LPS, also known as endotoxin, is recognized by the
mammalian innate immune system via the Toll-like receptor 4 (TLR4) - myeloid
differentiation factor 2 (MD-2) complex.1 Lipid A triggered TLR4
signaling is implicated in the pathogenesis of inflammatory and infectious
diseases. Based on the crystal structure of Ra-LPS with hTLR4/MD-2 complex
(3fxi),2 conformationally constrained Lipid A mimetics have
been developed to further investigate the structure-activity relationship
between Lipid A and the MD2/TLR4 complex. The main feature of the novel Lipid A
mimetics is the replacement of the β-(1→6) linked diglucosamine backbone by a non-reducing
trehalose type scaffold.
The challenging formation of the α,α-glycosidic bond was strongly influenced by the
protecting group pattern of both glycosyl donor and acceptor molecules. Thus, several
orthogonally protected mannose donors 1
and glucosamine acceptors 2 were
synthesized and coupled in a glycosylation reaction to afford key disaccharides
3. Subsequent regioselective
deprotection, acylation and phosphorylation steps on intermediate 3, furnished novel Lipid A mimetics 4 and 5.
Acknowledgments: Financial support from FWF (grant P 22116) is gratefully acknowledged.
1. Yamamoto, M., Akira, S. Adv. Exp. Med. Biol. 2010, 667: 59-68.
2.
Park, B.S., et al. Nature 2009, 458: 1191-1195.
