6?-derivatised ?-galcer analogues capable of inducing strong CD1d-mediated Th1-biased NKT cell responses in mice

Trappeniers, Matthias, Van Beneden, Katrien, Decruy, Tine, Hillaert, Ulrik, Linclau, Bruno, Elewaut, Dirk and Van Calenbergh, Serge (2008) 6?-derivatised ?-galcer analogues capable of inducing strong CD1d-mediated Th1-biased NKT cell responses in mice. Journal of the American Chemical Society, 130 (49), 16468-16469. (doi:10.1021/ja8064182).

Abstract

?-Galactosyl ceramide (?-GalCer, also known as KRN 7000) is known as the prototypical antigen for invariant natural killer T (NKT) cells. Stimulation of NKT cells by CD1d-mediated ?-GalCer presentation leads to rapid release of Th1 and Th2 cytokines. Since Th1 and Th2 cytokines antagonize each other’s effects, ?-GalCer analogues that induce a biased Th1/Th2 response are highly awaited. With the exception of a C-glycoside (?-C-GalCer), most of the known ?-GalCer analogues able to induce polarized cytokine responses are characterized by modifications of the phytosphingosine or fatty acyl chains, expected to alter the affinity for CD1d. Herein we describe the synthesis of 6?-modified ?-GalCer analogues with an intact phytoceramide moiety that are capable to skew the cytokine release profile to Th1, while maintaining strong antigenic activity. These analogues are characterized by the presence of an aromatic moiety that is connected via an amide or an urea linkage to C?-6 of the galactopyranose ring.

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Contributors

Author: Bruno Linclau

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