Receptor antagonism/agonism can be uncoupled from pharmacoperone activity. 2016

Jo Ann Janovick, and Timothy P Spicer, and Emery Smith, and Thomas D Bannister, and Terry Kenakin, and Louis Scampavia, and P Michael Conn
Departments of Internal Medicine and Cell Biology/Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, United States.

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.

UI MeSH Term Description Entries
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D006367 HeLa Cells The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for, among other things, VIRUS CULTIVATION and PRECLINICAL DRUG EVALUATION assays. Cell, HeLa,Cells, HeLa,HeLa Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D017483 Receptors, Vasopressin Specific molecular sites or proteins on or in cells to which VASOPRESSINS bind or interact in order to modify the function of the cells. Two types of vasopressin receptor exist, the V1 receptor in the vascular smooth muscle and the V2 receptor in the kidneys. The V1 receptor can be subdivided into V1a and V1b (formerly V3) receptors. Antidiuretic Hormone Receptors,Receptors, V1,Receptors, V2,V1 Receptors,V2 Receptors,Vasopressin Receptors,8-Arg-Vasopressin Receptor,Antidiuretic Hormone Receptor,Antidiuretic Hormone Receptor 1a,Antidiuretic Hormone Receptor 1b,Arginine Vasopressin Receptor,Argipressin Receptor,Argipressin Receptors,Receptor, Arginine(8)-Vasopressin,Renal-Type Arginine Vasopressin Receptor,V1 Receptor,V1a Vasopressin Receptor,V1b Vasopressin Receptor,V2 Receptor,Vascular-Hepatic Type Arginine Vasopressin Receptor,Vasopressin Receptor,Vasopressin Receptor 1,Vasopressin Type 1A Receptor,Vasopressin V1a Receptor,Vasopressin V1b Receptor,Vasopressin V2 Receptor,Vasopressin V3 Receptor,8 Arg Vasopressin Receptor,Hormone Receptor, Antidiuretic,Hormone Receptors, Antidiuretic,Receptor, Antidiuretic Hormone,Receptor, Arginine Vasopressin,Receptor, Argipressin,Receptor, V1,Receptor, V2,Receptor, Vasopressin,Receptor, Vasopressin V1b,Receptor, Vasopressin V3,Receptors, Antidiuretic Hormone,Receptors, Argipressin,Renal Type Arginine Vasopressin Receptor,V1b Receptor, Vasopressin,Vascular Hepatic Type Arginine Vasopressin Receptor,Vasopressin Receptor, V1b
D017510 Protein Folding Processes involved in the formation of TERTIARY PROTEIN STRUCTURE. Protein Folding, Globular,Folding, Globular Protein,Folding, Protein,Foldings, Globular Protein,Foldings, Protein,Globular Protein Folding,Globular Protein Foldings,Protein Foldings,Protein Foldings, Globular
D054852 Small Molecule Libraries Large collections of small molecules (molecular weight about 600 or less), of similar or diverse nature which are used for high-throughput screening analysis of the gene function, protein interaction, cellular processing, biochemical pathways, or other chemical interactions. It includes virtual libraries. Chemical Libraries,Molecular Libraries, Small,Libraries, Chemical,Libraries, Small Molecular,Libraries, Small Molecule,Molecule Libraries, Small,Small Molecular Libraries
D057166 High-Throughput Screening Assays Rapid methods of measuring the effects of an agent in a biological or chemical assay. The assay usually involves some form of automation or a way to conduct multiple assays at the same time using sample arrays. High-Throughput Screening,High-Throughput Biological Assays,High-Throughput Chemical Assays,High-Throughput Screening Methods,Assay, High-Throughput Biological,Assay, High-Throughput Chemical,Assay, High-Throughput Screening,Biological Assay, High-Throughput,Chemical Assay, High-Throughput,High Throughput Biological Assays,High Throughput Chemical Assays,High Throughput Screening,High Throughput Screening Assays,High Throughput Screening Methods,High-Throughput Biological Assay,High-Throughput Chemical Assay,High-Throughput Screening Assay,High-Throughput Screening Method,High-Throughput Screenings,Screening Assay, High-Throughput,Screening Method, High-Throughput,Screening, High-Throughput
D019151 Peptide Library A collection of cloned peptides, or chemically synthesized peptides, frequently consisting of all possible combinations of amino acids making up an n-amino acid peptide. Phage Display Peptide Library,Random Peptide Library,Peptide Phage Display Library,Phage Display Library, Peptide,Synthetic Peptide Combinatorial Library,Synthetic Peptide Library,Libraries, Peptide,Libraries, Random Peptide,Libraries, Synthetic Peptide,Library, Peptide,Library, Random Peptide,Library, Synthetic Peptide,Peptide Libraries,Peptide Libraries, Random,Peptide Libraries, Synthetic,Peptide Library, Random,Peptide Library, Synthetic,Random Peptide Libraries,Synthetic Peptide Libraries
D021381 Protein Transport The process of moving proteins from one cellular compartment (including extracellular) to another by various sorting and transport mechanisms such as gated transport, protein translocation, and vesicular transport. Cellular Protein Targeting,Gated Protein Transport,Protein Targeting, Cellular,Protein Translocation,Transmembrane Protein Transport,Vesicular Protein Transport,Protein Localization Processes, Cellular,Protein Sorting,Protein Trafficking,Protein Transport, Gated,Protein Transport, Transmembrane,Protein Transport, Vesicular,Traffickings, Protein
D065092 Antidiuretic Hormone Receptor Antagonists Endogenous compounds and drugs that inhibit or block the activity of ANTIDUIRETIC HORMONE RECEPTORS. Antidiuretic Hormone Antagonist,Antidiuretic Hormone Receptor Antagonist,Vasopressin Antagonist,Vasopressin Receptor Antagonist,Antidiuretic Hormone Antagonists,Vasopressin Antagonists,Vasopressin Receptor Antagonists,Antagonist, Antidiuretic Hormone,Antagonist, Vasopressin,Antagonist, Vasopressin Receptor,Antagonists, Antidiuretic Hormone,Antagonists, Vasopressin,Antagonists, Vasopressin Receptor,Hormone Antagonist, Antidiuretic,Hormone Antagonists, Antidiuretic,Receptor Antagonist, Vasopressin,Receptor Antagonists, Vasopressin

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