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: 8251668
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251668
• 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 Delivery Systems; 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; Screening procedure; 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; 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. PUBLIC HEALTH RELEVANCE: Many diseases involve problems with the functioning of membrane proteins called ion channels. These proteins are responsible for proper operation of the nervous system, the muscles, and virtually all other physiological events. Drugs that affect ion channel behavior have been developed for a variety of diseases, including heart problems, cystic fibrosis, and other diseases. Ion channels are difficult to study and, because of this, drugs directed at ion channels have been difficult to find. Photoswitch Biosciences proposes to develop methods to increase the ability to study ion channels, and, thus, to increase the number of ion channel drugs.

描述（由申请人提供）：离子通道是允许带电分子选择性移动通过细胞膜的膜蛋白。许多疾病状态，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鉴定为治疗干预的优良靶标，但由于涉及开发高质量、高通量功能性离子通道测定的技术障碍，“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。该拟议的II期SBIR项目的具体目标是：（1）产生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，用于销售给抢先体验合作者。作为具体目标2的一部分，我们将评估照明和检测策略，并实施最合适的。第一个商业化的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。使用全光学技术进行离子通道测定具有优于现有技术的几个优点：（1）消除了用于通道活化的液体添加，（2）对于高通量离子通道药物发现而言高度可扩展，（3）每个数据点的价格比自动电生理学低至少100倍，（4）通道活化比KCl添加快几乎100倍。这种新的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。膜电位的这种控制允许开发可扩展的高通量状态依赖性测定，这在当前技术下是不可能的。这项突破性的技术将最终允许充分利用离子通道作为药物靶点。 公共卫生相关性： 许多疾病都与称为离子通道的膜蛋白的功能有关。这些蛋白质负责神经系统，肌肉和几乎所有其他生理事件的正常运作。已经开发出影响离子通道行为的药物来治疗多种疾病，包括心脏病、囊性纤维化和其他疾病。离子通道很难研究，因此很难找到针对离子通道的药物。Photoswitch Biosciences提出开发方法来增加研究离子通道的能力，从而增加离子通道药物的数量。