NEW TOOLS FOR PROBING PEPTIDE-PROTEIN INTERACTIONS

七跨膜（7-TM）受体遍布全身， 大多数神经递质的主要目标 和肽激素。由于大量的7-TM受体和 大多数7-TM配体的灵活性，许多特定7-TM的激动剂 受体位点具有结合和激活许多其它位点的能力 并因此产生多种副作用。显然，一个 了解哪些因素控制激素与特定的 7-TM受体对于开发潜在的候选药物是必不可少的， 可以辨别相关的受体位点。 拟议的研究旨在检查一系列的整体效用 用于“作图”的基于内酰胺的构象受限的肽模拟物 7-TM受体的三维需求。具体而言是 促甲状腺激素释放激素7-TM受体TRH-R和P物质7-TM 受体NK 1将被研究。在这两种情况下，存在一对模型， 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，这些限制性类似物 将被合成并测试它们的亲和力和效力， 合适的7-TM受体。生物数据将被用来绘制 关于激素的受体结合构象的结论。 任何此类研究中的关键问题之一都涉及到 所需的约束类似物。许多这种性质的研究失败时， 不能制备所需的类似物。即使合成类似物， 如果合成太复杂，则 方法是非常有限的。由于这项工作的长期目标 是发展出普遍有用的策略， 肽的预测生物活性和实际生物活性之间 构象，拟议研究的主要目标之一将 是开发新的合成方法，快速构建内酰胺- 基于肽模拟物。

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.