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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘