1. From a Cone Snail Toxin to a Competitive MC4R Antagonist
- Author
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Steve Reynaud, Suli-Anne Laurin, Justyna Ciolek, Peggy Barbe, Anne-Cécile Van Baelen, Michaël Susset, Florian Blondel, Marine Ghazarian, Julia Boeri, Margot Vanden Driessche, Grégory Upert, Gilles Mourier, Pascal Kessler, Laure Konnert, Rémy Beroud, Mathilde Keck, Denis Servent, Michel Bouvier, Nicolas Gilles, Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Montréal (UdeM), and Smartox Biotechnologies
- Subjects
[SDV]Life Sciences [q-bio] ,Snails ,Drug Discovery ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,[CHIM]Chemical Sciences ,Animals ,Receptor, Melanocortin, Type 4 ,Molecular Medicine ,Amino Acid Sequence ,Conotoxins ,Ligands ,Melanocortins - Abstract
International audience; The melanocortin 4 receptor (MC4R) plays a role in energy homeostasis and represents a target for treating energy balance disorders. For decades, synthetic ligands have been derived from MC4R endogenous agonists and antagonists, such as setmelanotide used to treat rare forms of genetic obesity. Recently, animal venoms have demonstrated their capacity to provide melanocortin ligands with toxins from a scorpion and a spider. Here, we described a cone snail toxin, N-CTX-Ltg1a, with a nanomolar affinity for hMC4R but unrelated to any known toxins or melanocortin ligands. We then derived from the conotoxin the linear peptide HT1-0, a competitive antagonist of G s , G 15 , and β-arrestin2 pathways with a low nanomolar affinity for hMC4R. Similar to endogenous ligands, HT1-0 needs hydrophobic and basic residues to bind hMC4R. Altogether, it represents the first venom-derived peptide of high affinity on MC4R and paves the way for the development of new MC4R antagonists.
- Published
- 2022