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:
- 金额:$ 56.7万
- 依托单位:
- 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:
- 关键词:Adverse effectsAffectAffinityAgonistAmericanAnimal ModelAntigensAreaBackBasic ScienceBindingBinding SitesBiologicalBiological AssayBiophysicsBlood - brain barrier anatomyBrainCataplexyCellsChimeric ProteinsCircadian RhythmsComplexComputer SimulationCouplingCrystallizationDataDevelopmentDiseaseDockingEngineeringExhibitsFutureG-Protein-Coupled ReceptorsG-substrateGTP-Binding ProteinsGoalsHumanHypothalamic structureKnowledgeLateralLeadLifeLinkLipidsMeasuresMembraneMetabolicMetabolic DiseasesMetabolismMolecular ConformationMuscle functionMuscular AtrophyNarcolepsyNeuronsNeuropeptidesOral AdministrationPatientsPeptidesPharmaceutical ChemistryPharmaceutical PreparationsPhasePhysiologicalPlant RootsPositioning AttributePropertyReceptor ActivationReceptor SignalingRegulationResearchResolutionRoentgen RaysSignal PathwaySignal TransductionSiteSleepSleep ParalysisSleep Wake CycleStructureSynthesis ChemistrySystemTechniquesTherapeuticTherapeutic AgentsTranslatingWakefulnessX ray diffraction analysisX-Ray Diffractionbaseclinical investigationcomputational chemistrydesignexperimental studyextracellularfeedinghigh throughput screeninghuman diseasehypocretinimprovedinnovationinsightmilligrammolecular dynamicsnanobodiesnervous system disorderneurochemistrynovelobesity treatmentorexin B receptorpsychostimulantradioligandreceptorreceptor bindingresearch clinical testingscaffoldsimulationsmall moleculestructural biologytool
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(3)
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JEF KAREL DE BRABANDER其他文献
JEF KAREL DE BRABANDER的其他文献
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{{ truncateString('JEF KAREL DE BRABANDER', 18)}}的其他基金
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 - 财政年份:2017
- 资助金额:
$ 56.7万 - 项目类别:
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:
10241919 - 财政年份:2017
- 资助金额:
$ 56.7万 - 项目类别:
Development of Small Molecule Orexin Receptor Agonists for Treating Narcolepsy
治疗发作性睡病的小分子食欲素受体激动剂的开发
- 批准号:
7829541 - 财政年份:2009
- 资助金额:
$ 56.7万 - 项目类别:
Development of Small Molecule Orexin Receptor Agonists for Treating Narcolepsy
治疗发作性睡病的小分子食欲素受体激动剂的开发
- 批准号:
7937840 - 财政年份:2009
- 资助金额:
$ 56.7万 - 项目类别:
SYNTHESIS OF MARINE DERIVED MACROCYCLIC SALICYLATES
海洋衍生大环水杨酸盐的合成
- 批准号:
7721420 - 财政年份:2008
- 资助金额:
$ 56.7万 - 项目类别:
Identifying the Molecular Targets of Novel Cytotoxic Agents
识别新型细胞毒剂的分子靶点
- 批准号:
7315650 - 财政年份:2007
- 资助金额:
$ 56.7万 - 项目类别:
SYNTHESIS OF MARINE DERIVED MACROCYCLIC SALICYLATES
海洋衍生大环水杨酸盐的合成
- 批准号:
7355164 - 财政年份:2006
- 资助金额:
$ 56.7万 - 项目类别:
SYNTHESIS OF MARINE DERIVED MACROCYCLIC SALICYLATES
海洋衍生大环水杨酸盐的合成
- 批准号:
7180058 - 财政年份:2005
- 资助金额:
$ 56.7万 - 项目类别:
SYNTHESIS OF MARINE DERIVED MACROCYCLIC SALICYLATES
海洋衍生大环水杨酸盐的合成
- 批准号:
6977025 - 财政年份:2003
- 资助金额:
$ 56.7万 - 项目类别:
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