Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease [Pharmacology]
Polycystic kidney diseases (PKDs) are genetic disorders that can cause renal failure and death in children and adults. Lowering
cAMP in cystic tissues through the inhibition of the type-2 vasopressin receptor (V2R) constitutes a validated strategy to
reduce disease progression. We identified a peptide from green mamba venom that exhibits nanomolar affinity for the V2R without
any activity on 155 other G-protein–coupled receptors or on 15 ionic channels. Mambaquaretin-1 is a full antagonist of the
V2R activation pathways studied: cAMP production, beta-arrestin interaction, and MAP kinase activity. This peptide adopts
the Kunitz fold known to mostly act on potassium channels and serine proteases. Mambaquaretin-1 interacts selectively with
the V2R through its first loop, in the same manner that aprotinin inhibits trypsin. Injected in mice, mambaquaretin-1 increases
in a dose-dependent manner urine outflow with concomitant reduction of urine osmolality, indicating a purely aquaretic effect
associated with the in vivo blockade of V2R. CD1-pcy/pcy mice, a juvenile model of PKD, daily treated with 13
𝝁g of mambaquaretin-1 for 99 d, developed less abundant (by 33%) and smaller (by 47%) cysts than control mice. Neither tachyphylaxis
nor apparent toxicity has been noted. Mambaquaretin-1 represents a promising therapeutic agent against PKDs.
Publisher URL: http://feedproxy.google.com/~r/Pnas-RssFeedOfEarlyEditionArticles/~3/0_1ahzm3fPM/1620454114.short
DOI: 10.1073/pnas.1620454114
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