Université Paris-Sud, 15 Rue Georges Clemenceau, Orsay 91405 France.
Université Paris Saclay, CEA, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette 91191 France.
J Med Chem. 2020 Aug 13;63(15):8250-8264. doi: 10.1021/acs.jmedchem.0c00485. Epub 2020 Jul 16.
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 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.
动物毒液富含数百种具有非凡生物学活性的毒素。由于其复杂性以及大多数有毒物种提供的毒液数量有限，因此它们的开发具有一定难度。我们开发了一种结合了 191 种物种的转录组学和蛋白质组学特征的毒液组学方法，并鉴定出了 20206 种毒液毒素序列。两种基于固相合成和在 中重组表达的互补生产策略生成了 3597 种毒素的物理文库。在 hMC4R 上进行筛选，该文库的惊人命中率达到了 8%。在这里，我们重点关注两种新型毒素：具有抑制性半胱氨酸结 (ICK) 基序的 N-TRTX-Preg1a 和短蝎-CSαβ 结构的 N-BUTX-Ptr1a。N-TRTX-Preg1a 和 N-BUTX-Ptr1a 都不影响离子通道，即它们毒素支架的已知靶标，而是以低微摩尔亲和力与四个黑皮质素受体结合，并激活 hMC1R/Gs 通路。从系统发育学上看，这两种毒素在各自的家族中形成了新的群组，代表了与天然激动剂在结构上无关的新型 hMC1R 激动剂。
