Ion Channel Drug Discovery Using Photoswitch Technology

描述(申请人提供)：离子通道是膜蛋白，允许带电分子选择性地通过细胞膜移动。许多疾病状态，如囊性纤维化、肌营养不良、高血压和心律失常都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佳靶点，但由于开发高质量、高通量的功能离子通道分析所涉及的技术障碍，“离子通道药物”的开发一直令人失望。光开关生物科学公司已经开发出一种技术，可以将小的纳米机器连接到离子通道上，从而能够通过光快速和可逆地控制这些蛋白质。这个拟议的第二阶段SBIR项目的具体目标是：(1)产生几个稳定的表达光开关离子通道、辅助通道和测试通道的细胞系；(2)生产三种功能原型仪器，出售给早期访问的合作者。作为具体目标2的一部分，我们将评估照明和检测策略，并实施最合适的策略。将开发的第一批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分析和仪器。与现有技术相比，使用全光学技术进行离子通道分析具有几个优势：(1)无需为通道激活添加液体，(2)用于高通量离子通道药物发现的高可伸缩性，(3)每个数据点的价格至少比自动化电生理学低100倍，(4)通道激活几乎比添加KCl快100倍。这种新的离子通道检测技术最大的好处是能够快速而可靠地控制膜电位。这种膜电位的控制允许开发可扩展的高通量状态依赖分析，这在目前的技术中是不可能的。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。

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.