Stabilized Helical Peptides as Coactivators Antagonists

作为共激活剂拮抗剂的稳定螺旋肽

• 批准号: 7061348
• 负责人: FEDERICO BERNAL
• 金额: $ 5.04万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061348
• 关键词: combinatorial chemistry; confocal scanning microscopy; crosslink; drug /agent; flow cytometry; fluorescence microscopy; fluorescence resonance energy transfer; inhibitor /antagonist; ligands; mass spectrometry; nuclear magnetic resonance spectroscopy; nuclear receptors; peptide library; peptides; postdoctoral investigator; protein protein interaction; tissue /cell culture; toxin; transcription factor

DESCRIPTION (provided by applicant): The steroid xenobiotic receptor (SXR) is a ligand-dependent transcription factor responsible for the metabolism of foreign compounds in the cell. Activation of SXR by chemotherapeutic agents induces the production of cytochrome enzymes, which oxidatively degrade these agents, and efflux pumps which remove them from the cell. The activation of SXR requires the use of both a ligand and the coactivator peptide SRC-1. This proposal outlines experiments aimed at analyzing the activation of SXR through coactivator peptide interactions. Solid phase combinatorial peptide synthesis will quickly provide us with a wide variety of small compounds with the objective of antagonizing the SXR-SRC-1 interaction and blocking the degradation and expulsion of chemotherapeutic agents. Hydrophobic cross-links within the small peptides will confer them helicity, stability toward proteolytic degradation, and membrane permeability. The binding properties of the peptides will be studied by time-resolved FRET in vitro. The in vivo effects will be examined by luciferase transcription assays. This research will provide a novel way of investigating the problem of drug resistance in cancer cells. Moreover, it will give further insight into the role of coactivator peptides in the activation of a specific gene in a particular cell type.

描述（由申请人提供）： 类固醇异生物质受体（SXR）是一种配体依赖性转录因子，负责细胞中外来化合物的代谢。化疗药物激活 SXR 会诱导细胞色素酶的产生，细胞色素酶会氧化降解这些药物，并产生外排泵，将它们从细胞中清除。 SXR 的激活需要同时使用配体和共激活肽 SRC-1。该提案概述了旨在通过共激活肽相互作用分析 SXR 激活的实验。固相组合肽合成将快速为我们提供多种小化合物，其目的是拮抗SXR-SRC-1相互作用并阻止化疗药物的降解和排出。小肽内的疏水性交联将赋予它们螺旋性、蛋白水解降解的稳定性和膜渗透性。肽的结合特性将通过体外时间分辨 FRET 进行研究。体内效果将通过荧光素酶转录测定进行检查。这项研究将为研究癌细胞耐药性问题提供一种新方法。此外，它将进一步深入了解共激活肽在特定细胞类型中特定基因激活中的作用。