一种昆士兰锥形蜗牛的毒液中深藏成千上万种肽类毒素，被证明含有珍贵药物先导价值，或可以提供治疗疼痛和癌症药物的新线索。在发表在PNAS上的这篇研究中，研究人员描述了一种分析毒液毒素结构的新方法。

Paul Alewood是University of Queensland分子生物学的教授，他表示说这项研究是第一次给出了存在于一个单一的锥形蜗牛毒液中的毒素。研究的这种锥形蜗牛名叫conus episcopatus，生活在澳大利亚东海岸，是700种不同锥形蜗牛之一。锥形蜗牛毒液混合有许多复杂化学物质，而大部分的这些毒素在过去都被忽略了。

锥形蜗牛特征在于有一个复杂精细的毒液“装置”，负责生物合成和提供富含半胱氨酸毒素肽的复杂混合物。这些毒素折叠成小的高度结构化的框架（Frameworks），使它们能够强效和选择性地与异源离子通道和受体相互作用。

使用包含精确测量，分析结构、活性和内毒液蛋白的各种不同组合物的新分析方法，利用生物化学和生物信息学工具，研究人员发现在一个单一的锥形蜗牛毒素肽中表达量最多的一种，拥有3305个新的前提毒素序列。它含有药理活性的C-C-CC-C-C的抑制剂胱氨酸结和CC-C-C的特征序列。更重要的是，他们同时发现了六个原始的“框架”（三维形状的分子），可以作为药物前体。在过去的25年共有25个知名的框架结构被发现，而其中诸多都已经引用到针对几种疾病的药物或药物前体当中。

研究人员估计他们新发现的框架结构也将导致新的药物研发，可用于治疗疼痛、癌症和一系列的其他疾病。Alewood表示：“我们预计有很多有趣的分子将在其他物种的毒液被发现，我们渴望用我们新的方法来探索这些。我们新发现的这种方法也可用在其他相关领域，如从细胞中研究蛋白质的表达。这将有助于我们更好地理解生物学，寻找疾病模式，或发现潜在的新药物。” （来源：生物探索）

Optimized deep-targeted proteotranscriptomic profiling reveals unexplored Conus toxin diversity and novel cysteine frameworks

Abstract  Cone snails are predatory marine gastropods characterized by a sophisticated venom apparatus responsible for the biosynthesis and delivery of complex mixtures of cysteine-rich toxin peptides. These conotoxins fold into small highly structured frameworks, allowing them to potently and selectively interact with heterologous ion channels and receptors. Approximately 2,000 toxins from an estimated number of >70,000 bioactive peptides have been identified in the genus Conus to date. Here, we describe a high-resolution interrogation of the transcriptomes (available at www.ddbj.nig.ac.jp) and proteomes of the diverse compartments of the Conus episcopatus venom apparatus. Using biochemical and bioinformatic tools, we found the highest number of conopeptides yet discovered in a single Conus specimen, with 3,305 novel precursor toxin sequences classified into 9 known superfamilies (A, I1, I2, M, O1, O2, S, T, Z), and identified 16 new superfamilies showing unique signal peptide signatures. We were also able to depict the largest population of venom peptides containing the pharmacologically active C-C-CC-C-C inhibitor cystine knot and CC-C-C motifs (168 and 44 toxins, respectively), as well as 208 new conotoxins displaying odd numbers of cysteine residues derived from known conotoxin motifs. Importantly, six novel cysteine-rich frameworks were revealed which may have novel pharmacology. Finally, analyses of codon usage bias and RNA-editing processes of the conotoxin transcripts demonstrate a specific conservation of the cysteine skeleton at the nucleic acid level and provide new insights about the origin of sequence hypervariablity in mature toxin regions.

原文链接：http://www.pnas.org/content/early/2015/07/01/1501334112.full.pdf?sid=9b9654e8-270f-4687-a790-15acf32dd3a2