Synthetic Analogs of Glucagon for Diabetes Studies

用于糖尿病研究的胰高血糖素的合成类似物

• 批准号: 7471486
• 负责人: CECILIA G UNSON
• 金额: $ 36.9万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-09-15 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7471486
• 关键词: Address; Adenylate Cyclase; Affinity; Amides; Amino Acids; Binding; Binding Sites; Biochemical; Biological; Biological Availability; Cell Line; Chimera organism; Circular Dichroism; Clinical Research; Complement; Complex; Conceptions; Condition; Diabetes Mellitus; Family; Fluorescence Spectroscopy; Functional disorder; Future; Glucagon; Glucagon Receptor; Glucagon Receptor Binding; Goals; Helix (Snails); Hormone Antagonists; Hormone Receptor; Hormones; Hybrids; Hyperglycemia; Label; Lead; Ligands; Mammalian Cell; Mediating; Methods; Modeling; Molecular; Molecular Biology; Molecular Conformation; Monitor; N-terminal; NOESY; Nuclear Magnetic Resonance; Object Attachment; Peptide Library; Peptide Synthesis; Peptides; Phase; Pliability; Range; Receptor Activation; Role; Scanning; Signal Transduction; Site; Site-Directed Mutagenesis; Solid; Specificity; Structure; Structure-Activity Relationship; System; Tail; Techniques; Testing; Tetracycline; Tetracyclines; Vertebral column; analog; base; chemical synthesis; combinatorial; design; diabetes management; diabetic; disulfide bond; ear helix; extracellular; improved; innovation; insight; interdisciplinary approach; member; mutant; peptide analog; peptide hormone; receptor; receptor expression; stopped-flow fluorescence; time use; Address; Adenylate Cyclase; Affinity; Amides; Amino Acids; Binding; Binding Sites; Biochemical; Biological; Biological Availability; Cell Line; Chimera organism; Circular Dichroism; Clinical Research; Complement; Complex; Conceptions; Condition; Diabetes Mellitus; Family; Fluorescence Spectroscopy; Functional disorder; Future; Glucagon; Glucagon Receptor; Glucagon Receptor Binding; Goals; Helix (Snails); Hormone Antagonists; Hormone Receptor; Hormones; Hybrids; Hyperglycemia; Label; Lead; Ligands; Mammalian Cell; Mediating; Methods; Modeling; Molecular; Molecular Biology; Molecular Conformation; Monitor; N-terminal; NOESY; Nuclear Magnetic Resonance; Object Attachment; Peptide Library; Peptide Synthesis; Peptides; Phase; Pliability; Range; Receptor Activation; Role; Scanning; Signal Transduction; Site; Site-Directed Mutagenesis; Solid; Specificity; Structure; Structure-Activity Relationship; System; Tail; Techniques; Testing; Tetracycline; Tetracyclines; Vertebral column; analog; base; chemical synthesis; combinatorial; design; diabetes management; diabetic; disulfide bond; ear helix; extracellular; improved; innovation; insight; interdisciplinary approach; member; mutant; peptide analog; peptide hormone; receptor; receptor expression; stopped-flow fluorescence; time use

DESCRIPTION (provided by applicant): The long-range goal of this project is to investigate the mechanism of action of the peptide hormone glucagon and to contribute to the understanding of its role in the pathophysiology of diabetes mellitus. The principal approach towards this goal is to design and synthesize analogues of glucagon that will bind with high affinity to the glucagon receptor but will not activate adenylyl cyclase. These peptide analogues are expected to provide insight into the structural basis of glucagon action at the molecular level and should be potent antagonists of the hormone. A second complementary approach is to investigate structure-function relationships in the glucagon receptor by site-directed mutagenesis and the biochemical and pharmacological characterization of mutant receptors. Specifically, we will test the two-site binding model of the receptor and determine the residues of the receptor that dictate ligand selectivity. To augment both approaches, structural and biophysical methods will be used. We will determine the structure of glucagon bound to the Nterminal domain of the receptor and to the intact receptor by nuclear magnetic resonance (NMR) analysis. The dynamics of glucagon interaction with receptor and fragments of the receptor will be studied by circular dichroism and fluorescence spectroscopy. An interdisciplinary approach combining chemical synthesis, molecular biology, and structural and biophysical methods is very likely to advance the understanding of glucagon-mediated signal transduction and is crucial for the conception of three-dimensional receptor models to be used in the rational design of glucagon antagonists for the management of diabetes.

描述（由申请人提供）： 该项目的远程目标是研究肽激素胰高血糖素的作用机理，并有助于理解其在糖尿病的病理生理学中的作用。实现此目标的主要方法是设计和合成胰高血糖素的类似物，这些类似物将与胰高血糖素受体高亲和力结合，但不会激活腺苷酸环化酶。这些肽类似物有望提供对分子水平上胰高血糖素作用的结构基础的见解，应是激素的有效拮抗剂。第二种补充方法是通过定位的诱变以及突变受体的生化和药理表征研究胰高血糖素受体中的结构 - 功能关系。具体而言，我们将测试受体的两位点结合模型，并确定决定配体选择性的受体的残基。为了增加两种方法，将使用结构和生物物理方法。我们将通过核磁共振（NMR）分析确定与受体的N端结构域和完整受体结合的结构。胰高血糖素相互作用与受体和受体片段的动力学将通过圆形二色性和荧光光谱研究。结合化学合成，分子生物学以及结构和生物物理方法的跨学科方法很可能会促进对胰高血糖素介导的信号转导的理解，并且对于三维受体模型的概念至关重要，用于三维受体模型，用于用于葡萄糖拮抗剂的理性设计用于糖尿病的管理。