Using Dendrimers to Design Multivalent Therapeutic Agent

我们的研究计划的目标是利用有机化学家的工具来探索生物化学中的关键问题。目前，我们试图了解参与细胞信号传递的蛋白质-碳水化合物相互作用；最终，我们计划利用这些信息来研制多价治疗剂和疫苗。在这项建议中，我们描述了一种基于树枝状大分子的新系统，从该系统将开发出人工多价碳水化合物系统。我们正在开发的技术使我们的系统独特地适合于探索蛋白质-碳水化合物相互作用中多价效应的根本原因。此外，我们描述的快速合成非均相官能化树枝状大分子表面的新方法具有广泛的适用性。介绍了一种在G(4)和G(6)-PAMAM树枝状大分子表面引入不同浓度甘露糖单元的新方法。用微量热法、血凝法、酶联凝集素测定法和亲和柱/EPR研究来评价碳水化合物功能化树枝状大分子与凝集素的相互作用。还提出了一种使用TEMPO标记的树状大分子来表征新的树状大分子基序的策略。

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.