Abstract
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.