New approaches to target protein intramolecular interactions

目前大多数小分子药物是酶抑制剂或配体样 分子。它们在深结合口袋中与天然底物或配体竞争。 信号转导通常涉及蛋白质-蛋白质相互作用。药物开发 在破坏蛋白质-蛋白质相互作用方面取得了一些成功，例如p53-MDM 2 使用小分子和肽模拟物结合。我们最近的研究表明， 分子内相互作用介导对MDM 2自激活或自抑制作用 和MDMX在调节p53活性和应激反应中具有重要作用。 我们的研究结果揭示了p53治疗调节的潜在新靶点。 分子内的相互作用也涉及到许多其他的调节。 proteins.然而，稳定蛋白质分子内相互作用， 破坏蛋白质-蛋白质结合作为治疗方法在很大程度上尚未开发。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） 通过体外试验鉴定稳定MDMX分子内相互作用的肽 区室化筛选。(2)开发高通量筛选小 稳定MDMX分子内相互作用的分子。这项工作将提供 概念验证和先导化合物，用于开发靶向 重要的肿瘤抑制途径。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向。

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.