[en] 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 E. coli generated a physical bank of 3,597 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 affect ion channels, the known targets of their toxin scaffolds, but bind to four melanocortin receptors with low micromolar affinities and activate 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.
A Venomics approach coupled to high-throughput toxin production strategies identifies the first venom-derived melanocortin receptor agonists.
Publication date :
July 2020
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
American Chemical Society, United States
Peer reviewed :
Peer Reviewed verified by ORBi
European Projects :
FP7 - 278346 - VENOMICS - High-throughput peptidomics and transcriptomics of animal venoms for discovery of novel therapeutic peptides and innovative drug development
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