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Pharmacological Chaperones as Potential Therapeutic Strategies for Misfolded Mutant Vasopressin Receptors

  • Chapter
Targeting Trafficking in Drug Development

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 245))

Abstract

Pharmacological chaperones recently opened new possibilities in G protein-coupled receptor drug discovery. Even more interestingly, some unique ligands combine pharmacological chaperoning and biased agonism properties, boosting their therapeutic interest in many human diseases resulting from G protein-coupled receptor mutation and misfolding. These compounds displaying dual characteristics would constitute a perfect treatment for congenital Nephrogenic Diabetes Insipidus, a typical conformational disease. This X-linked genetic pathology is mostly associated with inactivating mutations of the renal arginine-vasopressin V2 receptor leading to misfolding and intracellular retention of the receptor, causing the inability of patients to concentrate their urine in response to the antidiuretic hormone. Cell-permeable pharmacological chaperones have been successfully challenged to restore plasma membrane localization of many V2 receptor mutants. In addition, different classes of specific ligands such as antagonists, agonists as well as biased agonists of the V2 receptor have proven their usefulness in rescuing mutant receptor function. This is particularly relevant for small-molecule biased agonists which only trigger Gs protein activation and cyclic adenosine monophosphate production, the V2-induced signaling pathway responsible for water reabsorption. In parallel, high-throughput screening assays based on receptor trafficking rescue approaches have been developed to discover novel V2 pharmacological chaperone molecules from different chemical libraries. These new hit compounds, which still need to be pharmacologically characterized and functionally tested in vivo, represent promising candidates for the treatment of congenital Nephrogenic Diabetes Insipidus.

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Abbreviations

AQP2:

Aquaporin-2

AVP:

Arginine-vasopressin

cAMP:

Cyclic adenosine monophosphate

cNDI:

Congenital nephrogenic diabetes insipidus

ER:

Endoplasmic reticulum

FDA:

US food and drug administration

GnRHR:

Gonadotropin-releasing hormone receptor

GPCR:

G protein-coupled receptor

Gs:

G protein subunit αs

LSD:

Lysosomal storage disorder

NMR:

Nuclear magnetic resonance

OT:

Oxytocin

PC:

Pharmacological chaperone, pharmacochaperone, pharmacoperone

PCT:

Pharmacological chaperone therapy

3D:

Three-dimensional

TM:

Transmembrane

V2R:

Vasopressin type 2 receptor

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Acknowledgments

We would like to dedicate this chapter in memory of P. Michael Conn.

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  1. Institut de Génomique Fonctionnelle, CNRS, INSERM, Université de Montpellier, 141 rue de la cardonille, 34094, Montpellier Cedex 05, France

    Bernard Mouillac & Christiane Mendre

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  1. Bernard Mouillac
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  2. Christiane Mendre
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Correspondence to Bernard Mouillac .

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Editors and Affiliations

  1. Red de Apoyo a la Investigación, National Autonomous University of Mexico and Instituto Nacional de Ciencias, Médicas y Nutrición SZ, Mexico City, Mexico

    Alfredo Ulloa-Aguirre

  2. Dep of Anatomy, Physiology and Pharmacology, Auburn University, College of Veterinary Medicine, Auburn, Alabama, USA

    Ya-Xiong Tao

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Mouillac, B., Mendre, C. (2017). Pharmacological Chaperones as Potential Therapeutic Strategies for Misfolded Mutant Vasopressin Receptors. In: Ulloa-Aguirre, A., Tao, YX. (eds) Targeting Trafficking in Drug Development. Handbook of Experimental Pharmacology, vol 245. Springer, Cham. https://doi.org/10.1007/164_2017_50

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