Résumé
In recent years, biased agonists as well as pharmacological chaperones have demonstrated the potential to harness G protein-coupled receptor signaling and trafficking and have collectively opened new possibilities in G protein-coupled receptor drug discovery. Combining pharmacological chaperoning and biased agonism properties into a unique given molecule would be of high therapeutic interest in many human diseases resulting from G protein-coupled receptor mutation and misfolding. This strategy perfectly applies to congenital nephrogenic diabetes insipidus which is a typical conformational disease. In most of the cases, it is 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 the receptor mutants and to rescue their function. Interestingly, different classes of specific ligands such as antagonists, agonists, as well as biased agonists of the V2 receptor have proven their usefulness as efficient pharmacological chaperones. These compounds, and particularly small-molecule-biased agonists which only trigger the V2-induced Gs protein-dependent signaling pathway, represent a potential therapeutic treatment of this X-linked genetic pathology.