More than 100,000 animal venom species exist on earth, all possessing a venom composed of hundreds of peptide toxins. These toxins are known to bind with high affinity and selectivity to their targets such as ion channels and G-Protein Coupled Receptors (GPCR). It is therefore widely recognized that these venoms represent a promising source of drug candidates. However, only a tiny fraction of this natural resource has been characterized, mostly due to the complexity of venom composition. Identifying a drug lead from a venom is a needle-in-a-haystack problem. Firstly, because most of the venomous animals are tiny in sizes and produce very little amount of venoms. Secondly, because the toxin of interest may be present only at a small proportion in a venom, making it difficult to catch.
We made our specialty the systematic exploration of venoms to identify toxin related to unmet medical needs. We have developed and optimized two complementary strategies, one based on bioguided screening, the other based on omics studies of animal venoms and high throughput production of toxins, named the Venomics bank. For each of these strategies, one example of toxins will be presented.
The melanocortin type 4 receptor (MC4R) is expressed in the hypothalamus and controls food intake. Its deficiency is link to morbid obesity. We screened the Venomics bank on MC4R and identified more than 200 hits, representing an astonishing 6% success rate. These toxins have broad diversity in animal origins, in sequences and structures. Here we describe two of these toxins with original melanocortin activities.
The vasopressin type 2 receptor (V2R) is expressed in the kidney and control the water homeostasis. Blocking V2R is a validated therapeutic line to treat hyponatremia and polycystic kidney disease. We discovered in the venom of the African mamba snake the most V2R selective antagonist. This toxin have been validated in various rodent disease models. We are now embarking on its clinical development.
Biography
Full time researcher at the Department of Medicines and Technologies for Health, in the Toxins Receptors and Ion channels team. In charge of the identification and therapeutic development of animal toxins active on G-Protein Coupled Receptors for human benefit.
Dr. Nicolas Gilles has a 20-year experience in the study of animal toxins. He is pioneering the investigation of animal toxins acting on GPCRs, the largest therapeutic target class. His strongest expertise lies in venom manipulations, HT screening, toxin production, selection of therapeutic targets, molecular pharmacology and in vivo experiments. When the pharmacological properties of these new ligands are deemed exceptional, a hit-too-lead process is realized and its therapeutic development initiates.
5 Key Recent Publications
Droctové L, Lancien M, Long Tran V, Susset M, Jego B, Theodoro F, Kessler P, Mourier G, Robin P, Siramakan Diarra S, Palea S, Flahault A, Chorfa A, Corbani M, Llorens-Cortes C, Mouillac B, Mendre C, Pruvost A, Servent D, Truillet C, Gilles N. (2020) A snake toxin as a theranostic agent for the type 2 vasopressin receptor. Theranostics. Sep 18;10(25):11580-11594. doi: 10.7150/thno.47485. IP 11.6.
Reynaud S, Ciolek J, Degueldre M, Saez NJ, Sequeira AF, Duhoo Y, Brás JLA, Meudal H, Cabo Díez M, Fernández Pedrosa V, Verdenaud M, Boeri J, Pereira Ramos O, Ducancel F, Vanden Driessche M, Fourmy R, Violette A, Upert G, Mourier G, Beck-Sickinger AG, Mörl K, Landon C, Fontes CMGA, Miñambres Herráiz R, Rodríguez de la Vega RC, Peigneur S, Tytgat J, Quinton L, De Pauw E, Vincentelli R, Servent D, Gilles N. (2020 ) A Venomics Approach Coupled to High-Throughput Toxin Production Strategies Identifies the First Venom-Derived Melanocortin Receptor Agonists. J Med Chem. Aug 13;63(15):8250-8264. doi: 10.1021/acs.jmedchem.0c00485. Epub 2020 Jul 16. PMID: 32602722. IP 7.4.
Ciolek, J., Reinfrank, H., Quinton, L., Viengchareun, S., Stura, E. A., Vera, L., Sigismeau, S., Mouillac, B., Orcel, H., Peigneur, S., Tytgat, J., Droctové, L., Beau, F., Nevoux, J., Lombès, M., Mourier, G., De Pauw, E., Servent, D., Mendre, C., Witzgall, R., and Gilles, N. (2017) Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease. Proc. Natl. Acad. Sci. U. S. A. 114, 7154–7159. IP 9.5.
Upert, G., Mourier, G., Pastor, A., Verdenaud, M., Alili, D., Servent, D., and Gilles, N. (2014) High-throughput production of two disulphide-bridge toxins. Chem. Commun. (Camb). 50, 8408–11. IP 6.0;
Palea, S., Maiga, A., Guilloteau, V., Rekik, M., Guérard, M., Rouget, C., Rischmann, P., Botto, H., Camparo, P., Lluel, P., and Gilles, N. (2013) Effects of ρ-Da1a a peptidic α1-adrenoceptor antagonist in human isolated prostatic adenoma and anaesthetized rats. Br. J. Pharmacol. 168, 618–31. IP 5.1.
Quinton, L., Girard, E., Maiga, A., Rekik, M., Lluel, P., Masuyer, G., Larregola, M., Marquer, C., Ciolek, J., Magnin, T., Wagner, R., Molgó, J., Thai, R., Fruchart-Gaillard, C., Mourier, G., Chamot-Rooke, J., Ménez, A., Palea, S., Servent, D., and Gilles, N. (2010) Isolation and pharmacological characterization of AdTx1, a natural peptide displaying specific insurmountable antagonism of the alpha1A-adrenoceptor. Br. J. Pharmacol. 159, 316–25. IP 4.9.
Nicolas Gilles, CEA/DRF/Institute of live science Joliot, Toxins, Receptors and Ion channels Team
https://www.researchgate.net/profile/Nicolas-Gilles
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