2002 Global Researcher Conference Proceeding
April 26 - 28, 2002
| Conference: | 2002 Global Researcher Conference |
|---|---|
| Title: | A pharmacological chaperone acting at the V2-vasopressin receptor offers a treatment for Nephrogenic Diabetes Insipidus |
| Authors: | Bernier, Virginie; Morello, Jean-Pierre; Salahpour, Ali; Arthus, Marie-Francoise; Laperriere, Andre; Lonergan, Michele; Bouvier, Michel |
| Institutions: | Universite de Montreal, University of Montreal, Hopital du Sacre-Coeur de Montreal |
Over 150 mutations in the coding sequence of the V2 vasopressin receptor (V2R) gene cause nephrogenic diabetes insipidus (NDI). When expressed, most of these mutant V2R don’t make it to the cell surface. We previously reported that cell permeable V2R antagonists can act as pharmacological chaperones to rescue the function of mutant V2R. We hypothesized that ligands with lower affinity for the V2R could represent better drug candidates. We demonstrate that a non-peptidic V1a antagonist dramatically increases cell surface expression and leads to the functional rescue of mutant V2R by facilitating its maturation. The functional rescue of receptor function therefore results from a pharmacological chaperone action that promotes the proper folding. To test the potential therapeutic action of pharmacological chaperones, the effects of this V1a antagonist was assessed in patients harbouring the W164S, del62-64, and R137H mutations. Administration of this antagonist to NDI-patients improves urine concentration and reduces urinary output. This strategy offers a proof-of-concept that pharmacological chaperone-mediated therapy could be effective in the treatment of diseases resulting from protein misfolding.
Bernier, et al., tested different types of chemical compounds called pharmacological chaperones to see if they could help restore the function of select mutant V2 vasopressin receptors (V2R) that result in NDI. They found that one chemical chaperone, a non-peptide V1a vasopressin antagonist, restored the ability of several mutant V2Rs by helping them achieve their proper shape and reach their full growth. Patients to whom the chaperone was administered experienced a reduction of their urine output and an increased ability to produce more concentrated urine.