Synthesis and antitumour activity of 6''-thio-6''-deoxy-α-galactosylceramide  — ASN Events
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Synthesis and antitumour activity of 6''-thio-6''-deoxy-α-galactosylceramide  (#91)

Benjamin Compton 1 , Karen Johnston 2 , Chingwen Tang 3 , Taryn Osmond 3 , David Larsen 4 , Ian Hermans 3 , Gavin Painter 1
  1. Victoria University of Wellington, Wellington, New Zealand
  2. GlycoSyn, Callaghan Innovation, Lower Hutt, New Zealand
  3. Malaghan Institute of Medical Research, Wellington, New Zealand
  4. Department of Chemistry, University of Otago, Dunedin, New Zealand

The glycolipid α-galactosylceramide (α-GalCer, KRN7000), when bound by CD1d, is a potent activator of invariant natural killer T (NKT) cells which in turn can drive an adaptive immune response. 

Previously, we have shown the conjugation of peptide antigens to a prodrug form of α-GalCer creates a vaccine construct capable of eliciting more efficient immune responses (i.e. increased proliferation and cytotoxicity of antigen-specific CTLs combined with better anti-tumour activity) as compared to ad-mixed controls.1 2 

Presented here, we have developed a novel analogue of α-GalCer (6''-thio-α-GalCer) whereby the 6''-OH group has been substituted for a sulfur atom. This modification appears to be well tolerated by the NKT cell TCR as demonstrated by the up-regulation of the cell surface marker CD86 on dendritic cells upon intravenous administration of 6''-thio-α-GalCer. When compared against α-GalCer as an adjuvant in a B16 mouse melanoma model, 6''-thio-α-GalCer was similarly effective in delaying tumour growth in a therapeutic setting. 

A major advantage of 6''-thio-α-GalCer over α-GalCer is that it contains a reactive thiol functionality which can readily undergo chemoselective conjugation with a wide range of chemical species. Here, we report the utility of 6''-thio-α-GalCer to undergo peptide conjugation to create new synthetic self-adjuvanting peptide vaccines    

  1. Anderson, R. J.; Tang, C-W,; Daniels, N. J.; Compton, B. J.; Hayman, C. M.; Johnston, K. J.; Knight, D. A.; Larsen, D. S.; Ronchese, F.; Painter, G. F.; Hermans, I. F. Nature Chemical Biology. 2014, 10, 943-949.
  2. Anderson, R. J.; Compton, B. J.; Tang, C-W.; Authier-Hall, A.; Hayman, C. M.; Swinerd, G. W.; Kowalczyk, R.; Harris, P.; Brimble, M. A.; Larsen, D. S.; Gasser, O.; Weinkove, R.; Hermans, I. F; Painter, G. F. Chemical Science. 2015, DOI: 10.1039/C4SC03599B