A Novel High Throughput Assay for Ion Channel Modulators

描述(申请人提供)：离子通道包括10-20%的已知药物靶标，用于治疗各种疾病，包括心律失常、中风、高血压、心力衰竭、哮喘、囊性纤维化、癫痫、偏头痛、精神障碍、肌肉营养不良和癌症。虽然离子通道提供了重要的治疗靶点，但它们往往是不受欢迎的药物相互作用的焦点，导致潜在的严重副作用。心脏钾通道HERG是频繁的有害药物相互作用的一个例子；阻断HERG可使个人容易发生心律失常。鉴于离子通道靶标的双重性质，需要高通量分析来解决治疗潜力和药物安全问题。ChanTest是一家离子通道公司，致力于为生物制药行业提供涉及离子通道的药物安全测试和药物发现的技术服务，该公司正在开发能够满足这两种需求的新型高通量屏幕。这些专利分析使用基于抗体的化学发光反应来监测离子通道的表达水平。这项建议的目标是开发使用HERG钾通道的分析方法，用于两个目的：1)HTXpress：高通量筛选各种化合物文库，在不影响通道动力学特性的情况下增加或降低HERG表达，以及2)HERG-Lite：高通量药物安全筛选，使用突变的HERG通道表面表达增加作为阻断生物传感器来识别阻断HERG的药物。对于HTXpress来说，这项建议的具体目标是通过筛选包含800多种化合物的结构多样化的化学库来优化分析。识别离子通道表达调节剂，即新型的激动剂和拮抗剂，是药物开发中一个尚未开发的领域，可以很容易地应用于HERG以外的通道。关于HERG-Lite，目的是验证该检测作为HERG块的快速安全测试的使用。80种药物(一半已知的HERG阻滞剂和一半的非阻滞剂)将在表达试验中进行行为检测。它们的效力和排列顺序将与标准电生理测量所检测的Herg块进行比较。其目标是将Herg-Lite作为一种快速、廉价和灵敏的筛查引入制药业，用于药物开发的早期HERG安全测试。

DESCRIPTION (provided by applicant): Ion channels comprise 10-20 percent of known drug targets for diseases including cardiac arrhythmias, stroke, hypertension, heart failure, asthma, cystic fibrosis, epilepsy, migraine, mental disorders, muscular dystrophy, and cancer. While ion channels provide important therapeutic targets, they are often the focal point of unwanted drug interactions leading to potentially serious side effects. The cardiac potassium channel hERG is an example of frequent unwanted drug interactions; block of hERG can predispose individuals to cardiac arrhythmias. Given the dual nature of ion channel targets, there is a need for high throughput assays that address the therapeutic potential as well as the drug safety issue. ChanTest, an ion channel company dedicated to providing technology services to the biopharmaceutical industry for drug safety testing and drug discovery involving ion channels, is developing novel high throughput screens that can address both needs. These proprietary assays monitor the level of expression of ion channels using an antibody-based chemiluminescent reaction. The goals of this proposal are to develop assays using the hERG potassium channel for two purposes: 1) HTXpress: high throughput screening of diverse chemical libraries for compounds which either increase or decrease hERG expression without affecting the kinetic properties of the channel, and 2) hERG-Lite: high throughput drug safety screening to identify drugs which block hERG using increased surface expression of mutant hERG channels as a biosensor for block. For HTXpress, the specific aim of this proposal is to optimize the assay by screening a structurally diverse chemical library of over 800 compounds. The identification of ion channel expression modulators, i.e. novel agonists and antagonists, is an untapped area of drug development and can be easily applied to channels other than hERG. With respect to hERG-Lite, the goal is to validate the use of this assay as a rapid safety test for hERG block. Eighty drugs (half known hERG blockers and half nonblockers) will be assayed for their behavior in the expression assay. Their potencies and rank order will be compared to hERG block assayed by standard electrophysiological measurements. The goal is to introduce hERG-Lite to the pharmaceutical industry as a rapid, inexpensive, and sensitive screen for hERG safety testing early in drug development.