Biased agonist pharmacochaperones of the AVP V2 receptor may treat congenital nephrogenic diabetes insipidus.
X-linked congenital nephrogenic diabetes insipidus (cNDI) results from inactivating mutations of the human arginine vasopressin (AVP) V2 receptor (hV(2)R). Most of these mutations lead to intracellular retention of the hV(2)R, preventing its interaction with AVP and thereby limiting water reabsorption and concentration of urine. Because the majority of cNDI-hV(2)Rs exhibit protein misfolding, molecular chaperones hold promise as therapeutic agents; therefore, we sought to identify pharmacochaperones for hV(2)R 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 hV(2)R, being unable to recruit arrestin, trigger receptor internalization, or stimulate mitogen-activated protein kinases. These characteristics make these hV(2)R agonist pharmacochaperones promising therapeutic candidates for cNDI.
Jean-Alphonse
Frédéric
F
CNRS UMR 5203, Institut de Génomique fonctionnelle, INSERM U661, and Université Montpellier I and II, Montpellier, France.
Perkovska
Sanja
S
Frantz
Marie-Céline
MC
Durroux
Thierry
T
Méjean
Catherine
C
Morin
Denis
D
Loison
Stéphanie
S
Bonnet
Dominique
D
Hibert
Marcel
M
Mouillac
Bernard
B
Mendre
Christiane
C
D001127:Arginine Vasopressin / Q000378:metabolism; D019393:Arrestin / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D018500:Diabetes Insipidus, Nephrogenic / Q000188:drug therapy*; D006031:Glycosylation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018832:Molecular Chaperones / Q000494:pharmacology* / Q000627:therapeutic use; D017483:Receptors, Vasopressin / Q000819:agonists* / Q000502:physiology
D019393:Arrestin; D018832:Molecular Chaperones; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; D000242:Cyclic AMP