Stabilized Helical Peptides as Coactivators Antagonists

作为共激活剂拮抗剂的稳定螺旋肽

• 批准号: 6888088
• 负责人: FEDERICO BERNAL
• 金额: $ 4.83万
• 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/6888088
• 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）： 类固醇异种受体（SXR）是负责外源化合物代谢的配体依赖性转录因子。化学治疗剂激活SXR会诱导细胞色素酶的产生，这些酶会氧化降解这些药物，并从细胞中除去它们。 SXR的激活需要使用配体和共激活肽SRC-1。该建议概述了旨在通过共激活因素相互作用来分析SXR激活的实验。固相结合肽合成将迅速为我们提供多种小型化合物，目的是拮抗SXR-SRC-1相互作用并阻止化学治疗剂的降解和驱逐。小肽内的疏水交联将赋予它们的螺旋，稳定性降解和膜渗透性。肽的结合特性将在体外通过时间分辨率进行研究。体内效应将通过荧光素酶转录测定法检查。这项研究将提供一种新的研究癌细胞中耐药性问题的新方法。此外，它将进一步了解共激活肽在特定细胞类型中特定基因激活中的作用。