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A Venomics Approach Coupled to High-Throughput Toxin Production Strategies Identifies the First Venom-Derived Melanocortin Receptor Agonists.
J Med Chem. 2020 Jul 16 [Online ahead of print]JM

Abstract

Animal venoms are rich in hundreds of toxins with extraordinary biological activities. Their exploitation is difficult due to their complexity and the small quantities of venom available from most venomous species. We developed a Venomics approach combining transcriptomic and proteomic characterization of 191 species and identified 20,206 venom toxin sequences. Two complementary production strategies based on solid-phase synthesis and recombinant expression in Escherichia coli generated a physical bank of 3597 toxins. Screened on hMC4R, this bank gave an incredible hit rate of 8%. Here, we focus on two novel toxins: N-TRTX-Preg1a, exhibiting an inhibitory cystine knot (ICK) motif, and N-BUTX-Ptr1a, a short scorpion-CSαβ structure. Neither N-TRTX-Preg1a nor N-BUTX-Ptr1a affects ion channels, the known targets of their toxin scaffolds, but binds to four melanocortin receptors with low micromolar affinities and activates the hMC1R/Gs pathway. Phylogenetically, these two toxins form new groups within their respective families and represent novel hMC1R agonists, structurally unrelated to the natural agonists.

Authors+Show Affiliations

Université Paris-Sud, 15 Rue Georges Clemenceau, Orsay 91405 France. Université Paris Saclay, CEA, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette 91191 France.Université Paris Saclay, CEA, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette 91191 France.Mass Spectrometry Laboratory, Université de Liège, Allée du six Aout 11, Quartier Agora, Liege 4000 Belgium. Department of Analytical Science Biologicals, UCB, Chemin du Foriest, Braine L'Alleud 1420 Belgium.Centre National de la Recherche Scientifique, Architecture et Fonction des Macromolécules Biologiques, Campus de Luminy, Marseille 13288 France. Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, QLD, Australia.Universidade de Lisboa, CIISA - Faculdade de Medicina Veterinária, Avenida da Universidade Técnica, Lisboa 1300-477 Portugal. NZYTech Lda, Genes & Enzymes, Estrada do Paço do Lumiar, Campus do Lumiar, Edifício E - R/C, Lisboa 1649-038 Portugal.Centre National de la Recherche Scientifique, Architecture et Fonction des Macromolécules Biologiques, Campus de Luminy, Marseille 13288 France. Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, QLD, Australia.Universidade de Lisboa, CIISA - Faculdade de Medicina Veterinária, Avenida da Universidade Técnica, Lisboa 1300-477 Portugal. NZYTech Lda, Genes & Enzymes, Estrada do Paço do Lumiar, Campus do Lumiar, Edifício E - R/C, Lisboa 1649-038 Portugal.Centre National de la Recherche Scientifique, Centre de Biophysique Moléculaire, rue Charles Sadron, Orléans 45071 France.Next-Generation Sequencing Laboratory, Sistemas Genómicos Ltd., Ronda de Guglielmo Marconi, 6, Paterna 46980 Spain.Next-Generation Sequencing Laboratory, Sistemas Genómicos Ltd., Ronda de Guglielmo Marconi, 6, Paterna 46980 Spain.Université Paris Saclay, CEA, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette 91191 France.Université Paris Saclay, CEA, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette 91191 France.Université Paris Saclay, CEA, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette 91191 France.Université Paris Saclay, CEA, Département IDMIT, 18 route du Panorama, 92265 Fontenay-aux-Roses, France.Université Paris Saclay, CEA, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette 91191 France.Alphabiotoxine Laboratory sprl, Barberie 15, Montroeul-au-bois 7911 Belgium.Alphabiotoxine Laboratory sprl, Barberie 15, Montroeul-au-bois 7911 Belgium.Université Paris Saclay, CEA, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette 91191 France.Université Paris Saclay, CEA, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette 91191 France.Institute of Biochemistry, Universitat Leipzig, Leipzig 04103 Germany.Institute of Biochemistry, Universitat Leipzig, Leipzig 04103 Germany.Centre National de la Recherche Scientifique, Centre de Biophysique Moléculaire, rue Charles Sadron, Orléans 45071 France.Universidade de Lisboa, CIISA - Faculdade de Medicina Veterinária, Avenida da Universidade Técnica, Lisboa 1300-477 Portugal. NZYTech Lda, Genes & Enzymes, Estrada do Paço do Lumiar, Campus do Lumiar, Edifício E - R/C, Lisboa 1649-038 Portugal.Next-Generation Sequencing Laboratory, Sistemas Genómicos Ltd., Ronda de Guglielmo Marconi, 6, Paterna 46980 Spain.Universite Paris-Sud, Ecologie, Systematique et Evolution, 15 rue Georges Clémenceau, Orsay 91405 France.Toxicology and Pharmacology, University of Leuven (KU Leuven), Herestraat 49, Leuven 3000 Belgium.Toxicology and Pharmacology, University of Leuven (KU Leuven), Herestraat 49, Leuven 3000 Belgium.Mass Spectrometry Laboratory, Université de Liège, Allée du six Aout 11, Quartier Agora, Liege 4000 Belgium.Mass Spectrometry Laboratory, Université de Liège, Allée du six Aout 11, Quartier Agora, Liege 4000 Belgium.Centre National de la Recherche Scientifique, Architecture et Fonction des Macromolécules Biologiques, Campus de Luminy, Marseille 13288 France.Université Paris Saclay, CEA, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette 91191 France.Université Paris Saclay, CEA, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette 91191 France.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32602722

Citation

Reynaud, Steve, et al. "A Venomics Approach Coupled to High-Throughput Toxin Production Strategies Identifies the First Venom-Derived Melanocortin Receptor Agonists." Journal of Medicinal Chemistry, 2020.
Reynaud S, Ciolek J, Degueldre M, et al. A Venomics Approach Coupled to High-Throughput Toxin Production Strategies Identifies the First Venom-Derived Melanocortin Receptor Agonists. J Med Chem. 2020.
Reynaud, S., Ciolek, J., Degueldre, M., Saez, N. J., Sequeira, A. F., Duhoo, Y., Brás, J. L. A., 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., ... Gilles, N. (2020). A Venomics Approach Coupled to High-Throughput Toxin Production Strategies Identifies the First Venom-Derived Melanocortin Receptor Agonists. Journal of Medicinal Chemistry. https://doi.org/10.1021/acs.jmedchem.0c00485
Reynaud S, et al. A Venomics Approach Coupled to High-Throughput Toxin Production Strategies Identifies the First Venom-Derived Melanocortin Receptor Agonists. J Med Chem. 2020 Jul 16; PubMed PMID: 32602722.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Venomics Approach Coupled to High-Throughput Toxin Production Strategies Identifies the First Venom-Derived Melanocortin Receptor Agonists. AU - Reynaud,Steve, AU - Ciolek,Justyna, AU - Degueldre,Michel, AU - Saez,Natalie J, AU - Sequeira,Ana Filipa, AU - Duhoo,Yoan, AU - Brás,Joana L A, AU - Meudal,Hervé, AU - Cabo Díez,Miguel, AU - Fernández Pedrosa,Victoria, AU - Verdenaud,Marion, AU - Boeri,Julia, AU - Pereira Ramos,Oscar, AU - Ducancel,Frédéric, AU - Vanden Driessche,Margot, AU - Fourmy,Rudy, AU - Violette,Aude, AU - Upert,Grégory, AU - Mourier,Gilles, AU - Beck-Sickinger,Annette G, AU - Mörl,Karin, AU - Landon,Céline, AU - Fontes,Carlos M G A, AU - Miñambres Herráiz,Rebeca, AU - Rodríguez de la Vega,Ricardo C, AU - Peigneur,Steve, AU - Tytgat,Jan, AU - Quinton,Loïc, AU - De Pauw,Edwin, AU - Vincentelli,Renaud, AU - Servent,Denis, AU - Gilles,Nicolas, Y1 - 2020/07/16/ PY - 2020/7/1/pubmed PY - 2020/7/1/medline PY - 2020/7/1/entrez JF - Journal of medicinal chemistry JO - J. Med. Chem. N2 - Animal venoms are rich in hundreds of toxins with extraordinary biological activities. Their exploitation is difficult due to their complexity and the small quantities of venom available from most venomous species. We developed a Venomics approach combining transcriptomic and proteomic characterization of 191 species and identified 20,206 venom toxin sequences. Two complementary production strategies based on solid-phase synthesis and recombinant expression in Escherichia coli generated a physical bank of 3597 toxins. Screened on hMC4R, this bank gave an incredible hit rate of 8%. Here, we focus on two novel toxins: N-TRTX-Preg1a, exhibiting an inhibitory cystine knot (ICK) motif, and N-BUTX-Ptr1a, a short scorpion-CSαβ structure. Neither N-TRTX-Preg1a nor N-BUTX-Ptr1a affects ion channels, the known targets of their toxin scaffolds, but binds to four melanocortin receptors with low micromolar affinities and activates the hMC1R/Gs pathway. Phylogenetically, these two toxins form new groups within their respective families and represent novel hMC1R agonists, structurally unrelated to the natural agonists. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/32602722/A_Venomics_approach_coupled_to_high-throughput_toxin_production_strategies_identifies_the_first_venom-derived_melanocortin_receptor_agonists L2 - https://doi.org/10.1021/acs.jmedchem.0c00485 DB - PRIME DP - Unbound Medicine ER -
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