FUNCTIONAL STRUCTURE OF CONOTOXINS TARGETING NICOTINIC ACETYLCHOLINE RECEPTOR

芋螺毒素靶向烟碱乙酰胆碱受体的功能结构

• 批准号: 6564574
• 负责人: J M MCINTOSH
• 金额: $ 14.53万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564574
• 关键词: Gastropoda; Xenopus; Xenopus oocyte; animal poison; calcium channel blockers; conformation; conotoxin; electrophysiology; neuropeptides; nicotinic receptors; nuclear magnetic resonance spectroscopy; peptide chemical synthesis; peptide library; protein sequence; protein structure function; receptor binding; receptor coupling; receptor sensitivity; site directed mutagenesis; toxin metabolism

A major problem in drug design is how to avoid side effects due to non specific reactivity as well as cross reactivity with closely related target receptors and receptor subtypes. In this regard,conotoxins are of particular interest. They are produced by venomous cone snails that prey, for example, on fish. The disparity in the mobility of predator and prey makes it absolutely imperative that the snail's toxins act rapidly. This means that once injected into the prey, a toxin molecule must be very focused, and not 'distracted' on the way to its target. In other words, the toxin must act with high selectivity. Furthermore, the snail is limited in the amount of venom it can deliver, so the toxin must act with high avidity as well. Cone snails have had 50 million years to evolve what we now have come to appreciate are incredibly efficient drugs. In this project, we hope to unlock the secret of the how cone snails produce toxins with such highly desirable pharmacological attributes. Among the constituents of cone venom are a large family of peptides, the alpha-conotoxins, which interact with the nicotinic acetylcholine receptor (nAChR) with a remarkably high degree of selectivity. This proposal explores the structural features which confer upon alpha- conotoxins their pharmacologically attractive features. This will be done by systematically altering their structures and examining the functional consequence. It is anticipated that this study will provide new information on drug-target interactions which will assist in the design of more efficacious drugs.

药物设计的一个主要问题是如何避免由于 非比反应性以及与密切相关的交叉反应性 靶受体和受体亚型。在这方面，结合毒素是 特别的兴趣。它们是由有毒的锥蜗牛捕食的， 例如，在鱼上。捕食者和猎物的流动性差异 绝对必须迅速起作用蜗牛的毒素。这 意味着一旦注入猎物，毒素分子就必须非常 集中精力，而不是“分心”到达目标的途中。换句话说， 毒素必须高选择性起作用。此外，蜗牛是 毒液量的限制有限，因此毒素必须与 高潮也很高。锥蜗牛已经有5000万年来发展 我们现在已经欣赏的是非常有效的药物。在这个 项目，我们希望解锁锥形蜗牛生产方式的秘密 具有高度理想的药理特性的毒素。 在锥毒的成分中，有一个大型肽家族， 与烟碱乙酰胆碱相互作用的α-抗毒素 具有高度选择性的受体（NACHR）。这 提案探讨了赋予α-的结构特征 结构毒素其药理具有吸引力的特征。这将完成 通过系统地改变其结构并检查功能 结果。预计这项研究将提供新的 有关药物目标相互作用的信息，这些互动将有助于设计 更有效的药物。