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

Reynaud S, Ciolek J, Degueldre M, Saez NJ, Sequeira AF, Duhoo Y, Brás JLA, Meudal H, Cabo Díez M, Fernández Pedrosa V, Verdenaud M, Boeri J, Pereira Ramos O, Ducancel F, Vanden Driessche M, Fourmy R, Violette A, Upert G, Mourier G, Beck-Sickinger AG, Mörl K, Landon C, Fontes CMGA, Miñambres Herráiz R, Rodríguez de la Vega RC, Peigneur S, Tytgat J, Quinton L, De Pauw E, Vincentelli R, Servent D, Gilles N
J Med Chem 63 8250-8264 (2020)
Cited: 8 times
EuropePMC logo PMID: 32602722

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.

Reviews citing this publication (5)

  1. Strategies for Heterologous Expression, Synthesis, and Purification of Animal Venom Toxins. Rivera-de-Torre E, Rimbault C, Jenkins TP, Sørensen CV, Damsbo A, Saez NJ, Duhoo Y, Hackney CM, Ellgaard L, Laustsen AH. Front Bioeng Biotechnol 9 811905 (2021)
  2. Structural and Functional Diversity of Animal Toxins Interacting With GPCRs. Van Baelen AC, Robin P, Kessler P, Maïga A, Gilles N, Servent D. Front Mol Biosci 9 811365 (2022)
  3. Ligands for Melanocortin Receptors: Beyond Melanocyte-Stimulating Hormones and Adrenocorticotropin. Yuan XC, Tao YX. Biomolecules 12 1407 (2022)
  4. Targeting tumor resistance mechanisms. Gerard L, Duvivier L, Gillet JP. Fac Rev 10 6 (2021)
  5. Natural Peptide Toxins as an Option for Renewed Treatment of Type 2 Vasopressin Receptor-Related Diseases. Gilles N. Biology (Basel) 12 544 (2023)

Articles citing this publication (3)

  1. Towards a generic prototyping approach for therapeutically-relevant peptides and proteins in a cell-free translation system. Wu Y, Cui Z, Huang YH, de Veer SJ, Aralov AV, Guo Z, Moradi SV, Hinton AO, Deuis JR, Guo S, Chen KE, Collins BM, Vetter I, Herzig V, Jones A, Cooper MA, King GF, Craik DJ, Alexandrov K, Mureev S. Nat Commun 13 260 (2022)
  2. Whole Genome Duplication and Gene Evolution in the Hyperdiverse Venomous Gastropods. Farhat S, Modica MV, Puillandre N. Mol Biol Evol 40 msad171 (2023)
  3. Characterization of the First Animal Toxin Acting as an Antagonist on AT1 Receptor. Van Baelen AC, Iturrioz X, Chaigneau M, Kessler P, Llorens-Cortes C, Servent D, Gilles N, Robin P. Int J Mol Sci 24 2330 (2023)


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