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New approaches to target protein intramolecular interactions

靶向蛋白质分子内相互作用的新方法

基本信息

批准号：
9171201
负责人：
JIANDONG CHEN
金额：
$ 22.45万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9171201
关键词：
Adverse effects Apoptosis Promoter Binding Binding Proteins Biological Biological Assay Cell Death Development Disease Dissociation Enzyme Inhibitor Drugs Future In Vitro Investigation Lead Ligands Luciferases MDM2 gene Mediating Methods Modeling Modification Molecular Conformation Pathway interactions Peptides Protein p53 Proteins Regulation Role Scaffolding Protein Screening procedure Signal Transduction Structure TP53 gene Therapeutic Therapeutic Intervention Tumor Suppressor Proteins Work biological adaptation to stress cancer therapy cell growth design drug development high throughput screening mimetics neoplastic cell new therapeutic target novel strategies peptidomimetics protein complex protein protein interaction research study small molecule src-Family Kinases success therapeutic target transcription factor

项目摘要

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.

目前大多数小分子药物都是酶抑制剂或配体类药物分子。它们与深结合袋中的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。药物研发已在破坏蛋白质-蛋白质相互作用（例如 p53-MDM2）方面取得了一些成功使用小分子和肽模拟物进行结合。我们最近的工作表明分子内相互作用介导 MDM2 的自动激活或自动抑制作用因此，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。分子内相互作用也涉及许多其他的调节蛋白质。然而，稳定蛋白质分子内相互作用，则相反破坏蛋白质-蛋白质结合，作为一种治疗方法在很大程度上尚未被探索。我们提出使用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) 通过体外鉴定稳定 MDMX 分子内相互作用的肽分区屏幕。 (2) 开发小尺寸高通量筛选稳定 MDMX 分子内相互作用的分子。这项工作将提供用于开发针对特定疾病的新药的概念验证和先导化合物重要的抑癌途径。这项研究的教训也适用于其他重要的疾病相关蛋白的治疗靶点。