Using Dendrimers to Design Multivalent Therapeutic Agent

我们研究计划的目的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导的蛋白质-碳水化合物相互作用；最终，我们计划利用这些信息来制定多价治疗剂和疫苗。在本提案中，我们描述了一种新的基于树突的系统，从中将开发人工多价含碳水化合物的系统。我们正在开发的技术使我们的系统非常适合探索蛋白质-碳水化合物相互作用中多价效应的潜在原因。此外，我们描述的快速合成多相功能化树突状表面的新方法具有广泛的应用前景。概述了一种将不同浓度的甘露糖单元结合到G(4)-和G(6)- pamam树状大分子表面的新方法。利用微量热法、血凝、酶联凝集素测定和亲和柱/EPR研究来评估碳水化合物功能化树状大分子与凝集素的相互作用。本文还提出了一种利用tempo标记的树状大分子对新的树状大分子基序进行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.