• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Selective GLP-1 receptor antagonists and glucagon/GLP-1 co-agonists discovered through an investigation into the structure-activity relationship in glucagon-related peptides.
【24h】

Selective GLP-1 receptor antagonists and glucagon/GLP-1 co-agonists discovered through an investigation into the structure-activity relationship in glucagon-related peptides.

机译：通过研究胰高血糖素相关肽的结构-活性关系，发现了选择性的GLP-1受体拮抗剂和胰高血糖素/ GLP-1共激动剂。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Glucagon and glucagon-like peptide-1 (GLP-1) are two hormones of similar structure with specific receptors that signal by related biochemical mechanisms but diverge in cellular action. This doctoral thesis research has established a chemical basis for understanding how GLP-1 peptide structure relates to biochemical function, and its application to the discovery of novel ligands of unique molecular pharmacology. Through a comprehensive evaluation of GLP-1 receptor peptides, we have identified structural elements in receptor activation that differentiate agonism from antagonism. Our structure-function analysis coupled with receptor mutagenesis studies have enabled the development of a model for how two homologous hormones such as GLP-1 and its reptilian counterpart exendin-4 (Ex-4) diverge in their bioactivities. In particular, Ex-4 possesses the unique ability to be N-terminally truncated to form an antagonist and proves much more promiscuous as an agonist to N-terminal substitution. Our findings indicate that structural reinforcement of the α-helix along with enhanced contacts with the GLP-1 receptor extracellular domain can account for these differences in biochemistry. Introduction of additional chemical modification was demonstrated to prolong in vivo duration of action rendering these peptides suitable for use in chronic pharmacology studies. Our structure-function analysis also identified peptides that act as co-agonists at the GLP-1 and glucagon receptors. These observations have furthered our mechanistic knowledge of the broader subfamily of glucagon-related G protein-coupled receptor hormones.
机译：胰高血糖素和胰高血糖素样肽-1（GLP-1）是具有类似受体结构的两种激素，它们具有通过相关生化机制发出信号但在细胞作用上有所不同的特定受体。这项博士论文研究为理解GLP-1肽结构如何与生化功能相关及其在发现独特分子药理学的新配体中的应用奠定了化学基础。通过对GLP-1受体肽的全面评估，我们已经确定了受体激活中区分激动和拮抗作用的结构元件。我们的结构功能分析与受体诱变研究相结合，已经为两种同源激素（例如GLP-1和其爬行动物对应的exendin-4（Ex-4））如何在生物活性方面发生差异提供了一种模型。特别地，Ex-4具有被N端截短以形成拮抗剂的独特能力，并被证明作为N端取代的激动剂更为混杂。我们的发现表明，α-螺旋的结构增强以及与GLP-1受体胞外域的增强接触可以解释这些生物化学差异。已证明引入其他化学修饰可延长体内作用时间，从而使这些肽适合用于慢性药理学研究。我们的结构功能分析还确定了在GLP-1和胰高血糖素受体上充当辅助激动剂的肽。这些观察结果进一步提高了我们对胰高血糖素相关的G蛋白偶联受体激素的更广泛亚家族的机制认识。

著录项

  • 作者

    Patterson, James T.;

  • 作者单位

    Indiana University.;

  • 授予单位 Indiana University.;
  • 学科 Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 164 p.
  • 总页数 164
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号