Structure-Activity Studies of Cysteine-Rich -Conotoxins that Inhibit High-Voltage-Activated Calcium Channels via GABAB Receptor Activation Reveal a Minimal Functional Motif
Structure-Activity Studies of Cysteine-Rich -Conotoxins that Inhibit High-Voltage-Activated Calcium Channels via GABAB Receptor Activation Reveal a Minimal Functional Motif
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DOI：
10.1002/anie.201600297
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发表时间：
2016-04-04
影响因子：
16.6
通讯作者：
Clark, Richard J.
中科院分区：
文献类型：
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作者：
Carstens, Bodil B.;Berecki, Geza;Clark, Richard J.
α-芋螺毒素是靶向烟碱乙酰胆碱受体的富含二硫化物的肽。最近，我们发现了几种芋螺毒素，也通过G蛋白偶联GABA（B）受体（GABA（B）R）激动剂调节电压门控钙通道。这些芋螺毒素是治疗慢性疼痛的有前途的药物线索。为了阐明的多样性-芋螺毒素，通过这种机制，我们合成和表征了一组肽的同源性-芋螺毒素已知抑制高电压激活的钙通道通过GABA（B）R激活。值得注意的是，活性芋螺毒素Pu1.2和Pn1.2的所有二硫键异构体以及先前研究的Vc1.1显示出相似的生物活性水平。通过NMR光谱的结构测定帮助我们鉴定了一个简化的生物活性八残基肽基序，其含有一个二硫键，是开发新一代镇痛肽药物的优良先导分子。
alpha-Conotoxins are disulfide-rich peptides that target nicotinic acetylcholine receptors. Recently we identified several -conotoxins that also modulate voltage-gated calcium channels by acting as G protein-coupled GABA(B) receptor (GABA(B)R) agonists. These -conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of -conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to -conotoxins known to inhibit high voltage-activated calcium channels via GABA(B)R activation. Remarkably, all disulfide isomers of the active -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.