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

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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.