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: 9513162
• 负责人: JEF KAREL DE BRABANDER
• 金额: $ 56.7万
• 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: 2017-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9513162
• 关键词: Adverse effects; 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; Circadian Rhythms; Complex; Computer Simulation; Coupling; Crystallization; Data; Development; Disease; Docking; Engineering; Exhibits; Future; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Proteins; Goals; Human; Hypothalamic structure; Knowledge; Lateral; Lead; 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; X-Ray Diffraction; base; 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; simulation; small molecule; structural biology; tool

Project Summary/Abstract 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.

项目概要/摘要 该提案的目标是获得对人类食欲素受体激动剂的生物物理学理解 结合和激活，并利用这些知识开发小分子食欲素受体激动剂 神经药理学工具和嗜睡症/猝倒症和其他疾病的潜在疗法。 发作性睡病是一种终生使人衰弱的疾病，影响着大约 20 万美国人， 其特征是无法保持清醒、睡眠发作、肌肉功能突然丧失和睡眠 麻痹。目前治疗发作性睡病的方法（例如精神兴奋药物）不能治疗潜在的症状 神经化学缺陷并表现出不良副作用。动物模型和人类临床研究 患者表明，发作性睡病是由食欲素（下丘脑分泌素）神经肽缺乏引起的。 下丘脑外侧神经元的研究表明，外源性替代食欲素活性可能会治愈这种疾病。 然而，食欲素不能用作治疗剂，因为它们是肽，不能渗透到体内。 血脑屏障，口服后因代谢分解而活性较差。 我们建议利用 GPCR 结构生物学的新技术来确定 X 射线结构 食欲素受体处于食欲素结合和小分子激动剂结合状态，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构象的变化 是激动剂结合的结果。在第二个目标中，我们将开发构象特异性纳米抗体 结合并稳定食欲素受体活性状态，并解析纳米抗体共晶结构以了解 连接细胞外神经肽结合位点的跨膜传播的结构变化 和细胞内G蛋白偶联位点。在第三个目标中，我们将把结构见解与 计算对接/模拟和药物化学，以提高小分子的亲和力和效力 先前在高通量筛选中鉴定出的分子食欲素受体激动剂。我们的组合 GPCR 结构生物学、合成和药物化学以及计算化学方面的优势 使我们处于独特的地位，可以设计具有类似药物特性的小分子食欲素模拟物 进一步发展成为治疗发作性睡病和其他神经系统疾病的疗法。