Development of Chemical Probes to Investigate Adhesion GPCR Tethered Agonism

开发用于研究粘附 GPCR 系链激动作用的化学探针

基本信息

批准号：
9917826
负责人：
Gregory Gordon Tall
金额：
$ 48.77万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917826
关键词：
ADGR1 gene Adhesions Adult Affinity Agonist Bilateral Binding Biochemical Biological Assay Brain Brain Injuries Cell Adhesion Cell Adhesion Molecules Cell Proliferation Cells Chemicals Chemistry Collaborations Collection Databases Deposition Development Disease Dissociation Engineering Enzymes Event Exhibits Fractionation Functional disorder G-Protein Signaling Pathway G-Protein-Coupled Receptors G13 Protein GTP-Binding Proteins Genomics Goals Growth Heterotrimeric GTP-Binding Proteins Human Informatics Injections Investigation Laboratories Libraries Ligands Luc Gene Luciferases Measures Mediating Michigan Microgyria Modeling Multiple Sclerosis Mutation Myelin Natural Products Nerve Neuraxis Neurodevelopmental Disorder Oligodendroglia Pathway interactions Patients Peptides Pharmaceutical Preparations Physiological Physiology Positioning Attribute Preparation Procedures Process Proteins Receptor Activation Reporter Genes Research Resources Rodent Role Schizophrenia Scientist Screening Result Serum Response Element Signal Transduction System Testing Therapeutic Universities Work base brain malformation counterscreen efficacy testing follow-up high throughput screening inhibitor/antagonist malignant neurologic neoplasms myelination nervous system disorder novel oligodendrocyte precursor peptidomimetics polypeptide precursor cell programs prospective protein activation protein aminoacid sequence protein reconstitution receptor receptor binding receptor function reconstitution repaired restoration scaffold screening small molecule small molecule libraries synthetic peptide therapeutic development therapeutic target tool

项目摘要

Summary/Abstract: GPR56/ADGRG1 is an Adhesion G protein Coupled Receptor (AGPCR) that is required for brain development and function by acting as a critical regulator of the cellular pathway responsible for myelin deposition in the brain. GPR56 mutations cause a debilitating human brain malformation disease. Our recent work unveiled the general AGPCR activation mechanism. AGPCRs are two-fragment receptors that arise from a single polypeptide following a defined self-cleavage event. The physical arrangement of the two bound receptor fragments conceals a peptide sequence, that when revealed by fragment dissociation, serves as a tethered-peptide self-activator (agonist) of the GPCR-like fragment. We used information from our delineation of the AGPCR mechanism to engineer model GPR56 receptors in high and low activity states. These receptors will be used to find small molecule compounds, through screening diverse chemical libraries, that inhibit the high-activity receptors or activate the low-activity receptors. The immediate application of our work will be to develop chemical probes that bind GPR56 for use in investigative studies of physiological AGPCR activation mechanism(s). In the longer term, our chemical scaffolds may be developed as therapeutics to correct defective brain myelination in a variety of disease contexts, including myelin-deficient schizophrenia patients. GPR56 promotes nerve myelination by controlling the growth of oligodendrocyte precursor cells (OPCs). OPCs become mature oligodendrocytes, which are the cells that wrap processes around nerves in the brain to produce the protective myelin coat. Past studies in which OPCs were injected into myelin-deficient rodent brains promoted nerve re-myelination and partial restoration of brain functions. OPC injection into human brains would not be a tenable therapy at present, but use of a new GPR56 activating drug to stimulate growth of natural OPCs might be a more realistic approach. The prospect of directing re- myelination programs in damaged brains by artificially activating GPR56 is a highly appealing goal for patients afflicted with diseases including schizophrenia or multiple sclerosis. We are confident that our endeavors to develop probes for GPR56 will be successful, as our pilot screening efforts with small compound libraries (5346 total compounds from four small libraries) identified a low-affinity, first-in-class GPR56 antagonist and a partial agonist. It is the combination of our well-honed screen and counter-screen assays and our exquisitely tuned G protein reconstitution secondary assays that made our pilot work successful. We are eager to apply our established assays to the large chemical libraries and natural product extract collections at the University of Michigan Center for Chemical Genomics to fulfill the critical, unmet need for AGPCR modulatory compounds.

摘要/摘要：GPR56/ADGRG1是必需的粘附G蛋白偶联受体（AGPCR）通过充当负责的细胞途径的关键调节剂来进行大脑发育和功能大脑中的髓磷脂沉积。 GPR56突变会导致人类脑畸形疾病令人衰弱。我们的最近的工作揭示了一般的AGPCR激活机制。 AGPCR是两碎受体在定义的自我切割事件之后，由单个多肽产生。两者的身体安排绑定的受体片段隐藏了肽序列，当通过片段解离揭示时，会发出作为GPCR样片段的束缚肽自动激活剂（激动剂）。我们使用了我们的信息在高活性状态和低活性状态下，对AGPCR机制的描述为GPR56型号。这些受体将通过筛选各种化学文库，用于查找小分子化合物，抑制高活动性受体或激活低活动性受体。立即应用我们工作将是开发结合GPR56的化学探针，用于生理研究 AGPCR激活机制。从长远来看，我们的化学支架可能会开发为在多种疾病中纠正脑部有缺陷的大脑髓鞘化的治疗剂，包括髓磷脂缺陷精神分裂症患者。 GPR56通过控制少突胶质细胞的生长来促进神经髓鞘前体细胞（OPC）。 OPC成为成熟的少突胶质细胞，这是包裹过程的细胞在大脑中的神经周围产生保护性髓磷脂外套。将OPC注入的过去的研究进入缺陷髓磷脂的啮齿动物大脑促进了神经重新髓鞘和脑功能的部分恢复。 OPC注入人的大脑目前不是一种可替代的疗法，而是使用新的GPR56激活刺激天然OPC生长的药物可能是一种更现实的方法。指导重新的前景人工激活GPR56在受损大脑中的髓鞘化程序对于患者来说是一个极具吸引力的目标患有精神分裂症或多发性硬化症在内的疾病。我们有信心我们努力 GPR56的开发探针将是成功的，因为我们在小型复合图书馆的飞行员筛选工作（来自四个小型文库的5346种化合物）确定了低亲和力，一流的GPR56拮抗剂和A 部分激动剂。这是我们良好的屏幕和反屏幕测定的结合以及我们精美的调谐G蛋白重建的次要测定，使我们的飞行员工作成功。我们渴望申请我们对大型化学图书馆和自然产品提取物收集的既定测定法密歇根化学基因组学中心满足了对AGPCR调节的关键，未满足的需求化合物。