title: Receptor antagonism/agonism can be uncoupled from pharmacoperone activity.
abstract: Pharmacoperones rescue misrouted mutants of the vasopressin receptor type 2 (V2R) and enable them to traffic to the correct biological locus where they function. Previously, a library of nearly 645,000 structures was interrogated with a high throughput screen; pharmacoperones were identified for V2R mutants with a view toward correcting the underlying mutational defects in nephrogenic diabetes insipidus. In the present study, an orthologous assay was used to evaluate hits from the earlier study. We found no consistent relation between antagonism or agonism and pharmacoperone activity. Active pharmacoperones were identified which had minimal antagonistic activity. This increases the therapeutic reach of these drugs, since virtually all pharmacoperone drugs reported to date were selected from peptidomimetic antagonists. Such mixed-activity drugs have a complex pharmacology limiting their therapeutic utility and requiring their removal prior to stimulation of the receptor with agonist.
authors.affiliation: Departments of Internal Medicine and Cell Biology/Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, United States.
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Janovick
authors.affiliation: Scripps Research Institute Molecular Screening Center, Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, FL, United States.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Spicer
authors.affiliation: Scripps Research Institute Molecular Screening Center, Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, FL, United States.
authors.forename: Emery
authors.initials: E
authors.lastname: Smith
authors.affiliation: Department of Chemistry, Scripps Research Institute, Jupiter, FL, United States.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Bannister
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, NC, United States.
authors.forename: Terry
authors.initials: T
authors.lastname: Kenakin
authors.affiliation: Scripps Research Institute Molecular Screening Center, Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, FL, United States.
authors.forename: Louis
authors.initials: L
authors.lastname: Scampavia
authors.affiliation: Departments of Internal Medicine and Cell Biology/Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, United States. Electronic address: michael.conn@ttuhsc.edu.
authors.forename: P Michael
authors.initials: PM
authors.lastname: Conn
mesh_terms: D065092:Antidiuretic Hormone Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D009154:Mutation; D019151:Peptide Library; D017510:Protein Folding / Q000187:drug effects; D021381:Protein Transport; D017483:Receptors, Vasopressin / Q000819:agonists / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: C585768:AVPR2 protein, human; D065092:Antidiuretic Hormone Receptor Antagonists; D019151:Peptide Library; D017483:Receptors, Vasopressin; D054852:Small Molecule Libraries
keywords: Antagonism; High throughput screening; Pharmacoperone; Receptor misfolding; Receptor trafficking; Therapeutic targeting of trafficking