NEW TOOLS FOR PROBING PEPTIDE-PROTEIN INTERACTIONS

7-跨膜(7-TM)受体遍布全身， 在他们的成员中计算大多数神经递质的主要靶标 和多肽激素。由于7-TM受体的数量很多，而且 大多数7-TM配体的灵活性，针对特定7-TM的许多激动剂 受体部位有能力结合和激活许多其他部位 并因此引起各种副作用。显然，一个 了解荷尔蒙与特定激素结合的因素 7-TM受体对于开发潜在的候选药物至关重要 可以在相关的受体位置之间辨别。 这项拟议的研究旨在检查一系列 以内酰胺为基础、构象受限的多肽模拟物用于“图谱” 7-TM受体的三维结构要求。具体地说， 促甲状腺激素释放激素7-TM受体TRH-R和P 7-TM物质 将对NK1受体进行研究。在这两种情况下，都有一对模型用于 负责结合的激素的构象，在这两种情况下 构象受限的类似物，能够区分 模型已经设计好了。在拟议的工作中，这些受限的类比 将合成并测试其亲和力和效力 适当的7-TM受体。然后，生物数据将被用来绘制 关于激素受体结合构象的结论。 任何这类研究中的关键问题之一都涉及到合成 所需的受限类比。许多这种性质的研究都失败了，因为 无法进行所需的类比。即使当合成类似物时， 如果合成过于复杂，那么 方法受到严重限制。由于这项工作的长期目标是 是为探索两国关系制定普遍有用的策略 多肽的预测生物活性与实际生物活性之间的关系 构象，拟议研究的主要目标之一将是 将开发新的合成方法来快速构建内酰胺- 基于多肽的模拟物。

Seven-transmembrane (7-TM) receptors are found throughout the body and count among their members the primary targets for most neurotransmitters and peptide hormones. Due to the large number of 7-TM receptors and the flexibility of most 7-TM ligands, many agonists for a particular 7-TM receptor site have the ability to bind and activate numerous other sites and hence give rise to a variety of side effects. Clearly, an understanding of what factors govern the binding of hormones to particular 7-TM receptors is essential for developing potential drug candidates that can discern between related receptor sites. The proposed research aims to examine the overall utility of a series of lactam-based, conformationally constrained peptide mimetics for "mapping" the three-dimensional requirements of 7-TM receptors. Specifically, the thyrotropin releasing hormone 7-TM receptor TRH-R and the substance P 7-TM receptor NK1 will be studied. In both cases, a pair of models exist for the conformation of the hormone responsible for binding, and in both cases conformationally restricted analogs capable of differentiating between the models have been designed. In the proposed work, these restricted analogs will be synthesized and tested for both their affinity and potency for the appropriate 7-TM receptor. The biological data will then be used to draw conclusions about the receptor bound conformation of the hormone. One of the key problems in any such study involves the synthesis of the desired constrained analogs. Many studies of this nature fail when the required analogs can not be made. Even when the analogs are synthesized, if the syntheses are too complex, then the general applicability of the approach is severely limited. Since the long range objective of this work is to develop generally useful strategies for probing the relationship between the predicted and actual biological activity of peptide conformations, one of the primary objectives of the proposed research will be to develop new synthetic methodology for rapidly constructing lactam- based peptide mimetics.