​For several years, Nicolas Gilles' team (Joliot/DMTS/SIMoS) has been studying the toxins present in animal venoms in order to discover potential drug candidates. Building on its success with the discovery and characterization of mambaquaretin, MQ1, a potent vasopressin type 2 receptor (V2R) antagonist, the team set about optimizing this peptide into a drug candidate currently being developed by CEA spin-off V4Cure, MQ232 (inset).

In this study, the researchers optimized MQ1 into MQ232 by introducing several mutations: 3 mutations were first introduced into the peptide to reduce its immunogenicity, and a 4^th mutation improved the peptide's affinity for the V2R by a factor of 10. These four mutations thus generated MQ232, which was then characterized in vitro (affinity and mode of action on the V2R) and in vivo (bio-distribution by PET imaging, toxicity and efficacy tests on models of hyponatremia and polycystic kidney disease). MQ232 proved to be highly selective in vivo for the kidney, the site of V2R expression, highly effective in pathological models and very low in toxicity.

MQ232 is non-toxic and binds effectively and durably to the vasopressin receptor, making it a powerful new-generation natural V2R antagonist and an alternative to tolvaptan, an expensive non-peptidic receptor antagonist with a number of side effects, for treating hyponatremia and polycystic kidney disease.

Contacts : Nicolas Gilles (nicolas.gilles@cea.fr) ; Charles Truillet (charles.truillet@universite-paris-saclay.fr)

© V4Cure​