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

Miguel Cabo Díez
  • Function : Author
Victoria Fernández Pedrosa
  • Function : Author
Annette Beck-Sickinger
Rebeca Miñambres Herráiz
  • Function : Author
Loïc Quinton

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-04461196 , version 1 (16-02-2024)

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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. ⟨10.1007/978-1-0716-3589-6_3⟩. ⟨hal-04461196⟩
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