Development of Chemical Probes for KCNQ Potassium Channels

KCNQ钾通道化学探针的研制

• 批准号: 7694079
• 负责人: Min Li
• 金额: $ 2.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7694079
• 关键词: Alleles; Animal Model; Biological Assay; Brain; Cardiac; Cell Line; Characteristics; Chemicals; Chemosensitization; Chinese Hamster Ovary Cell; Clinical; Code; Convulsants; Coupled; Cyclohexanones; Development; Disease; Epilepsy; Familial benign neonatal epilepsy; Family; Fluorescence; Foundations; Frequencies; G Protein-Coupled Receptor Signaling; Genes; Heart; Heart Diseases; Hormones; Human; Human Genome; Immune response; Ion Channel; Ion Channel Protein; Ions; Lead; Libraries; Ligands; Live Birth; Mediating; Membrane; Membrane Potentials; Molecular Cloning; Molecular Target; Muscarinic Acetylcholine Receptor; Mutation; Neurons; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Potassium; Potassium Channel; Protein Isoforms; Protocols documentation; Reagent; Reporting; Research; Rest; Sequence Homology; Signal Transduction; Specificity; Structure; Therapeutic; Tissues; Treatment Efficacy; Voltage-Gated Potassium Channel; Work; analytical tool; assay development; base; channel blockers; design; gamma-Aminobutyric Acid; high throughput screening; improved; inhibitor/antagonist; insight; member; novel; public health relevance; scaffold; small molecule; success; therapeutic development; tool; voltage

DESCRIPTION (provided by applicant): Voltage-gated potassium channels are critical for neuronal function. There are estimated 160 genes encoding different but highly homologous potassium channels in humans. Because of the considerable sequence homology, gene-specific channel modulators are very rare but they are sought-after reagents both for investigating channel function and developing therapeutics. The KCNQ (or Kv7) channel family includes five members: KCNQ1 to KCNQ5. Evidence from patient studies and animal models has shown that a small change in KCNQ expression by as little as 25% can cause disease conditions such as epilepsy. Therefore, chemical probes would be powerful analytical tools to investigate the structure and function of voltage-gated potassium channels, and in the case of KCNQ, these compounds may be very valuable for therapeutic development. To perform a large-scale compound screen, KCNQ channel cell lines have been generated and an HTS-ready protocol has been developed and optimized. The present application seeks to conduct a large scale compound screen using the developed assay. The specific aims of the proposal are: 1. To effectively work with the NIH-assigned MLPCN center to perform a large compound library (>100,000 compounds) and validate lead compounds that specifically ACTIVATE the heteromultimeric KCNQ2/3 potassium channel 2. To conduct the secondary assays and counter screen against KCNQ1, 4 and 5. 3. To perform initial characterization to allow for selection of potent lead compounds for detail functional analyses. The success of this project will lead to identification of novel compounds that are useful for developing therapeutics and investigating M-current and KCNQ ion channel function. PUBLIC HEALTH RELEVANCE: Small molecules that regulate ion flux are important tools to develop drugs to treat brain and heart diseases. They are also useful research probes to understand structure and function of ion channel proteins which mediate membrane ionic flux. This proposal is aimed at carrying out a screen of large compound library in an effort of finding novel chemical modulators for ion channels.

描述（由申请人提供）：电压门控钾通道对神经元功能至关重要。据估计，人类中有160个基因编码不同但高度同源的钾通道。由于相当大的序列同源性，基因特异性通道调节剂是非常罕见的，但它们是研究通道功能和开发治疗剂的抢手试剂。KCNQ（或Kv 7）通道家族包括五个成员：KCNQ 1至KCNQ 5。来自患者研究和动物模型的证据表明，KCNQ表达的25%的微小变化可能导致癫痫等疾病。因此，化学探针将是研究电压门控钾通道的结构和功能的强大分析工具，并且在KCNQ的情况下，这些化合物可能对治疗开发非常有价值。为了进行大规模的化合物筛选，已经产生了KCNQ通道细胞系，并且已经开发和优化了HTS就绪方案。本申请寻求使用所开发的测定法进行大规模化合物筛选。该提案的具体目标是：1。与NIH指定的MLPCN中心有效合作，建立大型化合物库（> 100，000种化合物），并验证特异性激活异源多聚体KCNQ 2/3钾通道2的先导化合物。对KCNQ 1、4和5进行二次检测和计数筛选。3.进行初步表征，以选择有效的先导化合物进行详细的功能分析。该项目的成功将导致鉴定新的化合物，这些化合物可用于开发治疗方法和研究M-电流和KCNQ离子通道功能。 公共卫生相关性：调节离子流的小分子是开发治疗脑和心脏疾病药物的重要工具。它们也是了解介导膜离子通量的离子通道蛋白的结构和功能的有用的研究探针。本研究的目的是筛选大型化合物库，寻找新型的离子通道化学调节剂。