Using Dendrimers to Design Multivalent Therapeutic Agent

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The objective of our research program is to probe key questions in biological chemistry using the tools of the organic chemist. Currently, we seek to understand the protein-carbohydrate interactions that are involved in cell signaling; ultimately, we plan to use this information to formulate multivalent therapeutic agents and vaccines. In this proposal, we describe a novel dendrimer-based system from which artificial multivalent carbohydrate-containing systems will be developed. The techniques we're developing make our system uniquely suited for probing the underlying causes of the multivalent effect in protein- carbohydrate interactions. In addition, the new methods we describe for rapid synthesis of heterogeneously-functionalized dendrimer surfaces are widely applicable. A new method for incorporation of varying concentrations of mannose units onto the surface of G(4)- and G(6)-PAMAM dendrimers is outlined. Evaluation of the interaction of carbohydrate-functionalized dendrimers with lectins using microcalorimetry, hemagglutination, an enzyme-linked lectin assay, and an affinity column/EPR study is proposed. A strategy for EPR characterization of the new dendrimer motifs using TEMPO-labeled dendrimers is also presented.