Nicolas Gilles
Institute of Biology and Technology of Saclay, France
Title: Animal toxins for human health, case of the mambaquaretin for the treatment of polycystic kidney diseases
Biography
Biography: Nicolas Gilles
Abstract
Autosomal dominant polykystose kidney disease affect 1 over 1,000 peoples, leading to end-stage renal disease. The blockage of the Vasopressin type 2 receptor (V2R) is a validated therapeutic line in human by preventing the vasopressin-induced elevation in intracellular cAMP concentration. Currently, only tolvaptan (jirnac) succeed to reach the market but with many concerns. Scorpions, spiders, snakes, conus, insects, miriapodes are often seen as dangerous, frightening and ugly animals. Their venoms are extremely rich in toxins historically identified for their toxicities. We believe that animal toxins are highly valuable in the context of human use and drug development. We developed a specific strategy in order to identified toxins with the purpose of discover novel drug candidates. Mambaquaretin was discovered in the green mamba venom by a bioguidage strategy directed against the V2R. This toxin belongs to the Kunitz fold peptide family, and its displays a nanomolar affinity for the V2R. Molecular pharmacological essays demonstrated that mambaquaretin is the most selective V2R antagonist. Daily injection of 13 µg 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 treated animals. Mambaquaretin is a promising drug candidate with an original mode of action. Molecular modelling and structure function analysis allowed us to propose a model of interaction of the mambaquaretin/V2R complex.