1. Receptor antagonism/agonism can be uncoupled from pharmacoperone activity.
- Author
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Janovick JA, Spicer TP, Smith E, Bannister TD, Kenakin T, Scampavia L, and Conn PM
- Subjects
- Antidiuretic Hormone Receptor Antagonists chemistry, HeLa Cells, High-Throughput Screening Assays, Humans, Peptide Library, Protein Folding drug effects, Protein Transport, Receptors, Vasopressin agonists, Receptors, Vasopressin chemistry, Receptors, Vasopressin metabolism, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Antidiuretic Hormone Receptor Antagonists pharmacology, Mutation, Receptors, Vasopressin genetics
- 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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2016
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