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Novel Keap1-Nrf2 Inhibitors as Chemopreventive Agents

作为化学预防剂的新型 Keap1-Nrf2 抑制剂

基本信息

批准号：
7321003
负责人：
LONGQIN HU
金额：
$ 7.73万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7321003
关键词：
3-Dimensional Address Adverse effects Affinity Alkenes Amides Antioxidants Binding Binding Sites Biological Assay Biological Factors Biosensor Carcinogens Catechols Cell Nucleus Chemicals Chemopreventive Agent Complex Computer Simulation Curcumin Cyclic Peptides Cysteine Development Dissociation Disulfides Dose Enzymes Evaluation Fluorescence Polarization Future Genes Gold High Performance Computing Inflammation Isothiocyanates Lead Link Luciferases Malignant Neoplasms Modification Oxidation-Reduction Oxidative Stress Pathway interactions Peptides Play Population Proteins Purpose Reactive Oxygen Species Reporter Research Research Project Grants Response Elements Risk Roentgen Rays Role Safety Screening procedure Signal Pathway Source Structure Sulfhydryl Compounds Sulforaphane Surface Plasmon Resonance System Tea Transcriptional Activation Triazoles Up-Regulation Virtual Library Work base biological adaptation to stress cancer chemoprevention cluster computing design fluorophore fruits and vegetables gallocatechol inhibitor/antagonist novel prevent protein protein interaction sensor small molecule

项目摘要

DESCRIPTION (provided by applicant): Research over the last decade has demonstrated that Keap1-Nrf2-antioxidant response element (ARE) system plays a key role in cancer chemoprevention by many chemicals like sulforaphane, curcumin, and epigallo- catechol gallate derived from natural sources such as fruits, vegetables, and tea products. Modification, by these natural electrophiles such as isothiocyanates and Michael acceptors, of sensitive cysteine residues found in the redox "sensor" protein Keap1 is believed to be responsible for causing the dissociation of Keap1- Nrf2 complex and subsequent upregulation of oxidative stress response enzymes. To address concerns over the general use of purified natural thiol-reactive compounds as chemopreventive agents, novel short peptides and small organic molecules are designed and screened specifically for the inhibition of Keap1-Nrf2 interaction. These inhibitors will mimic the actions of reactive oxygen species and electrophiles like isothiocyanates and Michael acceptors in the induction of cytoprotective enzymes but will potentially be more selective and specific. Two structure-based approaches are proposed here to start from the recently available 3-D X-ray cocrystal structure of Keap1 Kelch domain with Nrf2 peptide to discover novel selective Keap1-Nrf2 inhibitors: a) to design conformationally restricted cyclic peptides to mimic the ¿-hairpin loop of Nrf2 that interacts with Keap1 and b) to use in silico screening of virtual libraries for small molecules that could bind to Keap1 with high affinity and thus prevent the binding of Nrf2. These studies will provide important information about, and novel small molecule inhibitors of, the protein-protein interaction between Keap1 and Nrf2, and facilitate the development of more potent and selective Keap1-Nrf2 inhibitors as inducers of oxidative stress response enzymes.

描述（由申请人提供）：过去十年的研究表明，Keap 1-Nrf 2-抗氧化反应元件（ARE）系统在许多化学物质（如萝卜硫素、姜黄素和表没食子儿茶酚没食子酸酯）的癌症化学预防中发挥着关键作用，这些化学物质来源于水果、蔬菜和茶产品等天然来源。通过这些天然亲电体如异硫氰酸酯和迈克尔受体，在氧化还原“传感器”蛋白Keap 1中发现的敏感半胱氨酸残基的修饰被认为是导致Keap 1-Nrf 2复合物解离和随后氧化应激反应酶上调的原因。为了解决纯化的天然硫醇反应性化合物作为化学预防剂的一般用途的问题，新的短肽和小的有机分子被设计和筛选，特别是用于抑制Keap 1-Nrf 2相互作用。这些抑制剂将模拟活性氧和亲电体如异硫氰酸酯和迈克尔受体在诱导细胞保护酶中的作用，但可能更具选择性和特异性。本文提出了两种基于结构的方法，从最近获得的Keap 1 Kelch结构域与Nrf 2肽的三维X射线共晶结构出发，发现新的选择性Keap 1-Nrf 2抑制剂：a）设计构象限制性环肽，模拟Nrf 2肽的构象，- 与Keap 1相互作用的Nrf 2的发夹环，和B）使用计算机模拟筛选虚拟文库中的小分子，这些小分子可以以高亲和力与Keap 1结合，从而阻止Nrf 2的结合。这些研究将提供有关Keap 1和Nrf 2之间蛋白质-蛋白质相互作用的重要信息和新型小分子抑制剂，并促进开发更有效和选择性的Keap 1-Nrf 2抑制剂作为氧化应激反应酶的诱导剂。