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Séminaire Chimie ED459

Les venins de Mamba pour lutter contre la polykystose rénale

Dr. Nicolas Gilles (CEA-Saclay, iBiTecS Institut de Biologie et de Technologie de Saclay, Gif-sur-Yvette, France)

publié le

Le Jeudi 29 Septembre 2016 à 13h45
UM Fac Pharmacie, Salle TD2 (bâtiment I, entrée par l’extérieur côté Voie Domitienne)

Co-auteurs :
Laura Droctové,[1], Justyna Ciolek,[1] Helen Reinfrank [2] Denis Servent,[1] Gilles Mourier,[1] Nicolas Floquet,[5] Bernard Mouillac,[3] Loïc Quinton,[4] Christiane Mendre,[3] Ralph Witzgall,[2] Nicolas Gilles.[1]
[1] CEA-Saclay, Institut de Biologie et de Technologie de Saclay (iBiTecS), 91191 Gif-sur-Yvette, France
[2] Institute of molecular and cellular anatomy, university of Regensburg, Germany
[3] Institute of functional genomic, CNRS, Montpellier, France
[4] Laboratoire de spectrométrie de masse – Département de Chimie- GIGA-R– Université de Liège, Liège B-4000, Belgium
[5] Institut de Génomique Fonctionnelle, UMR5203 CNRS U1191 INSERM, UM, 141 rue de la cardonille, 34094 Montpellier, France

(la conférence sera donnée en français)

Animal venoms can be seen as large natural libraries of biologically active molecules that are continuously refined by the evolution process, up to the point where every molecule is endowed with pharmacological properties that are highly valuable in the context of human use and drug development.

In order to develop a novel therapeutic strategy against the orphan kidney polykystose diseases, we looked for an animal toxin able to selectively block the vasopressin receptor type 2 (V2R). Polykystose kidney diseases affect 1 over 1,000 people, leading to end-stage renal disease in 50% of the patients and are responsible of about 15% of renal transplantation in France. The blockage of the V2R is a validated therapeutic line in human by preventing the vasopressin-induced elevation in intracellular cAMP concentration and MAP kinase activities. No safe drug currently exists as the only existing vasopressin receptor antagonists, the vaptans, are all substrate of P450.

Mambaquaretin was discovered in the green mamba venom by a bioguidage strategy. This toxin belongs to the Kunitz fold peptide family, with 56 residues and 3 disulfide bridges. Its synthetic homologue displays a nanomolar affinity for the V2R and absolute selectivity versus 160 others GPCR and 8 cardiac channels.

Mambaquaretin is able to fully antagonize V2R. Daily injection of 0.1 μmol/kg of mambaquaretin to pcy mice, a model of juvenile recessive kidney polykystose, over a period of 99 days, allowed the drug candidate to inhibit cyst growth area by almost 30%. No apparent toxicity was observed in control or treated animals.
A model of the interaction is presented and proposed explanations of the origin of the selectivity of the toxin for the V2R.

Contact local ICGM : Dr. Nicolas Floquet (DAPP)


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