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Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus

Frédéric Jean-Alphonse^*, Sanja Perkovska^*, Marie-Céline Frantz, Thierry Durroux^*, Catherine Méjean^*, Denis Morin^*, Stéphanie Loison, Dominique Bonnet, Marcel Hibert, Bernard Mouillac^* and Christiane Mendre^*

*CNRS UMR 5203, Institut de Génomique fonctionnelle, INSERM U661, and Université Montpellier I and II, Montpellier, France; and
CNRS UMR 7175, Institut Gilbert Laustriat, and Université Louis Pasteur, Illkirch, France

Correspondence: Dr. Christiane Mendre or Bernard Mouillac, IGF, 141 rue de la Cardonille, 34094 Montpellier Cedex, France. Phone: +33-467-142-984/467-142-922; Fax: +33-467-542-432; E-mail: christiane.mendre{at}igf.cnrs.fr or bernard.mouillac{at}igf.cnrs.fr

Received for publication December 22, 2008. Accepted for publication June 30, 2009.

X-linked congenital nephrogenic diabetes insipidus (cNDI) results from inactivating mutations of the human arginine vasopressin (AVP) V2 receptor (hV₂R). Most of these mutations lead to intracellular retention of the hV₂R, preventing its interaction with AVP and thereby limiting water reabsorption and concentration of urine. Because the majority of cNDI-hV₂Rs exhibit protein misfolding, molecular chaperones hold promise as therapeutic agents; therefore, we sought to identify pharmacochaperones for hV₂R that also acted as agonists. Here, we describe high-affinity nonpeptide compounds that promoted maturation and membrane rescue of L44P, A294P, and R337X cNDI mutants and restored a functional AVP-dependent cAMP signal. Contrary to pharmacochaperone antagonists, these compounds directly activated a cAMP signal upon binding to several cNDI mutants. In addition, these molecules displayed original functionally selective properties (biased agonism) toward the hV₂R, being unable to recruit arrestin, trigger receptor internalization, or stimulate mitogen-activated protein kinases. These characteristics make these hV₂R agonist pharmacochaperones promising therapeutic candidates for cNDI.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673