MOLECULAR RECOGNITION IN BIOMIMETIC RECEPTORS

描述(逐字摘自申请人的摘要)：本申请代表一个 旨在设计能够识别的合成试剂的重大新计划 蛋白质的外表面。我们的主要目标将是开发一种 和模块化的蛋白质表面识别方法，将允许 通过修改识别来靶向一系列不同的蛋白质表面 人工合成受体的特性。电荷的独特分布， 每种蛋白质表面的疏水和亲水基团都会导致 有选择性地结合强烈的人造受体。我们建议设计一种 并合成含有多个连接的多肽环的合成受体 到一个中心结构核心。这些代理将包含大型(&gt；400A2)和 功能化的表面积，以识别 靶蛋白。 在初步结果中，我们表明，在适度和未经优化的系列 合成受体我们可以识别具有不同表面的强效化合物 绑定到并影响一系列 不同的蛋白质靶标。这些药物包括丝氨酸的纳米分子抑制剂。 凝乳蛋白酶、凝血酶与生长因子/受体拮抗剂 酪氨酸激酶相互作用在250 nm和250 nm阻断细胞信号通路 在裸鼠模型中抑制人肿瘤生长。这些蛋白质中的每一种 结合剂对其蛋白质靶标具有很强的亲和力 高离子强度的生理条件，表明这种联系 涉及疏水和静电相互作用的组合。在 拟议的项目我们将修改中央核心，以允许不对称 多肽环路的处理。我们还将调查不同的环路和 核心支架结构，以优化与目标蛋白的结合。 同时，我们将使用溶液法和固相法来开发 我们的人工受体库具有广泛的不同识别能力 然后可以筛选将活动绑定到不同 蛋白质。我们将研究针对这种干扰的蛋白质表面受体 两种具有重要治疗作用的丝氨酸蛋白酶，凝血酶和弹力酶。我们 也将以参与异常细胞增殖途径的蛋白质为目标， 包括生长因子(如PDGF、VEGF和EGF)。

DESCRIPTION (verbatim from applicant's abstract): This application represents a major new program aimed at the design of synthetic agents that can recognize the exterior surface of proteins. Our primary goal will be to develop a general and modular approach to protein surface recognition that will allow the targeting of a range of different protein surfaces by modifying the recognition characteristics of synthetic receptors. The unique distribution of charged, hydrophobic and hydrophilic groups on the surface of every protein will lead to artificial receptors that bind strongly and selectively. We propose to design and synthesize synthetic receptors that contain multiple peptide loops linked to a central structural core. These agents will contain a large (>400A2) and functionalized surface area to recognize the complementary surface of the target protein. In preliminary results we show that with a modest and unoptimized series of synthetic receptors we can identify potent compounds with different surface characteristics that bind to and influence the reactivity of a range of different protein targets. These include nanomolar inhibitors of the serine proteases chymotrypsin and thrombin and antagonists of growth factor/receptor tyrosine kinase interactions that block cell signaling pathways at 250nM and inhibit the growth of human tumors in nude mouse models. Each of these protein binding agents retains strong affinity for its protein target even in physiological conditions of high ionic strength, suggesting that association involves a combination of hydrophobic and electrostatic interactions. In the proposed project we will modify the central core to allow unsymmetrical disposition of the peptide loops. We will also investigate different loop and core scaffold structures in order to optimize binding to the target proteins. At the same time we will use solution and solid phase methods to develop libraries of our artificial receptors with widely diverse recognition properties that can then be screened for binding activity to different proteins. We will investigate protein surface receptors aimed at the disruption of two therapeutically important serine proteases, thrombin and elastase. We will also target proteins involved in aberrant cell proliferation pathways, including growth factors (such as PDGF, VEGF and EGF).