Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease

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,...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2017-06, Vol.114 (27), p.7154-7159
Main Authors: Ciolek, Justyna, Reinfrank, Helen, Quinton, Loïc, Viengchareun, Say, Stura, Enrico, Vera, Laura, Sigismeau, Sabrina, Mouillac, Bernard, Orcel, Hélène, Peigneur, Steve, Tytgat, Jan, Droctové, Laura, Beau, Fabrice, Nevoux, Jerome, Lombès, Marc, Mourier, Gilles, de Pauw, Edwin, Servent, Denis, Mendre, Christiane, Witzgall, Ralph, Gilles, Nicolas
Format: Article
Language:English
Subjects:
Life Sciences
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1620454114