COMBINATORIAL APPROACH TO ARTIFICIAL RECEPTOR DESIGN

人工受体设计的组合方法

• 批准号: 2378306
• 负责人: ANDREW D HAMILTON
• 金额: $ 10.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2378306
• 关键词: biosensor device; chemical structure function; chemical synthesis; colorimetry; fluorimetry; ion transport; ligands; metals; pyridine; receptor; receptor binding

The power of combinatorial strategies for the generation of large populations of molecules has long been recognized in biology. It has been estimated that 5xlO-7 new antibody forming B cells are produced in the body every day, each producing a unique antibody molecule. This enormous variety provides a large range of binding regions that can be selected for their given complementarity for a target antigen in the immune system. In recent years there have been increasing attempts to reproduce the power of diversity in the generation of medium and large libraries of small molecules. These combinatorial methods have been directed to the formation either of oligomeric or of small molecule libraries designed to bind to a target (usually biological) receptor. The primary focus of this proposal is the development of libraries of synthetic receptors as the foundation of a novel approach to metal ion and molecule sensor design. An effective receptor requires the presence of multiple binding groups in a well- defined spacial arrangement and directed towards a central binding cleft or cavity. This can only be achieved by a convergent approach which allows different binding regions to be pre-formed before assembling them together to generate the final recognition site. This proposal represents a major new program aimed at the development of a combinatorial approach to the design of libraries of artificial molecular receptors. The central concept is that a templating metal scaffold can function both as a one step source of structural diversity and as an internal spectroscopic probe of substrate binding. Thus, both key problems in combinatorial chemistry are solved; a facile and compatible route to functional libraries and an internal screening device for identifying strong and effective binding ligands. The strength of the combinatorial approach is that it allows the generation of a large library of synthetic molecule or metal ion receptors that can then be screened for the desired selectivity. To achieve these goals we will prepare a series of terpyridine ligands functionalized with different binding regions which will then self-assemble around a transition metal center. The internal spectroscopic probe will then be used to screen the receptor library for strong and selective binding to a range of biologically interesting substrates. We anticipate that the receptor library strategy can be extended to the formation metal templated ionophores that change their colorimetric or fluorescence properties on binding to target metal ions. We will also prepare a series of functionalized bipyridine derivatives metal that will form a metal templated recognition site with three potential substrate binding regions.

组合策略的力量，用于产生大型 分子群体在生物学中早已被认识。已经 据估计，5 × 10 -7个新的抗体形成B细胞产生于 每一种抗体都产生一种独特的抗体分子。这个巨大 多样性提供了大范围的结合区域，可以选择用于 它们对免疫系统中靶抗原的互补性。在 近年来，人们越来越多地试图复制 在中小型图书馆的产生多样性 分子。这些组合方法已经被引导到形成 寡聚体或小分子文库，其被设计为结合到 靶向（通常是生物学）受体。该提案的主要重点是 是发展合成受体库作为基础 金属离子和分子传感器设计的新方法。有效 受体需要在孔中存在多个结合基团- 限定的空间布置并指向中央结合裂缝 或空腔。这只能通过一种趋同的方法来实现， 在将它们组装在一起之前预先形成不同的结合区域 以生成最终的识别位点。 该提案是一项旨在发展 一种设计人工免疫细胞库的组合方法 分子受体核心概念是， 支架可以作为结构多样性的一步来源， 并作为底物结合的内部光谱探针。因此，两者 解决了组合化学中的关键问题， 到功能库和内部筛选设备的兼容路由 用于鉴定强且有效的结合配体。的强度 组合方法的另一个优点是它允许产生大型文库， 合成分子或金属离子受体， 所需的选择性。为了实现这些目标，我们将准备一系列 用不同的结合区域官能化的三联吡啶配体， 然后会围绕过渡金属中心自组装。内部 然后将使用光谱探针筛选受体文库， 与一系列生物学上感兴趣 印刷受体.我们预计受体库策略可以 延伸到形成金属模板的离子载体， 比色或荧光性质。 我们还将制备一系列功能化的联吡啶衍生物 金属，将形成一个金属模板识别位点， 潜在的底物结合区。