A Venomics Approach Coupled to High-Throughput Toxin Production Strategies Identifies the First Venom-Derived Melanocortin Receptor Agonists - Archive ouverte HAL Access content directly
Journal Articles Journal of Medicinal Chemistry Year : 2020

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

Steve Reynaud
  • Function : Author
Justyna Ciolek
  • Function : Author
Michel Degueldre
  • Function : Author
Natalie Saez
  • Function : Author
Ana Filipa Sequeira
  • Function : Author
Yoan Duhoo
  • Function : Author
Joana Brás
  • Function : Author
Herve Meudal
Miguel Cabo Díez
  • Function : Author
Victoria Fernández Pedrosa
  • Function : Author
Marion Verdenaud
Julia Boeri
  • Function : Author
Oscar Pereira Ramos
  • Function : Author
Frédéric Ducancel
  • Function : Author
Margot Vanden Driessche
  • Function : Author
Rudy Fourmy
  • Function : Author
Aude Violette
  • Function : Author
Grégory Upert
  • Function : Author
Gilles Mourier
  • Function : Author
Annette Beck-Sickinger
  • Function : Author
Karin Mörl
  • Function : Author
Celine Landon
Carlos Fontes
  • Function : Author
Rebeca Miñambres Herráiz
  • Function : Author
Ricardo Rodríguez de La Vega
Steve Peigneur
  • Function : Author
Jan Tytgat
  • Function : Author
Loïc Quinton
Edwin de Pauw
  • Function : Author
Denis Servent
Nicolas Gilles
  • Function : Author

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.
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Dates and versions

hal-02936788 , version 1 (20-11-2020)

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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⟩
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