Ion Channel Drug Discovery Using Photoswitch Technology

使用光开关技术进行离子通道药物发现

• 批准号: 8417658
• 负责人: Andrew Blatz
• 金额: $ 60万
• 依托单位: PHOTOSWITCH BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-04 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417658
• 关键词: Affect; Area; Arrhythmia; Beds; Behavior; Biological Assay; Cell Culture Techniques; Cell Line; Cells; Cellular Membrane; Charge; Complement; Computer software; Cystic Fibrosis; Detection; Development; Devices; Disadvantaged; Disease; Drug Targeting; Dyes; Economics; Electrophysiology (science); Ensure; Event; Exhibits; Fluorescence; Generations; Goals; Heart; Hypertension; Industry; Ion Channel; Light; Lighting; Liquid substance; Market Research; Measures; Membrane Potentials; Membrane Proteins; Methods; Movement; Muscle; Muscular Dystrophies; Nervous system structure; Optics; P-Q type voltage-dependent calcium channel; Pathology; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiological; Price; Proteins; Protocols documentation; Reader; Reagent; Reporting; Research; Rest; Sales; Small Business Innovation Research Grant; System; Techniques; Technology; Testing; Therapeutic Intervention; Tube; assay development; base; charge coupled device camera; commercialization; design; detector; drug discovery; insight; instrument; instrumentation; inward rectifier potassium channel; light intensity; meetings; nanomachine; novel; operation; phase 1 study; photomultiplier; prototype; quantum; response; screening; software development; stable cell line; success; voltage

DESCRIPTION (provided by applicant): Ion channels are membrane proteins that allow the selective movement of charged molecules through cellular membranes. Many disease states, such as cystic fibrosis, muscular dystrophies, hypertension, and cardiac arrhythmias are caused by ion channel pathologies. Ion channels have been identified by the drug discovery industry as excellent targets for therapeutic intervention but because of the technical hurdles involved in developing quality, high- throughput functional ion channel assays, the development of "ion channel drugs" has been disappointing. Photoswitch Biosciences has developed technology, which allows attaching small nanomachines to ion channels enabling rapid and reversible control of these proteins by light. The Specific Aims of this proposed Phase II SBIR project are: (1) generation of several stable cell lines expressing photoswitched ion channels, accessory channels, and test channels; (2) produce three functional prototype instruments for sale to early access collaborators. As part of Specific Aim 2 we will evaluate illumination and detection strategies and implement the most appropriate. The first commercial products to be developed will be all-optical ion channel assays and instruments for high- throughput ion channel drug discovery. The use of all-optical technology for ion channel assays has several advantages over existing techniques: (1) Elimination of liquid additions for channel activation, (2) Highly scalabl for high-throughput ion channel drug discovery, (3) Price per datapoint is at least 100X less than automated electrophysiology, (4) Channel activation is almost 100X faster than KCl addition. The most important benefit of this new ion channel assay technology is the ability to rapidly and reliably control membrane potential. This control of membrane potential allows for the development of scalable high-throughput state-dependent assays, which is impossible with current technology. This breakthrough technology will finally allow the full exploitation of ion channels as drug targets.

描述（由申请人提供）：离子通道是允许带电分子通过细胞膜选择性移动的膜蛋白。许多疾病状态，例如囊性纤维化、肌营养不良、高血压和心律失常是由离子通道病理引起的。离子通道已被药物发现行业确定为治疗干预的极好靶标，但由于开发高质量、高通量功能性离子通道测定法所涉及的技术障碍，“离子通道药物”的开发一直令人失望。 Photoswitch Biosciences 开发了一种技术，可以将小型纳米机器连接到离子通道上，从而通过光快速、可逆地控制这些蛋白质。拟议的第二阶段 SBIR 项目的具体目标是：（1）生成几种表达光开关离子通道、辅助通道和测试通道的稳定细胞系； (2) 生产三种功能原型仪器以出售给早期合作者。作为特定目标 2 的一部分，我们将评估照明和检测策略并实施最合适的策略。第一批开发的商业产品将是用于高通量离子通道药物发现的全光学离子通道测定和仪器。与现有技术相比，使用全光学技术进行离子通道测定有几个优点：(1) 消除了通道激活的液体添加，(2) 高通量离子通道药物发现的高度可扩展性，(3) 每个数据点的价格至少比自动电生理学低 100 倍，(4) 通道激活几乎比添加 KCl 快 100 倍。这种新型离子通道测定技术最重要的好处是能够快速可靠地控制膜电位。这种膜电位的控制允许开发可扩展的高通量状态依赖性测定，这在当前技术中是不可能的。这项突破性技术最终将允许充分利用离子通道作为药物靶点。