A high throughput screening platform for label-free identification and characterization of GPCR ligands using...

Real-time cell analysis (RTCA) is a biosensor technology that enables kinetic monitoring of cellular activities via electrical impedance. Among its multiple applications, this label-free method offers a holistic approach to monitoring the activity of G protein-coupled receptors (GPCRs) by capturing integrated cellular responses upon pharmacological modulation. GPCRs represent an important class of drug targets, covered by one third of all therapeutics approved by regulatory authorities. Modern drug discovery efforts targeting GPCRs are often initiated with a high-throughput screening (HTS) campaign, typically relying on the detection of downstream signaling events. This approach is often well-suited for sufficiently characterized receptors; however, it is less applicable for less studied (e.g. orphan) GPCRs, with unknown ligands and signaling pathways. Our study presents the integration of the xCELLigence RTCA HT system into a fully automated HTS system, to enable large-scale screening for GPCR agonists. The results obtained in a "proof-of-concept" pilot HTS demonstrate the compatibility of impedance-based RTCA with robotic HTS platforms, as well as the potential of this method for the identification of GPCR ligands.