Using Dendrimers to Design Multivalent Therapeutic Agent

我们的研究计划的目标是探索生物化学中的关键问题，使用有机化学家的工具。目前，我们试图了解参与细胞信号传导的蛋白质-碳水化合物相互作用;最终，我们计划使用这些信息来制定多价治疗药物和疫苗。在这个建议中，我们描述了一种新的树状聚合物为基础的系统，人工多价含碳水化合物的系统将开发。我们正在开发的技术使我们的系统特别适合于探测蛋白质-碳水化合物相互作用中多价效应的根本原因。此外，我们所描述的快速合成异质官能化树枝状聚合物表面的新方法具有广泛的适用性。提出了一种将不同浓度的甘露糖单元引入到G（4）-和G（6）-PAMAM树枝状大分子表面的新方法。碳水化合物官能化的树枝状大分子与凝集素的相互作用，使用微量热法，血凝，酶联凝集素测定，亲和柱/EPR研究的评价。还提出了使用TEMPO标记的树枝状聚合物的新树枝状聚合物图案的EPR表征的策略。

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.