Despite their biological importance, there are no methods available to systematically and efficiently produce asymmetrically branched N-glycans needed to populate diverse glycan libraries and investigate the specificities and biology of glycan binding proteins. We report here the chemical synthesis of a pentasaccharide that is common to all eukaryotic N-linked glycans and is modified at positions where branching points can occur with the protecting groups levulinoyl (Lev), fluorenylmethyloxycarbonate (Fmoc), allyloxycarbonate (Alloc), and 2-naphthylmethyl (Nap). A library of complex branched bi-, tri-, and tetra-antennary structures has been generated by sequential removal of the protecting groups followed by chemical glycosylations using a diverse set of glycosyl donors. Furthermore, the use of acetylated or benzylated LacNAc and GlcNAc donors gave precursor glycans that at each antenna could be selectively extended by a panel of glycosyltransferases to rapidly give large numbers of highly complex asymmetrically substituted N-glycans. A similar strategy was employed to prepare a library of core-fucose modified N-linked glycans. The glycans were printed as microarrays and screened for binding to lectins and influenza-virus hemagglutinins, which demonstrated that recognition is modulated by presentation of minimal epitopes in the context of complex N-glycans.

General approach for the synthesis of libraries of symmetrical and asymmetrical N-glycans

247th National Meeting (2014)

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