Modified multivalent poly-N-acetyllactosamine glycans as novel ligands of human galectin-3

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The functional role of carbohydrates in biological systems has been an area of intense research in recent years. Carbohydrates, formerly considered as inert molecules protecting the cell surface, are now recognized as important information transmitters in cellular processes. Cell surface glycoproteins and glycolipids can serve as protein ligands, thereby providing an anchor for intercellular adhesion or a receptor for viral and bacterial invasion. Their role in regulation of differentiation processes is generally acknowledged. Glycoconjugates and glycomimetics have, therefore, a significant pharmaceutical potential. For physiological applications of carbohydrates two important issues have to be addressed: i) multivalency - dictated by the fact of rather weak carbohydrate-protein interactions occurring in natural structures (multiantennary glycoproteins); ii) stability of structure and protection from cleavage of natural O-glycosidic bonds by numerous glycosidases in the organism. This obstacle can be overcome by preparation of artificial multivalent neoglycoconjugates and by introduction of unnatural carbohydrate linkages leading to a glycomimetic concept. Chemical extension of complex multivalent or multi-linear glycoclusters is virtually impossible due to high complexity and intrinsic properties of carbohydrates, e.g., presence of a large number of rather similar OH groups that can only be distinguished by complex and labor-demanding protection/deprotection strategy. Enzymatic methods have already become a viable alternative to organic chemistry in the synthesis of complex carbohydrate structures, especially due to their selectivity and simplicity. Here, in contrast to glycosidases, glycosyltransferases offer an ideal tool for selective modification of such structures due to their absolute stereoselectivity and high regioselectivity. Since these enzymes modify complex multi-antennary structures in nature they are able to work on multi-linear and multivalent glycoclusters containing LacNAc structures. In the present joint proposal of the Elling and Kren group glycosyltransferases, glycosynthases and galactose oxidase as glycan modifying enzyme will be applied to create a library of modified poly-LacNAc conjugated to stable linkers. Complementary approaches and materials from both groups will be used. Selectivity for binding to human galectin-3, an important galectin in tumor progression and angiogenesis, shall be addressed by the synthesis of specific glycan epitopes in cascade reactions of glycosyltransferases. This small library of epitope carrying poly-LacNAc oligomers will be used for the next step addressing their multivalent presentation. This shall be accomplished by selective oxidation of galactose moieties of poly-LacNAc oligomers and subsequent chemical conjugation of epitope carrying poly-LacNAc oligomers. In this way a library of modified unnatural branched poly-LacNAc oligomers will be obtained as potential inhibitors of Gal-3.