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: 6410430
• 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: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6410430
• 关键词: Gastropoda; Xenopus; Xenopus oocyte; animal poison; calcium channel blockers; conformation; electrophysiology; neuropeptides; neurotoxins; 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因药物引起的副作用 非特异性反应性以及与密切相关的交叉反应性 目标受体和受体亚型。就此而言，芋螺毒素具有 特别感兴趣。它们是由捕食的有毒锥形蜗牛产生的， 例如，鱼。捕食者和猎物的移动能力差异 这使得蜗牛的毒素必须迅速发挥作用。这 意味着一旦注射到猎物体内，毒素分子必须非常有效 在实现目标的过程中集中注意力，而不是“分心”。换句话说， 毒素必须具有高选择性。此外，蜗牛是 它可以释放的毒液量有限，因此毒素必须与 热情也很高。锥形蜗牛用了 5000 万年的时间进化出了什么 我们现在已经认识到这些药物非常有效。在这个 项目，我们希望解开锥形蜗牛如何产生的秘密 具有如此非常理想的药理学特性的毒素。 锥毒的成分中有一大类肽， α-芋螺毒素，与烟碱乙酰胆碱相互作用 受体（nAChR）具有非常高的选择性。这 提案探讨了赋予 alpha- 的结构特征 芋螺毒素具有吸引人的药理学特征。这将完成 通过系统地改变它们的结构并检查功能 结果。预计这项研究将提供新的 有关药物与靶标相互作用的信息，这将有助于设计 更有效的药物。