Issue in Honor of Prof Richard R. Schmidt ARKIVOC 2013 (ii) 363-377
binding interactions between the glycolipid and CD1d, and therefore increasing the stability of the complex, could result in greater levels of IFN-. release and consequently promoting and prolonging the TH1 response. Conversely, a less stable .-GalCer/CD1d complex could shorten NKT stimulation time resulting in a TH2 biased response.4 Also, other factors, such as the mode of loading the glycolipid into CD1d and the rate of glycolipid dissociation from CD1d in lysosomes, could greatly influence the cytokine release profile as well.
NH(CH2)24CH3 O HO O OHHO OH (CH2)13CH3 OH O NH(CH2) S HO O OHHO OH (CH2)13CH3 OH O Ph n OH OH
KRN7000
1 n = 10 2 n = 11
Figure 1. Structures of KRN7000 and target molecules 1 and 2.
Recent crystallographic analysis has indicated that the lipid chains of .-GalCer are buried in a groove in CD1d containing two hydrophobic pockets (denoted as A' and C') and the galactose ring is exposed for the recognition by NKT TCR.8 The phytosphingosine chain sits in the hydrophobic C' pocket which ideally accommodates 18 carbons, while the longer acyl chain binds in the other hydrophobic A' pocket that can accommodate up to 26 carbons. In addition, several hydrogen bonds were identified and are assumed to anchor .-GalCer in a distinct orientation and position it in the lipid-binding groove. As such, the modification of the lipid chains of .-GalCer is a very important aspect for designing .-GalCer analogues seeing that the chains are strongly involved in the binding with CD1d. For instance, if the lipid chains could be rationally modified to enhance their hydrophobic interaction with CD1d, as mentioned above, the resultant complex may preferably induce the release of TH1 cytokines, which are thought to be responsible for the antitumor, antiviral and antibacterial effects of .-GalCer. In this regard, a paper by Wong and co-workers attracted our attention, wherein several .-GalCer analogues with greater anticancer efficacy were reported.9 They introduced different aromatic groups into the fatty acyl chain with a view to designing tighter CD1d-binding glycolipids since X-ray crystal structures showed that the CD1d A' binding groove was lined with numerous aromatic side-chain residues. These analogues were expected to introduce extra aromatic interactions which could increase the stability of the CD1d/glycolipid complex, thereby favouring the induction of TH1 cytokines. Indeed, some of these analogues with the appropriate fatty acid acyl chain length were four times more potent than .-GalCer itself and were biased towards IFN-. secretion.9,10 Computational, docking of these analogues in the human CD1d hydrophobic groove was also conducted, and the results indicated that their binding mode did not vary much from the crystal structure of .-GalCer bound to hCD1d. In each case, the phytosphingosine chain was bound to
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