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Scientific result | High-throughput screening | Proteomics | Transcriptomics
In an article published in the Journal of Medicinal Chemistry, a European collaboration led by a SIMoS team shows the interest of creating toxin libraries to identify molecules regulating therapeutic targets.
It is estimated that there are more than 200,000 species that produce a venom for their defence or predation. The toxins that go into the composition of these venoms are peptides that act on many physiological processes. They constitute a breeding ground for the development of future therapeutic molecules (to treat pain, diabetes, allergies, etc.). This pool is all the more important as recent advances in identification methods (omics) suggest a huge number of these molecules: 40 million, whereas only 5,000 of them have been characterised pharmacologically.
In the early 2010's, a European consortium, Venomics, coordinated by SIMoS and funded by the European Union, was created with the aim not only to study the enormous diversity of these peptides through the development of omics technologies, but also to reproduce this diversity in vitro by generating large libraries of synthetic combinatorial peptides that can be used in drug discovery programmes.
Using proteomic and transcriptomic approaches, the consortium has identified more than 20,000 venom peptide sequences from 191 different species. In a second step, through two complementary approaches to peptide production (solid phase synthesis and recombinant expression in bacteria), a library of 3597 toxins was generated.
Surprisingly, the researchers showed by screening that 8% of the toxins in this library appear to regulate the activity of melanocortin receptor 4, a member of the large family of G protein-coupled receptors (GPCRs). The MCR4 gene encoding this receptor is considered to be the most common cause of monogenic obesity, making it a therapeutic target for treating certain eating disorders. Among the 286 toxins in the MCR4 regulatory library, the researchers were intrigued by two of them, N-TRTX-Preg1a and N-BUTX-Ptr1a, whose cysteine motifs suggested they were inhibitors of ion channels rather than GPCR. Several functional assays show that these two toxins do not affect ion channels but bind to four melanocortin receptors (MC1R, MC3R, MC4R and MC5R) and that, in vitro, they activate the MC1R signaling pathway. Determination of their three-dimensional structures shows that these two toxins do not resemble natural MC1R agonists and that they constitute new structural groups within their respective families.
This work published in the Journal of Medicinal Chemistry highlights the interest of a library such as Venomics in identifying ligands of unusual structure and pharmacological activity. In addition, it paves the way for the development of new modulators of MCR.
Nicolas Gilles (firstname.lastname@example.org)
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.