity of these analogues was characterized and the results showed the unique substitution group manipulated the immune responses of NKT cells. Computer modeling and simulation study indicated the analogues had unique binding mode when forming CD1d/glycolipid/NKT TCR complex, comparing to original α-GalCer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD1d / metabolism
  • Cytokines / biosynthesis
  • Cytokines / drug effects*
  • Galactosylceramides / chemistry*
  • Galactosylceramides / pharmacology
  • Glycolipids
  • Humans
  • Immune System / drug effects
  • Ligands
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism
  • Receptors, Antigen, T-Cell / metabolism

Substances

  • Antigens, CD1d
  • Cytokines
  • Galactosylceramides
  • Glycolipids
  • Ligands
  • Receptors, Antigen, T-Cell
  • alpha-galactosylceramide