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

为药物与生物分子靶标结合提供快速有效的读数的能力是生物制药管道中的一项关键驱动技术，例如在高通量筛选中。光学读数很常见，但提供了一个有点二元的答案，而质谱学(MS)在靶标异质性、结合的化学计量和结构效应(使用离子迁移率)方面的应用迄今受到缺乏稳健性和当前使用的样品进样方法的低吞吐量的阻碍。当一种新的声学液体处理方法(“Echo”)首次用于MS分析时，人们认识到了这一点，该方法具有每小时注入10,000个样品的能力。这项技术现在被托管在Medicines Discovery Catapult(MDC，Alderley Edge)，使配基筛选(直接结合检测)的高通量分析成为可能。我们正在开发新的在线分离和纯化方法，并与利兹工程部的同事合作，进一步开发基于液滴的进气系统。这将实现更可靠的读数，例如从细胞提取物中读出，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.