Spatial screening of cyclic neoglycopeptides: identification of polyvalent wheat-germ agglutinin ligands.

Natural and synthetic polyvalent ligands can act as inhibitors of biological processes or as effectors of signal-transduction pathways. 2] In the case of carbohydrate–lectin interactions, polyvalency is of particular importance because individual carbohydrate epitopes are usually bound with only weak affinity and often broad specificity. The potency of a polyvalent inhibitor depends on the spatial presentation of the carbohydrates and the associated possibility of occupying several binding sites simultaneously. If the 3D structure of the protein is known, suitable polyvalent ligands may be obtained by rational design. This has been impressively demonstrated for the bacterial AB5 toxins [5] as well as for non-carbohydrate systems (“directed” polyvalency). However, if the threedimensional orientation of the binding sites of a polyvalent lectin is not known, many potential ligands have to be synthesized and screened to determine the required orientation of the carbohydrate units. This holds true particularly for conformationally restricted glycoclusters which may lead in such cases to ligands with especially strong affinities. 6,8] Screening of a library of spatially diverse glycoclusters could accelerate this process significantly. St. Hilaire, Meldal, et al. reported on split-and-mix libraries of linear glycopeptides. First studies on the behavior of dynamic combinatorial carbohydrate libraries of four and 21 compounds in the presence of lectins have been published as well. Here we report the first example of a split-and-mix library of conformationally restricted, spatially diverse glycoclusters, and their screening for binding to the N-acetylglucosamine(GlcNAc)-binding plant lectin wheat-germ agglutinin (WGA). As scaffold molecules (templates) for the presentation of the carbohydrate residues we chose side-chain-cyclized pep-