A Venomics Approach Coupled to High-Throughput Toxin Production Strategies Identifies the First Venom-Derived Melanocortin Receptor Agonists

Steve Reynaud (1) , Justyna Ciolek (1) , Michel Degueldre (2, 3) , Natalie Saez (4, 5) , Ana Filipa Sequeira (6) , Yoan Duhoo (4, 5) , Joana Brás (6) , Herve Meudal (7) , Miguel Cabo Díez (8) , Victoria Fernández Pedrosa (8) , Marion Verdenaud (1) , Julia Boeri (1) , Oscar Henrique Pereira Ramos (1) , Frédéric Ducancel (9) , Margot Vanden Driessche (1) , Rudy Fourmy (10) , Aude Violette (10) , Grégory Upert (1) , Gilles Mourier (1) , Annette Beck-Sickinger (11) , Karin Mörl (11) , Celine Landon (7) , Carlos M.G.A. Fontes (6) , Rebeca Miñambres Herráiz (8) , Ricardo Rodríguez de La Vega (12) , Steve Peigneur (13) , Jan Tytgat (13) , Loïc Quinton (2) , Edwin de Pauw (2) , Renaud Vincentelli (4) , Denis Servent (1) , Nicolas Gilles (1)

1 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
2 MS LAB - Mass Spectrometry Laboratory
3 UCB Pharma [Brussels]
4 AFMB - Architecture et fonction des macromolécules biologiques
5 Institute for Molecular Bioscience
6 CIISA - Centro de Investigaçao Interdisciplinar em Sanidade Animal
7 CBM - Centre de biophysique moléculaire
8 Auteur indépendant
9 IDMIT - Infectious Diseases Models for Innovative Therapies
10 Alphabiotoxine Laboratory SPRL
11 Leipzig University / Universität Leipzig
12 ESE - Ecologie Systématique et Evolution
13 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven

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.

Domaines: Sciences du Vivant [q-bio]

Steve Reynaud, Justyna Ciolek, Michel Degueldre, Natalie Saez, Ana Filipa Sequeira, 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, 63 (15), pp.8250-8264. ⟨10.1021/acs.jmedchem.0c00485⟩. ⟨hal-02936788⟩