Skip to Main content Skip to Navigation
Journal articles

Biased agonist pharmacochaperones of the AVP V2 receptor may treat congenital nephrogenic diabetes insipidus.

Abstract : 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.
Document type :
Journal articles
Complete list of metadatas

Cited literature [4 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-00421838
Contributor : Bernard Mouillac <>
Submitted on : Sunday, October 4, 2009 - 2:21:19 PM
Last modification on : Wednesday, May 27, 2020 - 12:40:02 AM
Long-term archiving on: : Saturday, November 26, 2016 - 12:42:48 PM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

Citation

Frédéric Jean-Alphonse, Sanja Perkovska, Marie-Céline Frantz, Thierry Durroux, Catherine Méjean, et al.. Biased agonist pharmacochaperones of the AVP V2 receptor may treat congenital nephrogenic diabetes insipidus.. Journal of the American Society of Nephrology, American Society of Nephrology, 2009, 20 (10), pp.2190-203. ⟨10.1681/ASN.2008121289⟩. ⟨inserm-00421838⟩

Share

Metrics

Record views

743