Novel high-throughput approaches for the rapid analysis of target engagement by mass spectrometry

通过质谱快速分析目标参与的新颖高通量方法

• 批准号: 2444767
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2444767
• 关键词: Novel; throughput; approaches; rapid; analysis

The ability to provide fast and efficient readouts for drug engagement with biomolecular targets is a key driving technology in the biopharma pipeline, e.g. in high-throughput screening. Optical readouts are common but provide a somewhat binary answer, whereas the application of mass spectrometry (MS) to target heterogeneity, stoichiometry of binding and also structural effects (using ion mobility) has so far been hampered by the lack of robustness and the low-throughput of currently used sample inlet methods. This was recognized when a novel acoustic liquid-handling approach ("Echo") with a capability of injecting 10,000 samples/hour was first adapted to MS analysis. This technology, now hosted at the Medicines Discovery Catapult (MDC, Alderley Edge), enables high-throughput assays for ligand screening (direct binding detection). We are developing novel in-line separation and purification methods as well as further developing droplet-based inlet systems in collaboration with colleagues at Leeds' Engineering department. This will enable more robust readouts, e.g. from cellular extracts, without need for complex sample preparation, as well as structural/conformational readouts (using ion mobility) and top-down sequencing.

为药物与生物分子靶标的结合提供快速有效的读数的能力是生物制药管道中的关键驱动技术，例如在高通量筛选中。光学读数很常见，但提供了某种程度的二元答案，而质谱（MS）在目标异质性、结合化学计量以及结构效应（使用离子淌度）方面的应用迄今为止因当前使用的样品入口方法缺乏稳健性和低通量而受到阻碍。当一种能够每小时注入 10,000 个样品的新型声学液体处理方法（“Echo”）首次应用于 MS 分析时，人们认识到了这一点。该技术目前由 Medicines Discovery Catapult（MDC，Alderley Edge）托管，可实现配体筛选（直接结合检测）的高通量测定。我们正在与利兹工程部的同事合作开发新颖的在线分离和纯化方法，并进一步开发基于液滴的入口系统。这将实现更稳健的读数，例如来自细胞提取物，无需复杂的样品制备，以及结构/构象读数（使用离子淌度）和自上而下的测序。