Performing ADMET Assays in Nanodroplets

在纳米液滴中进行 ADMET 测定

• 批准号: 7056586
• 负责人: ALEXANDER D SHENDEROV
• 金额: $ 12.8万
• 依托单位: NANOLYTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2007-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056586
• 关键词: adsorption; bioassay; biotechnology; cheminformatics; excretion; experimental designs; metabolism; method development; microcapsule; microfluidics; molecular dynamics; molecular probes; nanotechnology; polymerase chain reaction; small molecule; technology /technique development; toxicology

DESCRIPTION (provided by applicant): The objective of this proposal is to develop a fully integrated nanoliter droplet (nanodroplet)-based electrowetting (EW) device to accelerate the drug discovery process, in particular the field of adsorption, distribution, metabolism, excretion, and toxicology (ADMET). Traditionally, drug discovery has been a sequential process from therapeutic target identification/validation to primary screening for initial (lead) chemical compounds to chemical optimization for potency. These steps are followed by ADMET evaluation, pre-clinical/clinical trials, manufacturing and marketing. Recent data suggests 80% of all potential drugs are eliminated from the pipeline due to poor ADMET properties. This observation has caused a dramatic change in the process. The biopharmaceutical industry is now searching for technologies that will enable the simultaneous screening of chemical compounds for optimal therapeutic potency and the most favorable ADMET properties. By promoting only chemical leads that possess this combination of appropriate "drug- like" characteristics, it is predicted that the pharmaceutical development will realize a dramatic cost savings and accelerate the overall drug development process. In Phase I, we intend to demonstrate the applicability of EW to various ADMET methodologies. Several simple biochemical assays have already been demonstrated on our platform. However, for ADMET, more complex systems are often employed. Therefore, our studies will demonstrate the ability to perform microsomal cytochrome P-450 assays, adherent and non-adherent cell-based assays, and quantitative polymerase chain reaction. This family of protocols will serve an experimental foundation for the integration of a large suite of ADMET assays in Phase II. The biochemical versatility of the EW platform is attractive, as are several other features of EW. By utilizing only nanodroplets, each assay requires ~1,000 times less reagents compared to current methods. Thus, precious chemical compounds, target proteins, and cell lines used in the drug screening process are conserved. In addition, EW facilitates the rapid execution of multiple assay protocols concurrently. So, in Phase II, we anticipate a single chip generating greater than 100,000 data points/day. This represents a dramatic increase in through-put versus the industry screening standard. Consequently, the Nanolytics' EW platform is uniquely positioned to help facilitate the acceleration of the drug discovery process. Nanolytics will design and commercialize an instrument that uses extremely small volumes to facilitate the development of effective and safe therapeutic drugs. Based on current data, implementation of this kind of instrument would represent the single largest cost savings opportunity for biopharmaceutical companies.

描述（由申请人提供）：本提案的目的是开发一种完全集成的基于纳升液滴（nanodroplet）的电润湿（EW）设备，以加速药物发现过程，特别是吸附、分布、代谢、排泄和毒理学（ADMET）领域。传统上，药物发现一直是一个顺序的过程，从治疗靶点鉴定/验证到初始（先导）化合物的初步筛选，再到效力的化学优化。这些步骤之后是ADMET评价、临床前/临床试验、生产和上市。最近的数据表明，80%的潜在药物由于ADMET性能差而被淘汰。这一观察结果导致了这一进程的巨大变化。生物制药行业现在正在寻找能够同时筛选化合物以获得最佳治疗效力和最有利的ADMET特性的技术。通过仅促进具有适当的“药物样”特征的这种组合的化学先导物，预测药物开发将实现显著的成本节约并加速整个药物开发过程。在第一阶段，我们打算证明EW的适用性，各种ADMET方法。我们的平台上已经展示了几种简单的生化分析。然而，对于ADMET，通常采用更复杂的系统。因此，我们的研究将证明进行微粒体细胞色素P-450测定、粘附和非粘附细胞测定以及定量聚合酶链反应的能力。这一系列方案将为II期中大量ADMET检测试剂盒的整合奠定实验基础。电子战平台的生化多功能性是有吸引力的，电子战的其他几个特点也是如此。通过仅使用纳米液滴，与当前方法相比，每个检测需要的试剂减少约1，000倍。因此，药物筛选过程中使用的珍贵化合物、靶蛋白和细胞系得以保存。此外，EW还可同时快速执行多个检测方案。因此，在第二阶段，我们预计单个芯片每天产生超过10万个数据点。这代表了与行业筛选标准相比吞吐量的显著增加。因此，Nanolytics的EW平台具有独特的定位，有助于加速药物发现过程。Nanolytics将设计并商业化一种使用极小体积的仪器，以促进有效和安全的治疗药物的开发。根据目前的数据，这种工具的实施将是生物制药公司节省成本的最大机会。