The development of new methods for spatially arranging ligands for optimal interactions with protein targets is an increasingly important area of research. Polymers, dendrimers, and peptides have served as useful scaffolds for ligand display to maximize polyvalent interactions. Typically these systems randomly orient the ligands of interest and are relatively flexible. Recently, the Huisgen cycloaddition reaction (an example of """"""""Click"""""""" chemistry) has been employed to link ligands in the presence of the protein target, giving rise to templated systems with picomolar affinities. In the proposed research we will apply Click chemistry in ligand templating reactions involving protein/carbohydrate recognition processes. Unique contributions to this area of research will be made by employing conformationally-biased scaffolds to link the ligands of interest. Over the past several years we have developed technologies for the synthesis of amide-linked carbohydrates with stable secondary structures in water. This research has established new methods for synthesizing sugar amino acids and solid-phase strategies for preparing oligomeric materials. Neuraminic acid (NeuAc) has proven to be a versatile starting material for the construction of homooligomers having helical secondary structures. NeuAc is preferable to other more commonly encountered sugars because it is a natural amino acid having a polyhydroxylic sidechain that imparts desirable solubility characteristics. Moreover, several different analogs having unique secondary structures are readily available. The proposed research will apply our established protocols to the synthesis of scaffold libraries for application in ligand templating of pathogenic carbohydrate/lectin recognition processes.
|Lu, Yan; Gervay-Hague, Jacquelyn (2007) Synthesis of C-4 and C-7 triazole analogs of zanamivir as multivalent sialic acid containing scaffolds. Carbohydr Res 342:1636-50|