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P2081
GPCR Screening and Profiling Using Arrestin Reveals Unique Pharmacology for Compounds on Known Receptors and Provides a Platform For Oprhan GPCRs in Discovery and Repositioning Applications
Presenter Keith R. Olson, DiscoveRx Corporation, USA
Additional Authors:
DiscoveRx had modified the well-known enzyme fragment complementation (EFC) technology to enable a new family of cell-based assays utilizing protein-protein interaction as the detection method. Using a small peptide-tag added to the extreme C-terminus of the GPCR, we have developed a platform of biosensor cell lines totaling over 150 GPCR targets for screening and profiling based on interaction of a target GPCR with ƒÒ-arrestin. One key feature of this assay is that it provides absolute specificity for the expressed GPCR, making it ideal for orphan targets. To date, we have developed a panel of 35 orphan targets that will be very useful tools for additional screening and de-orphanization programs, and we will highlight screening of a small library against a set of orphan targets. Of equal interest are our observations of unique compound behaviors at a set of known receptors when arrestin is used as the assay method. Arrestin has successfully been used to identify compound hits that were not found with second messenger approaches, and has also shown different behaviors with respect to agonism versus antagonism compared to standard measurement methods. Taken together, we have demonstrated the value of arrestin as an important screening tool for new targets, as well as known targets based on the ability to identify unique compounds that may have been missed previously using traditional methods, suggesting that arrestin may have value as a tool for re-screening certain key GPCR targets.