Conus Peptides and Their Receptor Targets: Towards Constellation Pharmacology.

节目概要 该计划利用生物多样性进行基础生物医学研究， 应用.该计划的重点是发现，表征和发展强大的 靶向信号分子的药理学试剂（例如，受体和离子通道）。的来源 这些是> 10，000种有毒的海洋蜗牛（特别是锥形蜗牛，芋螺）。的毒液 这些蜗牛是复杂的，含有ca。100种不同的肽（“芋螺肽，芋螺毒素”），每种都高度 对特定受体或离子通道具有选择性。由于它们的目标分子的复杂性， 芋螺肽对于理解这些多肽的分子同种型的功能特别有用。 信号分子它们已逐渐成为神经药理学中的标准试剂， 分子遗传学的重要补充，用于了解神经元功能和神经元的回路。 神经系统生理回路的基础是细胞之间的化学和电通信， 其由多种不同的信号分子介导。研究生理学的障碍 电路是受体和离子通道的内在分子复杂性;基因编码的蛋白质亚基 家族形成多聚体复合物（最常见的是四聚体或五聚体）。由于内在的 功能性多聚体离子通道复合物的组合性质，不同受体的大量补充 离子通道可以由几个基因产生。为了了解受体和离子通道的功能， 最好使用区分密切相关的受体和离子通道的高选择性配体 同种型。我们的项目使用了由有毒的海洋蜗牛进化而来的肽， 它们的猎物、捕食者和竞争者作为这种高度选择性配体的主要来源。据估计 海洋蜗牛毒素中含有200多万种生物活性肽，是开发生物活性肽的基础。 研究受体和离子通道的分子复杂性的药理学工具，并定义 大量受体/离子通道亚型的功能作用。足够大的数量的双折射 通过该计划已经开发了靶向的芋头肽，以允许它们组合使用。的 主要目标是使用这些芋螺肽组合来研究受体/离子的不同互补 通道亚型存在于每个神经元亚类中。这就引出了一个使用XML的新范例 活性化合物，我们称之为“星座药理学”。

Program Summary This program uses biodiversity for basic biomedical research, with direct therapeutic and diagnostic applications. The program focuses on the discovery, characterization and development of powerful pharmacological agents targeted to signaling molecules (e.g., receptors and ion channels). The source of these are >10,000 species of venomous marine snails (particularly the cone snails, Conus). The venoms of these snail are complex, containing ca. 100 different peptides ("conopeptides, conotoxins"), each highly selective for a particular receptor or ion channel. Because of the molecular complexity of their targets, conopeptides have been particularly useful for understanding the function of molecular isoforms of these signaling molecules. Increasingly, they have become standard reagents in neuropharmacology, and serve as an essential complement to molecular genetics for understanding neuronal function and the circuitry of the nervous system. The basis of physiological circuits is chemical and electrical communication between cells, which is mediated by a vast diversity of different signaling molecules. A barrier to investigating physiological circuits is the intrinsic molecular complexity of receptors and ion channels; protein subunits encoded by gene families form multimeric complexes (most commonly tetramers or pentamers). Because of the intrinsic combinatorial nature of functional multimeric ion channel complexes, a large complement of different receptors and ion channels can be generated from a few genes. For understanding receptor and ion channel function, it is optimal to use highly selective ligands that distinguish between closely-related receptor and ion channel isoforms. Our program uses the peptides that have been evolved by venomous marine snails to interact with their prey, predators and competitors as a prime source of such highly selective ligands. It is estimated that there are over 2 million biologically active peptides in marine snail venoms, which are the basis for developing the pharmacological tools to investigate the molecular complexity of receptors and ion channels, and to define the functional roles of the vast array of receptor/ion channel isoforms. A sufficiently large number of diversely targeted conopeptides have been developed by this program to allow these to be used in combination. The primary goal is to use these conopeptide combinations to investigate the distinct complement of receptor/ion channel isoforms present in each neuronal subclass. This leads to a new paradigm for using pharmacologically active compounds, which we refer to as "Constellation Pharmacology".