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

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。光学读数是常见的，但提供了一个有点二元的答案，而质谱（MS）的应用目标异质性，化学计量的结合和结构效应（使用离子迁移率）迄今为止一直受到阻碍，缺乏鲁棒性和低通量的目前使用的样品入口方法。当具有每小时注入10，000个样品的能力的新型声学液体处理方法（“Echo”）首次适用于MS分析时，认识到了这一点。这项技术现在由Medicines Discovery Catapult（MDC，阿尔德利Edge）托管，能够进行高通量配体筛选（直接结合检测）。我们正在开发新的在线分离和纯化方法，并与利兹工程部门的同事合作，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的读数，而不需要复杂的样品制备，以及结构/构象读数（使用离子迁移率）和自上而下的测序。

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.