Highly Multiplexed Cell-Based GPCR Assay.

Project Summary/Abstract Our goal is to commercialize a new assay system that detects and quantifies receptor downregulation/desensitization, and receptor resensitization, for large numbers of human GPCRs in parallel. This miniaturized, multiplexed and scalable system enables diverse GPCR discovery projects, and it dramatically lowers the cost-per-target in primary and secondary drug screens, thereby relieving major bottlenecks in the development of new therapeutic molecules. In phase 1 of the proposed project, we will validate in array transfection and assay automation for 23 human lipid and nucleoside receptors. In phase 2 the set will be extended to include the complete human endogenous GPCR repertoire. The new system will: (1) enable chemical and biologic libraries to be screened against the complete human GPCR repertoire in a highly multiplexed format, (2) improve drug development by revealing selectivity patterns that can be addressed to produce more precisely targeted, and more effective, therapeutic molecules, (3) provide an efficient means to deorphanize human GPCRs of uncertain function, of which more than 100 presently exist, and (4) provide a new and affordable tool for basic research. !Project Narrative. Our goal is to develop and commercialize an automated system that interrogates microarrays of reverse-transfected mammalian cells to detect and quantify GPCR responses to agonists, inverse agonists, and other classes of ligand. By enabling screening against large numbers of human GPCRs in parallel, the system will dramatically expand the scope of GPCR drug discovery and development projects without expanding their costs, and thus lead to new therapeutic treatments for neurological and mental diseases and conditions.