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Discovery of small organic compounds arresting arrestin functions

Non‐visual members of the arrestin family, the βarrestins (βarr), play important roles in G Proteins Coupled Receptors (GPCR) biology by acting as adaptors between different signaling partners. In addition to their implication in the desensitization and endocytosis of the receptors, βarrs can also lead to the activation of G protein‐independent signaling cascades. However, there is no pharmacological modulator of βarrs that could help to further understand their multiple roles. Our project aims at developing small molecules that would interact and modulate specific functions of βarrs. To identify active compounds, virtual screening of 30,000 compounds using the autodock‐4 software was performed on a molecular model of the GPCR docking site within the polar core of βarr. The biological activity of 66 compounds with the best predicted virtual affinity or of close analogues was characterized using Bioluminescence Resonance Energy Transfer (BRET)‐based βarr/receptor interaction and cell surface expression assays with the V2‐vasopressin receptor as the model receptor. Two of the compounds block agonist‐promoted βarr‐receptor interaction and receptors endocytosis indicating that they impact βarr functions. This project should lead to the development of new molecular tools useful for dissecting the non‐visual arrestins cellular and physiological functions. Research support: CIHR, Heart and Stroke foundation of Canada (HSFC), CIHR Team Grant in G Protein Coupled Receptor Allosteric regulation (CTiGAR).