Pharmacology of neuroendocrine peptides

神经内分泌肽的药理学

• 批准号: 7429659
• 负责人: JEAN E RIVIER
• 金额: $ 38.05万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7429659
• 关键词: Affect; Affinity; Agonist; Amino Acid Sequence; Amino Acids; Antibodies; Binding; Biological; Biological Assay; CRF receptor type 2; Calcitonin; Cardiovascular system; Chemicals; Class; Collaborations; Computer Simulation; Consensus; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Dipeptides; Diuretics; Drug Kinetics; End Point; Endocrine; Etiology; Extracellular Domain; G Protein-Coupled Receptor Genes; Gastric Inhibitory Polypeptide; Glucagon; Hormones; Immune; Investigation; Laboratories; Lead; Letters; Ligand Binding; Ligands; Ligation; Mammals; Mental Depression; Modeling; Molecular Conformation; Mono-S; Mutate; Neurosecretory Systems; Parathyroid Hormones; Peptide Synthesis; Peptides; Peripheral; Pharmacologic Substance; Pharmacology; Physiological; Protein Fragment; Purpose; Reagent; Reporting; Research; Research Personnel; Role; Secretin; Side; Somatotropin-Releasing Hormone; Specificity; Stimulus; Stress; Structure; Structure-Activity Relationship; Tracer; aminoproline; analog; astressin B; base; design; gastrointestinal function; gastrointestinal system; human PTH protein; insight; novel; peptide analog; peptide structure; pharmacophore; pituitary adenylate cyclase activating polypeptide; programs; receptor; response; tool; urocortin

Peptidic antagonists of corticotropin releasing factor (CRF) and the urocortins (Ucn) have been critical in the understanding of endocrine, immune, cardiovascular and gastrointestinal functions in response to different stress stimuli. Nonpeptide CRF antagonists are developed for the treatment of depression. Further, the actual function, distribution and specificity of the two different CRF receptors (CRFR1 and CRFR2) and their subtypes are now better understood due to the availability of CRF-receptor-selective agonists and antagonists. However, significant amino acid sequence differences between the multiple CRF native ligands (CRF and Ucn 1, 2 and 3 in mammals) and the wide distribution of CRFR1 and CRFR2 with their concomitant modulation of multiple functions remain to be integrated and understood. There are two complementary end points to this Project: a) structural and b) pharmacological/biological. Both end points depend heavily on the synthesis of peptides (SPPS) and proteins (fragment chemical ligation). a) We propose to design and synthesize CRF/Ucn analogs and extra cellular domains 1 (ECD1s) of class B1 GPCR for functional and structural investigations using NMR in collaboration with Dr. Riek's project. Preliminary results have yielded a model of the interaction between the ECD1 of CRFR2 and the CRF antagonist, astressin B. Additional studies are mandatory to identify the actual contact points between ligands and the respective ECDs1 responsible for the initial steps of recognition and binding. This will be achieved with binding assays of mutated ECD1s and complementarily derivatized analogs of selected ligands. From these studies, we will derive consensus bioactive/binding conformations of the CRFR1 -selective and CRFR2-selective ligands and the pharmacophores of the respective receptors, b) We will use these pharmacophores in models for the rational design of novel peptide and nonpeptide CRFR1 and CRFR2 ligands. In particular, we propose to pursue the design of peptide CRFR1-selective antagonists using several approaches distinct from that used for the characterization of stressing a potent and CRFR1-selective agonist and astressin2-B, a potent and long acting CRFR2-selective antagonist. We will use these selective and potent reagents to identify through collaborations within this Program Project, and with outside investigators, the etiology of pathophysiological states for possible treatment.

促肾上腺皮质激素释放因子 (CRF) 和尿皮质素 (Ucn) 的肽拮抗剂对于了解内分泌、免疫、心血管和胃肠道功能对不同应激刺激的反应至关重要。非肽 CRF 拮抗剂被开发用于治疗抑郁症。此外，由于 CRF 受体选择性激动剂和拮抗剂的出现，现在可以更好地了解两种不同 CRF 受体（CRFR1 和 CRFR2）及其亚型的实际功能、分布和特异性。然而，多个 CRF 天然配体（CRF 和 Ucn 1、2 和 3（哺乳动物中的 Ucn 1、2 和 3）以及 CRFR1 和 CRFR2 的广泛分布及其伴随的多种功能调节仍有待整合和理解。该项目有两个互补的终点：a) 结构终点和 b) 药理学/生物学终点。两个终点在很大程度上取决于肽（SPPS）和蛋白质（片段化学连接）的合成。 a) 我们建议与 Riek 博士的项目合作，设计和合成 B1 类 GPCR 的 CRF/Ucn 类似物和细胞外结构域 1 (ECD1)，用于使用 NMR 进行功能和结构研究。初步结果已经建立了 CRFR2 的 ECD1 与 CRF 拮抗剂 astressin B 之间相互作用的模型。其他研究包括 必须确定配体和负责识别和结合初始步骤的相应 ECD 之间的实际接触点。这将通过突变的 ECD1 和所选配体的互补衍生类似物的结合测定来实现。从这些研究中，我们将得出 CRFR1 选择性和 CRFR2 选择性配体的一致生物活性/结合构象以及各自受体的药效团，b) 我们将在模型中使用这些药效团来合理设计新型肽和非肽 CRFR1 和 CRFR2 配体。特别是，我们建议使用几种不同于用于 CRFR1 的方法的方法来设计肽 CRFR1 选择性拮抗剂。 应激强效 CRFR1 选择性激动剂和 astressin2-B（强效长效 CRFR2 选择性拮抗剂）的表征。我们将使用这些选择性和有效的试剂，通过本计划项目内的合作以及与外部研究人员的合作，确定可能治疗的病理生理状态的病因。