Screening For Modulators Of Orphan Receptors

Seven hundred twenty genes belong to the GPCR super family in the human genome and approximately half of them encode sensory receptors. Of the remaining 360 receptors, ligands have been identified for 210; the other 150 are considered orphan receptors89-92 (described in detail in Chapter 16). Because several known GPCR modulators have proven clinically useful drugs, the orphan GPCRs are viewed by the pharmaceutical and biotechnology industries as rich sources of novel drug targets. Thus, many companies are engaged in identifying the natural ligands and small molecule modulators for these orphan targets. Several strategies now used for identification of ligands for orphan receptors have been reviewed.93-98

The key to capitalizing on the potential therapeutic benefits of these orphan GPCRs lies in the ability to identify selective ligands for them; this will allow elucidation of the functions and clinical potentials of these receptors. The primary method for screening the receptors is based on function, using cell-based assays. The microphysiometer assay has been used to identify natural ligands for the human APJ receptor and apelin was identified as the natural ligand.99 Utilization of FLIPR to measure intracellular Ca2+ mobilization identified ligands for several orphan GPCRs. Many orphan receptors have undergone deorphaning through Ga16 coupling. Aequorin-based Ca2+ assays, cAMP assays, reporter gene assays, melanophore-based assays, electrophysiological measurements, and high-content receptor internalization assays have also served as tools for finding ligands for orphan receptors.

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