Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease
Justyna Ciolek
(1)
,
Helen Reinfrank
(2)
,
Loïc Quinton
(3)
,
Say Viengchareun
(4)
,
Enrico Stura
(5)
,
Laura Vera
(1)
,
Sabrina Sigismeau
(1)
,
Bernard Mouillac
(6)
,
Hélène Orcel
(6)
,
Steve Peigneur
(7)
,
Jan Tytgat
(7)
,
Laura Droctové
(1)
,
Fabrice Beau
(1)
,
Jerome Nevoux
(8)
,
Marc Lombès
(4)
,
Gilles Mourier
(1)
,
Edwin de Pauw
(9)
,
Denis Servent
(10)
,
Christiane Mendre
(6)
,
Ralph Witzgall
(2)
,
Nicolas Gilles
(11)
1
JOLIOT -
Institut des Sciences du Vivant Frédéric JOLIOT
2 University of Regensburg - Institute for Molecular and Cellular Anatomy
3 MS LAB - Mass Spectrometry Laboratory
4 UP11 - Université Paris-Sud - Paris 11
5 Centre de recherche du CEA/DSV/iBiTec-S/SIMOPRO
6 IGF - Institut de Génomique Fonctionnelle
7 Laboratory of Toxicology
8 Service d’ORL et de chirurgie cervico-faciale [CHU Le Kremlin-Bicêtre]
9 Laboratory of Mass Spectrometry-GIGA-Proteomics
10 Département d'Ingénierie et d'Etudes des Protéines
11 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
2 University of Regensburg - Institute for Molecular and Cellular Anatomy
3 MS LAB - Mass Spectrometry Laboratory
4 UP11 - Université Paris-Sud - Paris 11
5 Centre de recherche du CEA/DSV/iBiTec-S/SIMOPRO
6 IGF - Institut de Génomique Fonctionnelle
7 Laboratory of Toxicology
8 Service d’ORL et de chirurgie cervico-faciale [CHU Le Kremlin-Bicêtre]
9 Laboratory of Mass Spectrometry-GIGA-Proteomics
10 Département d'Ingénierie et d'Etudes des Protéines
11 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
Enrico Stura
- Fonction : Auteur
- PersonId : 1354443
- ORCID : 0000-0001-6718-2118
Nicolas Gilles
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 864212
- IdHAL : nicolas-gilles
- ORCID : 0000-0001-6853-9764
Connectez-vous pour contacter l'auteur
Résumé
Significance Polycystic kidney diseases (PKDs) are genetic disorders in which multiple cysts grow in kidneys, leading to end-stage renal failure. Vasopressin antagonists (vaptans) currently used to treat PKDs have side effects due to liver toxicity. We report the characterization of Mambaquaretin-1, a Kunitz-fold polypeptide isolated from mamba venom that selectively and fully inhibits three major signaling pathways of the vasopressin type-2 receptor. Mambaquaretin-1 induces a purely aquaretic effect on mice and reduces cyst development in a mouse model. We produced mambaquaretin-1 by peptide synthesis and determined its X-ray structure, its binding mode, and functional properties. With high selectivity and without toxic metabolic byproducts associated with its peptidic nature, mambaquaretin-1 could become the preferential treatment for these disorders.