The contribution of the N-and O-linked oligosaccharides to a variety of glycoprotein-mediated biological phenomena has recently attracted broad interest. Synthetic glycopeptides are needed as the tools to ascertain the biological roles played by the oligosaccharides. A series of investigations on glycopeptide synthesis thus far made in our research group is presented in this minireview. In order to facilitate the construction of N-and O-linked oligosaccharides, we have been employing a benzyl group for protection of the hydroxyl groups. Having thus prepared glycosylated amino acid building blocks, we tackled the solid-phase synthesis of glycopeptides. Syntheses of the part structures of such biologically important glycoproteins as glycophorin, leukosialin, α2HS glycoprotein, hCG, CD52, and emmprin are described.
Sialylation of glycoproteins and glycolipids plays an important role in many cell surface processes; of special interest in this context are changes in tissue involved in diseases and especially changes during infections. Therefore, inhibitors of sialyltransferases regulating sialylation might be of medicinal interest, especially in the therapy of virus and cancer diseases. The present paper reviews the development of sialyltransferase inhibitors; thus acceptor analogs, donor analogs, transition-state analogs, and bisubstrate analogs were designed based on sialic acid derivatives as well as on structural mimetics. This way, very potent sialyltransferase inhibitors with inhibition constants in the low nanomolar range have been recently found.
The last decade of glycodendrimers research has witnessed tremendous sophistication in both their design and in their biological applications. Some of these artificial multiantennary glycans have reached animal testing and preliminary results are very encouraging, particularly those involving bacterial antiadhesins and antibody neutralization as observed with the Galili antigen implicated in xenotransplantation. Key scaffolding structures have become commercially available on large scale and several dendrimers were shown to be none toxic in cell and animal assays. These beautiful architectures have permitted to shed new lights on multivalent carbohydrate protein interactions. In fact, their potent ability to cross-link multivalent or aggregated protein receptors is helping redefine the classical glycoside cluster effect. The multivalent effect will be reexamined with a recent case involving cyanovirin, a high affinity oligomannose binding protein from Nostoc ellipsosporum. Advantages of glycodendrimers, in comparison to glycopolymers, will then be briefly discussed followed by the detailed description on synthetic strategies and common scaffolds used for their preparation. Structural glycodendrimer drawbacks will be described and solutions brought to solve problems associated with their steric hindrance, and thus lack of sugar accessibility at higher generation, will be presented. Both most common chemical ligations and chemoenzymatic synthesis will be outlined. Finally, the synthesis of “smart” glycodendrimers and glycoclusters' newer generation involving rapid covalent assembly of sugars by transition metal catalyzed cross-coupling reactions using palladium and cobalt will be described. The state of the art preparation of glycodendrimers library by dynamic combinatorial chemistry (adaptive chemistry) and self-assembly around various transition metals is now opening the field to an even higher level of creativity. These novel strategies are of particular interest given the fact that several protein receptors (ex. galectins) are actually contemplating the binding of the same carbohydrate ligands which they can although select on the basis of the valency and three dimensional topology.