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A Pharmacochaperone-based strategy for identifying chemical probes of brain-derived orphan GPCRs

A Pharmacochaperone-based strategy for identifying chemical probes of brain-derived orphan GPCRs
基于药物伴侣的策略,用于识别脑源性孤儿 GPCR 的化学探针
批准号:
10183333
负责人:
Michael Jackson
金额:
$87.6万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-06-05 至 2025-03-31

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中文摘要
翻译
项目摘要 没有什么地方比在治疗中更迫切地需要疾病修饰治疗化合物 精神健康障碍尽管在药物和行为干预方面取得了重大进展, 精神分裂症、抑郁症和焦虑症等疾病与药物滥用障碍相结合, 给社会带来越来越大的负担。孤儿G蛋白偶联受体(oGPCR)代表了一种 这些疾病的潜在新药靶点尚未开发,但缺乏药理学工具 需要验证这些目标,以防止其治疗利用。作为利用这一点的第一步, 为了开发新的药物类别,我们建议找到结合oGPCR的化合物, 用于验证它们是否为药物靶点。利用最近的高分辨率基因表达图谱, 重要的大脑回路,我们确定了27个oGPCR,其在人脑中的离散表达模式 使其成为高价值的神经科学药物靶点。根据《公约》的规定, 每个受体的生物学数据(如遗传学、与疾病的联系),目标是 与心理健康相关性最大的oGPCR。对于前10个优先目标,我们将进行高通量 使用创新的配体诱导的正向运输试验对约50,000种化合物的库进行筛选 我们最近发表的。在该测定中,每个oGPCR被工程化以保留在内质网中,从而使oGPCR在细胞中的表达增加。 一种通过结合配体实现正向运输的状态。因此,贩运oGPCR是 使用分裂β-半乳糖苷酶报告系统监测。以这种方式,结合并诱导 将鉴定oGPCR中的构象变化。使用一组交叉和计数器筛选测定, 将确认命中并显示与天然oGPCR接合。药物化学将用于改善 效力和选择性,并产生具有物理化学属性的化学探针, 探索靶oGPCR的功能和药理学的细胞测定。探针的选择性将是 使用包括GPCR、离子通道、核受体和酶在内的多种靶点进行评估。 当特异性oGPCR在人iPSC衍生的神经元培养物中高度表达时,我们将研究其在人iPSC衍生的神经元中的表达。 使用微电极阵列测定系统的特异性受体的探针影响神经网络的能力 我们开发的。我们预计这些努力将产生>10种针对高优先级oGPCR的新型探针。 我们的目的是迅速将这些分发给科学界,以加速对这些问题的理解。 大脑富集的oGPCR,有助于验证它们作为心理障碍的药物靶标。
英文摘要
PROJECT SUMMARY Nowhere is the need for disease modifying therapeutic compounds more urgently needed than in the treatment of mental health disorders. Despite significant advances in pharmaceutical and behavior interventions, mental illnesses such as schizophrenia, depression and anxiety, combined with substance abuse disorders remain a significant and growing burden to society. Orphan G-protein coupled receptors (oGPCRs) represent an untapped reservoir of potential new drug targets for these diseases but the lack of pharmacological tools needed to validate these targets prevents their therapeutic exploitation. As a first step towards tapping this reservoir to develop new classes of medicines, we propose to find compounds that bind the oGPCRs and can be used to validate them as drug targets. Leveraging recent high-resolution gene expression maps of important brain circuits, we identified 27 oGPCRs whose discrete patterns of expression in the human brain make them high value neuroscience drug targets. These were further prioritized based on the body of biological data available for each receptor (e.g. genetics, linkage to disease) with the goal of focusing on oGPCRs of greatest relevance to mental health. For the top 10 priority targets we will conduct high-throughput screens against a library of ~50,000 compounds using an innovative ligand-induced forward trafficking assay we recently published. In this assay, each oGPCR is engineered to be retained in the endoplasmic reticulum in a state in which forward transport is enabled by the binding of a ligand. Trafficking of the oGPCR is then monitored using a split beta-galactosidase reporter system. In this way, compounds (hits) that bind and induce a conformational change in the oGPCR will be identified. Using a panel of cross and counter screen assays, hits will be confirmed and shown to engage native oGPCR. Medicinal chemistry will be used to improve potency and selectivity, and to generate chemical probes with physicochemical attributes suitable for use in cellular assays exploring the function and pharmacology of target oGPCRs. Selectivity of probes will be evaluated using a diverse panel of targets including GPCRs, ion channels, nuclear receptors and enzymes. Where a specific oGPCR is highly expressed in human iPSC-derived neuronal cultures, we will investigate the ability of probes to the specific receptor to affect neural networks using a microelectrode array assay system we developed. We anticipate that these efforts will generate >10 novel probes against high priority oGPCRs. Our intention is to rapidly distribute these to the scientific community to accelerate the understanding of these brain enriched oGPCRs, contributing to their validation as drug targets for psychological disorders.
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Targeting the mutant promoter of Telomerase Reverse Transcriptase (TERT)
  • 批准号:
    10677899
  • 项目类别:
  • 资助金额:
    $77.22万
  • 财政年份:
    2023
  • 负责人:
    Michael Jackson
  • 依托单位:
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