PathHunter® β-Arrestin Assays: Determination of Pharmacology Differences Between Human and Ortholog GPCRs

Version:: SBSP_0410
File Name/Number:: SBS 2010
Year:: 2010

DiscoveRx previously introduced a protein-protein interaction system using enzyme fragment complementation that provides a robust, HTS friendly format for monitoring the interaction of activated GPCRs and β-arrestin. To date, DiscoveRx has applied this technology to generate over 170 pre-validated human cell lines. More recently, the coupling of mouse and rat GPCRs in the arrestin signaling pathway has been investigated. A systematic analysis of the chemokine receptor family and their respective mouse and human ligands revealed distinct efficacy and pharmacology differences as demonstrated by the dramatic differences in the ability of the ligands to activate both mouse and human receptors. Several ligands were found that provided no cross-functionality. By contrast, one mouse ligand was found to act as a super-agonist on the corresponding human receptor. Over 80 ortholog GPCR cell lines have now been developed using the PathHunter^® β-Arrestin platform to support ongoing drug development programs and to expand the role of Arrestin screening in cross-species compound validation.