Structural elucidation and development of agonists for the human orexin receptors

人类食欲素受体激动剂的结构阐明和开发

• 批准号: 9751989
• 负责人: JEF KAREL DE BRABANDER
• 金额: $ 55.63万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751989
• 关键词: Affect; Affinity; Agonist; American; Animal Model; Antigens; Area; Back; Basic Science; Binding; Binding Sites; Biological; Biological Assay; Biophysics; Blood - brain barrier anatomy; Brain; Cataplexy; Cells; Chimeric Proteins; Complex; Computer Simulation; Coupling; Crystallization; Data; Development; Disease; Docking; Engineering; Exhibits; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Human; Hypothalamic structure; Knowledge; Lateral; Life; Link; Lipids; Measures; Membrane; Metabolic; Metabolic Diseases; Metabolism; Molecular Conformation; Muscle function; Muscular Atrophy; Narcolepsy; Neurons; Neuropeptides; Oral Administration; Patients; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Physiological; Plant Roots; Positioning Attribute; Property; Receptor Activation; Receptor Signaling; Regulation; Research; Resolution; Roentgen Rays; Signal Pathway; Signal Transduction; Site; Sleep; Sleep Paralysis; Sleep Wake Cycle; Structure; Synthesis Chemistry; System; Techniques; Therapeutic; Therapeutic Agents; Translating; Wakefulness; X ray diffraction analysis; base; circadian; clinical investigation; computational chemistry; design; experimental study; extracellular; feeding; high throughput screening; human disease; hypocretin; improved; innovation; insight; milligram; molecular dynamics; nanobodies; nervous system disorder; neurochemistry; novel; obesity treatment; orexin B receptor; psychostimulant; radioligand; receptor; receptor binding; research clinical testing; scaffold; side effect; simulation; small molecule; structural biology; therapeutic lead compound; tool

The goal of this proposal is to gain a biophysical understanding of human orexin receptor agonist binding and activation, and to use this knowledge to develop small-molecule orexin receptor agonists as neuropharmacological tools and potential therapeutics for narcolepsy/cataplexy and other diseases. Narcolepsy is a life-long debilitating disorder affecting approximately 200,000 Americans, which is characterized by an inability to maintain wakefulness, sleep attacks, sudden loss of muscle function, and sleep paralysis. Current treatments for narcolepsy (such as psychostimulant drugs) do not treat the underlying neurochemical deficits and exhibit undesirable side-effects. Animal models and clinical investigations of human patients show that narcolepsy is caused by deficiency of the orexin (hypocretin) neuropeptides produced by neurons of the lateral hypothalamus, and that exogenous replacement of orexin activity may cure the disease. However, orexins cannot be used as therapeutic agents because they are peptides, which do not penetrate the blood-brain barrier and show poor activity after oral administration due to metabolic decomposition. We propose to use new technical advances in GPCR structural biology to determine X-ray structures of the orexin receptors in orexin-bound and small-molecule agonist-bound states, revealing the detailed non- covalent interactions that stabilize these complexes as well as changes in conformation of the receptors that are a consequence of agonist binding. In the second Aim, we will develop conformation-specific nanobodies that bind and stabilize the orexin receptor active state, and solve nanobody co-crystal structures to understand the propagated structural changes across the membrane that link the extracellular neuropeptide binding site and the intracellular G protein coupling site. In the third Aim, we will integrate structural insights with computational docking/simulation and medicinal chemistry to improve the affinity and potency of small- molecule orexin receptor agonists that were previously identified in a high-throughput screen. Our combination of strengths in GPCR structural biology, synthetic and medicinal chemistry, and computational chemistry places us in a unique position to design small-molecule orexin mimics with drug-like properties that can be further developed into therapeutics for the treatment of narcolepsy and other neurological disorders.

该提案的目的是获得对人Orexin受体激动剂的生物物理理解 结合和激活，并利用这些知识来发展小分子奥列海素受体激动剂作为 神经药理学工具和潜在的睡病/瘫痪和其他疾病的疗法。 睡病是一种终身衰弱的疾病，影响了约20万美国人，这是 其特征是无法保持清醒，睡眠攻击，突然肌肉功能和睡眠 麻痹。目前对睡病的治疗方法（例如精神刺激药物）不治疗潜在的 神经化学缺陷和表现出不良的副作用。动物模型和人类的临床研究 患者表明，发作性疾病是由由Orexin（低孔蛋白）神经肽的缺乏引起的 下丘脑外侧的神经元，以及外源性替代Orexin活性可能治愈该疾病。 但是，甲虫不能用作治疗剂，因为它们是肽，不会穿透 由于代谢分解，口服给药后血脑屏障和活性较差。 我们建议使用GPCR结构生物学的新技术进步来确定 奥雷敦蛋白结合和小分子激动剂结合的状态中的Orexin受体，揭示了详细的非 - 稳定这些复合物的共价相互作用以及受体的构象变化 是激动剂结合的结果。在第二个目标中，我们将开发特定于构象的纳米体 结合和稳定Orexin受体活性状态，并求解纳米植物的共结晶结构 在整个膜之间的传播结构变化，这些变化连接了细胞外神经肽结合位点 和细胞内G蛋白偶联位点。在第三个目标中，我们将结构性见解与 计算对接/模拟和药物化学，以提高小型的亲和力和效力 先前在高通量筛选中鉴定出来的分子或分子蛋白受体激动剂。我们的组合 GPCR结构生物学，合成和药物化学以及计算化学的优势 将我们处于设计小分子或具有类似药物特性的小分子的独特位置 进一步发展为治疗麻醉症和其他神经系统疾病的治疗剂。