ArticleJournal of biomolecular screening2016
Identification of Potential Pharmacoperones Capable of Rescuing the Functionality of Misfolded Vasopressin 2 Receptor Involved in Nephrogenic Diabetes Insipidus.
Article in Journal of biomolecular screening, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 20 citations in OpenAlex.
- Identification of Potential Modulators of the RGS7/Gβ5/R7BP Complex.SLAS discovery : advancing life sciences R & D · 2021Article
- Case Report: A Case of Congenital Nephrogenic Diabetes Insipidus Caused by Thr273Met Mutation in Arginine Vasopressin Receptor 2.Frontiers in pediatrics · 2021Article
- Rescue of mutant gonadotropin-releasing hormone receptor function independent of cognate receptor activity.Scientific reports · 2020Article
- Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis.Chemical reviews · 2019Article
- Pharmacoperones as Novel Therapeutics for Diverse Protein Conformational Diseases.Physiological reviews · 2018Review
- Improved Scalability of Neuron-Based Phenotypic Screening Assays for Therapeutic Discovery in Neuropsychiatric Disorders.Molecular neuropsychiatry · 2018Article
- A Rapid Phenotypic Whole-Cell Screening Approach for the Identification of Small-Molecule Inhibitors That Counter β-Lactamase Resistance in Pseudomonas aeruginosa.SLAS discovery : advancing life sciences R & D · 2018Article
- Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update.International journal of molecular sciences · 2017Review
- Pharmacoperone rescue of vasopressin 2 receptor mutants reveals unexpected constitutive activity and coupling bias.PloS one · 2017Article
- Receptor antagonism/agonism can be uncoupled from pharmacoperone activity.Molecular and cellular endocrinology · 2016Article
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
Abstract
Pharmacoperones correct the folding of otherwise misfolded protein mutants, restoring function (i.e., providing "rescue") by correcting their trafficking. Currently, most pharmacoperones possess intrinsic antagonist activity because they were identified using methods initially aimed at discovering such functions. Here, we describe an ultra-high-throughput homogeneous cell-based assay with a cAMP detection system, a method specifically designed to identify pharmacoperones of the vasopressin type 2 receptor (V2R), a GPCR that, when mutated, is associated with nephrogenic diabetes insipidus. Previously developed methods to identify compounds capable of altering cellular trafficking of V2R were modified and used to screen a 645,000 compound collection by measuring the ability of library compounds to rescue a mutant hV2R [L83Q], using a cell-based luminescent detection system. The campaign initially identified 3734 positive modulators of cAMP. The confirmation and counterscreen identified only 147 of the active compounds with an EC50 of ≤5 µM. Of these, 83 were reconfirmed as active through independently obtained pure samples and were also inactive in a relevant counterscreen. Active and tractable compounds within this set can be categorized into three predominant structural clusters, described here, in the first report detailing the results of a large-scale pharmacoperone high-throughput screening campaign.
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