New sterol-binding targets and optimized EBP inhibitors for promoting remyelination
用于促进髓鞘再生的新甾醇结合靶点和优化的 EBP 抑制剂
基本信息
- 批准号:10544790
- 负责人:
- 金额:$ 40.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAffinityAntihistaminesAxonBindingBiologyBrainBrain StemCell physiologyCellsCentral Nervous SystemChemicalsCholesterolClinicalDataDemyelinating DiseasesDevelopmentDiseaseDrug TargetingEnhancersEnzyme InhibitionEnzymesFDA approvedFamilyFutureGoalsHumanImmuneImmune systemIn VitroLeadLibrariesLipidsMass Spectrum AnalysisMediatingMedicineMembraneModelingMultiple SclerosisMusMyelinNatural regenerationNatureNeural ConductionNeurologic DeficitNeuronsNeurophysiology - biologic functionOligodendrogliaOptic NerveOptic NeuritisOrganic SynthesisOrganoidsPathway interactionsPatientsPharmaceutical ChemistryPharmaceutical PreparationsPropertyProteinsProteomePublishingReagentReportingResearch PersonnelRoleSeriesSignal TransductionSignaling MoleculeSteroidsSterolsStructure-Activity RelationshipTechniquesTestingTherapeuticWorkbrain cellcellular targetingcholesterol biosynthesisdisabilitydrug candidatedrug developmentdrug discoveryenzyme biosynthesishigh throughput screeningimmunoregulationin vivoin vivo evaluationinhibitorinnovationmouse modelmultidisciplinarymultiple sclerosis patientnervous system disordernew therapeutic targetnoveloligodendrocyte progenitoroxysterol binding proteinpreventreceptorregenerative therapyremyelinationrepairedscreeningsmall moleculesmall molecule librariesstem cellssuccesstool
项目摘要
ABSTRACT
Demyelinating diseases, including multiple sclerosis, are characterized by loss of myelin-producing
oligodendrocytes in the central nervous system and cause severe disability for millions of patients.
Existing therapies for MS exclusively modulate the immune system to prevent additional myelin loss;
no regenerative therapies are available that replenish lost oligodendrocytes and repair lost myelin.
Multiple researchers have used high-throughput screening of small-molecule libraries to identify drugs
that increase the formation of oligodendrocytes from oligodendrocyte progenitor cells (OPCs) in vitro
and enhance functional remyelination in vivo. One such molecule, the FDA-approved antihistamine
clemastine, was recently shown to enhance optic nerve conduction velocity in MS patients with optic
neuritis, providing the first clinical evidence that small molecule treatments can enhance remyelination
in the human CNS.
While this trial provides proof-of-concept for future remyelinating therapeutics, greater clarity around
the optimal pathways and targets controlling oligodendrocyte formation is critical to the success of
future translational efforts. Our multi-disciplinary team has leveraged synergistic expertise in glial
biology, chemical biology, and organic synthesis to provide compelling preliminary evidence, now
published in Nature and Cell Chemical Biology, that almost all promyelinating small molecules identified
by HTS enhance oligodendrocyte formation by inhibiting a small number of adjacent enzymes within
cholesterol biosynthesis. Inhibition of these enzymes causes accumulation of specific, structurally-
related cholesterol precursors (8,9-unsaturated sterols) which are sufficient to enhance the formation
of oligodendrocytes from OPCs. Mass spectrometry-based sterol profiling has demonstrated more
than three dozen promyelinating small molecules function by this mechanism, including clemastine.
This application advances two parallel goals. First, we seek to understand how 8,9-unsaturated sterol
accumulation drives oligodendrocyte formation, including defining the optimal sterols and elucidating
their cellular target (Aims 1 and 2). Additionally, we aim to optimize the first selective and brain-
penetrant EBP inhibitor and to validate that this molecule promotes remyelination in vivo and human
myelin formation in vitro (Aim 3). Organic synthesis is a key technique throughout the application,
enabling the synthesis of novel 8,9-unsaturated sterols (Aim 1), photoaffinity pulldown reagents (Aim
2), and novel derivatives of our recently-published EBP-inhibiting lead molecules CW9009 and
CW9956. Together these studies will accelerate the emerging field of remyelinating therapeutics by
developing optimized small molecules for further drug development and identifying novel drug targets
that underlie the oligodendrocyte-enhancing effects of 8,9-unsaturated sterols.
摘要
脱髓鞘疾病,包括多发性硬化症,以髓鞘生成丧失为特征。
中枢神经系统中的少突胶质细胞,并导致数百万患者严重残疾。
现有的治疗多发性硬化症的方法仅限于调节免疫系统,以防止额外的髓鞘丢失;
目前还没有可用于补充丢失的少突胶质细胞和修复丢失的髓鞘的再生疗法。
多名研究人员已经使用小分子文库的高通量筛选来识别药物
促进少突胶质前体细胞(OPC)在体外形成少突胶质细胞
并在体内增强功能性再髓鞘形成。FDA批准的抗组胺药物就是这样一种分子
氯马斯汀最近被证明可以提高MS患者的视神经传导速度
神经炎,提供了小分子治疗可以促进髓鞘再生的第一个临床证据
在人类中枢神经系统中。
虽然这项试验为未来的重新髓鞘疗法提供了概念验证,但更清楚的是
控制少突胶质细胞形成的最佳途径和靶点是成功的关键
未来的翻译工作。我们的多学科团队利用了Glial方面的协同专业知识
生物学、化学生物学和有机合成提供令人信服的初步证据,现在
发表在《自然》和《细胞化学生物学》上,几乎所有的早髓鞘小分子都被发现
HTS通过抑制体内少量相邻酶促进少突胶质细胞的形成
胆固醇的生物合成。抑制这些酶会导致特定的、结构上的-
相关的胆固醇前体(8,9-不饱和甾醇),足以促进形成
来自OPC的少突胶质细胞。基于质谱学的甾醇图谱显示了更多
30多个早髓鞘小分子通过这种机制发挥作用,包括克莱斯汀。
这个应用程序提出了两个并行的目标。首先,我们试图了解8,9-不饱和甾醇是如何
积聚驱动少突胶质细胞的形成,包括定义最适的甾醇和阐明
他们的细胞目标(目标1和2)。此外,我们的目标是优化第一个选择性和大脑-
渗透性EBP抑制剂,并验证该分子促进体内和人的再髓鞘形成
体外髓鞘形成(目标3)。有机合成是贯穿整个应用的关键技术,
能够合成新型8,9-不饱和甾醇(AIM 1)、光亲和下拉试剂(AIM
2),以及我们最近发表的抑制EBP的铅分子CW9009和CW9009的新衍生物
CW9956。总之,这些研究将通过以下方式加速重新髓鞘疗法的新兴领域
为进一步的药物开发和确定新的药物靶点开发优化的小分子
这是8,9-不饱和甾醇增强少突胶质细胞作用的基础。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Drew James Adams其他文献
Drew James Adams的其他文献
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{{ truncateString('Drew James Adams', 18)}}的其他基金
Selective Inhibitors of T Cell Activation Target Exportin-1 at Cys528 to Suppress Pathological T Cell Activation
T 细胞激活的选择性抑制剂 Cys528 靶点 Exportin-1 抑制病理性 T 细胞激活
- 批准号:
10659905 - 财政年份:2023
- 资助金额:
$ 40.48万 - 项目类别:
New sterol-binding targets and optimized EBP inhibitors for promoting remyelination
用于促进髓鞘再生的新甾醇结合靶点和优化的 EBP 抑制剂
- 批准号:
10327726 - 财政年份:2020
- 资助金额:
$ 40.48万 - 项目类别:
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