EE Just lecture, 1996 - Conus venom peptides, receptor and ion channel targets, and drug design: 50 million years of neuropharmacology
EE Just lecture, 1996 - Conus venom peptides, receptor and ion channel targets, and drug design: 50 million years of neuropharmacology
复制标题
DOI：
10.1091/mbc.8.11.2101
复制
发表时间：
1997-11-01
影响因子：
3.3
通讯作者：
Olivera, BM
中科院分区：
文献类型：
--
作者：
Olivera, BM
食肉锥螺（Conus）是最成功的海洋动物（500个物种）之一。每个芋螺物种都是神经药理学专家，并使用毒液捕获猎物，逃离和防御捕食者，并可能阻止竞争对手。一个单独的锥形蜗牛的毒液含有不同的药物成分，大多数是小的，结构限制的肽（芋螺毒素）。单个肽选择性地靶向受体或离子通道的特定同种型。已经鉴定了多种这样的靶点，包括许多电压门控和配体门控离子通道亚型，以及G蛋白连接受体。虽然芋螺毒素中只有少数广泛共享的结构基序（这些毒液中的25，000种肽中的大多数可能只属于六个基因超家族），但肽的序列在不同的芋螺物种之间存在显着差异。我们认为，锥螺进行物种形成，在效果上，一个突变表型，它的作用，特别是对基因片段编码的成熟毒素区。在它们5000万年的进化过程中，锥形蜗牛预见了现代制药业的许多特征：一次性皮下注射针头、联合药物治疗和药物发现的组合策略。最近的研究结果表明，芋螺肽系统可能提供了一种新的范例，用于设计配体，区分受体和离子通道的大家族的密切相关的成员。许多芋螺肽可能是“Janus配体”，具有两个不同的识别面，朝向不同的方向，这种设计应该使更大的靶特异性成为可能。
The predatory cone snails (Conus) are among the most successful living marine animals (500 living species). Each Conus species is a specialist in neuropharmacology, and uses venom to capture prey, to escape from and defend against predators and possibly to deter competitors. An individual cone snail’s venom contains a diverse mixture of pharmacological agents, mostly small, structurally constrained peptides (conotoxins). Individual peptides are selectively targeted to a specific isoform of receptor or ion channel. A variety of such targets have been identified, including many voltage-gated and ligand-gated ion channel subtypes, as well as G protein-linked receptors. Although there are only a few widely shared structural motifs in conotoxins (the majority of the 25,000 peptides in these venoms probably belong to only half a dozen gene superfamilies), the sequences of peptides are remarkably divergent from one Conus species to another. We suggest that cone snails undergoing speciation have, in effect, a mutator phenotype which acts specifically on the gene segment encoding the mature toxin region. In their 50 million years of evolution, cone snails anticipated many features of the modern drug industry: disposable hypodermic needles, combination drug therapy, and combinatorial strategies for drug discovery. Recent results indicate that the Conus peptide system may provide a novel paradigm for designing ligands that discriminate between closely related members of large families of receptors and ion channels. Many Conus peptides may be “Janus-ligands,” with two distinct recognition faces oriented in different directions, a design which should make far greater target specificity possible.