Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
Department of Biochemistry and Molecular Biology, Bio21 Institute, University of Melbourne, Parkville, VIC, Australia.
PLoS One. 2014 Feb 5;9(2):e87648. doi: 10.1371/journal.pone.0087648. eCollection 2014.
Animal venoms represent a vast library of bioactive peptides and proteins with proven potential, not only as research tools but also as drug leads and therapeutics. This is illustrated clearly by marine cone snails (genus Conus), whose venoms consist of mixtures of hundreds of peptides (conotoxins) with a diverse array of molecular targets, including voltage- and ligand-gated ion channels, G-protein coupled receptors and neurotransmitter transporters. Several conotoxins have found applications as research tools, with some being used or developed as therapeutics. The primary objective of this study was the large-scale discovery of conotoxin sequences from the venom gland of an Australian cone snail species, Conus victoriae. Using cDNA library normalization, high-throughput 454 sequencing, de novo transcriptome assembly and annotation with BLASTX and profile hidden Markov models, we discovered over 100 unique conotoxin sequences from 20 gene superfamilies, the highest diversity of conotoxins so far reported in a single study. Many of the sequences identified are new members of known conotoxin superfamilies, some help to redefine these superfamilies and others represent altogether new classes of conotoxins. In addition, we have demonstrated an efficient combination of methods to mine an animal venom gland and generate a library of sequences encoding bioactive peptides.
动物毒液代表了一个拥有丰富生物活性肽和蛋白质的宝库，这些物质不仅具有研究工具的潜力，而且还可以作为药物先导物和治疗方法。这一点在海洋锥螺（Conus 属）中得到了清晰的体现，其毒液由数百种肽（conotoxin）组成，这些肽具有多种多样的分子靶点，包括电压门控和配体门控离子通道、G 蛋白偶联受体和神经递质转运体。一些 conotoxin 已被用作研究工具，其中一些已被用作或正在开发为治疗方法。本研究的主要目标是从澳大利亚锥螺物种 Conus victoriae 的毒腺中大规模发现 conotoxin 序列。使用 cDNA 文库归一化、高通量 454 测序、从头转录组组装和 BLASTX 注释和 profile hidden Markov models，我们从 20 个基因超家族中发现了 100 多种独特的 conotoxin 序列，这是迄今为止在单一研究中报告的 conotoxin 多样性最高的一次。鉴定出的许多序列是已知 conotoxin 超家族的新成员，有些有助于重新定义这些超家族，而另一些则代表全新类别的 conotoxin。此外，我们还展示了一种高效的组合方法，用于挖掘动物毒腺并生成编码生物活性肽的序列文库。
