SIGNAL TRANSDUCTION PROBED BY CONSOLIDATED LIGANDS

我们将研制出与蛋白质的重要成分结合的试剂 通过Src同源物（SH）2参与细胞内转导， SH3结构域 所涉及的蛋白质，Grb 2，Lck，Hck，Crk，Abl， 和STAT1是生长因子介导的细胞转化的中心， 免疫反应，慢性骨髓性白血病的病因， 对细胞因子的反应。 结合位点组织的问题， 抑制剂的设计，以及途径的描绘，然后可能是 可用于许多特定的病理学研究，包括癌症， 糖尿病、自身免疫性疾病和对感染的反应。 试剂 从这些配体中开发的药物可能具有广泛的研究价值， 潜在的治疗应用。 该方法使用了统一的配体，其中天然的多个 信号转导蛋白的结合位点，含有多个 结构域，将由通过连接在一起的双配体补充， 专门设计的连接器。 这种方法已被证明是 对于Abl SH（32）已经实用。 小分子组合肽 基于结构洞察力的库，具有拓扑和类似长度 将通过生物化学方法筛选变异，以结合 目标，而那些结合力强的将受到进一步的 发展，通过合理的和组合的方法。

We shall develop reagents to bind to significant elements of proteins involved in intracellular transduction via their Src Homology (SH) 2, and SH3 domains. The proteins involved, Grb2, Lck, Hck, Crk, Abl, and STAT1 are central to growth factor mediated cell transformation, the immune response, causation of chronic myologenous leukemia, and the responses to cytokines. The issues of binding site organization, design of inhibitors, and delineation of pathways is then likely to be useful in many specific pathological investigations, including cancer, diabetes, autoimmune disorders, and response to infections. Reagents developed from these ligands may have broad investigational, and potentially therapeutic, application. The approach used consolidated ligand, in which the natural multiple binding sites of signal transducing proteins, containing multiple domains, will be complemented by dual ligands tethered together by specifically designed linkers. This approach has been shown to be practical already for Abl SH (32). Small combinatorial peptide libraries based on structural insights, with topological and liker length variation will be screened by biochemical means for binding to the target, and those binding strongly will be subject to further development, by rational and combinatorial methods.