New approaches to target protein intramolecular interactions

目前的小分子药物大多是酶抑制剂或配体样药。 分子。它们与天然底物或配体在深结合口袋中竞争。 信号转导往往涉及蛋白质与蛋白质之间的相互作用。药物开发已经 在扰乱蛋白质-蛋白质相互作用方面取得了一些成功，如p53-MDM2 结合使用小分子和多肽模拟物。我们最近的研究表明 分子内相互作用介导MDM2的自激活或自抑制效应 和MDMX，因此在调节P53活性和应激反应中具有重要作用。 我们的发现揭示了P53治疗调控的潜在新靶点。 分子内相互作用也牵涉到许多其他 蛋白质。然而，稳定蛋白质分子内相互作用，与 破坏蛋白质-蛋白质结合，作为一种治疗方法在很大程度上还没有被探索出来。我们 建议使用MDMX作为模型来研究稳定蛋白质的可行性 P53激活的分子内相互作用。提出了两个具体目标：(1) 体外筛选稳定MDMX分子内相互作用的多肽 分区屏幕。(2)开发面向小型企业的高通量屏幕 稳定MDMX分子内相互作用的分子。这项工作将提供 针对ANS的新药开发的概念验证和先导化合物 重要的肿瘤抑制通路。这项研究的经验教训也将适用于 其他重要疾病相关蛋白的治疗靶点。

Most current small molecule drugs are enzyme inhibitors or ligand-like molecules. They compete with natural substrates or ligands in deep binding pockets. Signal transduction often involves protein-protein interactions. Drug development has achieved some success in disrupting protein-protein interactions such as p53-MDM2 binding using small molecules and peptide mimetics. Our recent work suggests that intramolecular interactions mediate auto-activating or auto-inhibitory effects on MDM2 and MDMX, thus have important roles in regulating p53 activity and stress response. Our findings reveal potential new targets for the therapeutic modulation of p53. Intramolecular interaction has also been implicated in the regulation of numerous other proteins. However, stabilizing protein intramolecular interaction, the opposite of disrupting protein-protein binding, is largely unexplored as a therapeutic approach. We propose to use MDMX as a model to investigate the feasibility of stabilizing protein intramolecular interaction for p53 activation. Two specific aims are proposed: (1) Identify peptides that stabilize MDMX intramolecular interaction by in vitro compartmentalization screen. (2) Develop a high throughput screen for small molecules that stabilize MDMX intramolecular interaction. This work will provide proof of concept and lead compounds for the development of new drugs that target an important tumor suppressor pathway. Lessons from this study will also be applicable to the therapeutic targeting of other important disease-associated proteins.