Carstens Bodil B, Berecki Géza, Daniel James T, Lee Han Siean, Jackson Kathryn A V, Tae Han-Shen, Sadeghi Mahsa, Castro Joel, O'Donnell Tracy, Deiteren Annemie, Brierley Stuart M, Craik David J, Adams David J, Clark Richard J
Institute for Molecular Biosciences, The University of Queensland, Brisbane, Qld, 4072, Australia.
Health Innovations Research Institute, RMIT University, Melbourne, Vic, 3083, Australia.
Angew Chem Int Ed Engl. 2016 Apr 4;55(15):4692-6. doi: 10.1002/anie.201600297. Epub 2016 Mar 7.
α-Conotoxins are disulfide-rich peptides that target nicotinic acetylcholine receptors. Recently we identified several α-conotoxins that also modulate voltage-gated calcium channels by acting as G protein-coupled GABA(B) receptor (GABA(B)R) agonists. These α-conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of α-conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to α-conotoxins known to inhibit high voltage-activated calcium channels via GABA(B)R activation. Remarkably, all disulfide isomers of the active α-conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity. Structure determination by NMR spectroscopy helped us identify a simplified biologically active eight residue peptide motif containing a single disulfide bond that is an excellent lead molecule for developing a new generation of analgesic peptide drugs.
α-芋螺毒素是富含二硫键的肽，作用于烟碱型乙酰胆碱受体。最近我们鉴定出几种α-芋螺毒素，它们还通过作为G蛋白偶联的γ-氨基丁酸B型受体（GABA(B)R）激动剂来调节电压门控钙通道。这些α-芋螺毒素有望成为治疗慢性疼痛的药物先导物。为了阐明通过这种机制起作用的α-芋螺毒素的多样性，我们合成并表征了一组与已知通过GABA(B)R激活抑制高电压激活钙通道的α-芋螺毒素具有同源性的肽。值得注意的是，活性α-芋螺毒素Pu1.2和Pn1.2以及先前研究的Vc1.1的所有二硫键异构体都表现出相似水平的生物活性。通过核磁共振光谱进行的结构测定帮助我们鉴定出一种简化的具有生物活性的八残基肽基序，其含有单个二硫键，这是开发新一代镇痛肽药物的优良先导分子。
