FUNCTIONAL STRUCTURE OF CONOTOXINS TARGETING NICOTINIC ACETYLCHOLINE RECEPTOR

药物设计中的一个主要问题是如何避免因以下原因引起的副作用 非特异性反应性以及与密切相关的交叉反应性 靶受体和受体亚型。在这方面，芋螺毒素是 特别感兴趣。它们是由有毒的锥形蜗牛产生的， 例如，在鱼身上。捕食者和被捕食者的机动性不同 因此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 集中精力，而不是在通往目标的路上分心。换句话说， 毒素必须具有很高的选择性。此外，蜗牛是 由于它能传递的毒液数量有限，所以毒素必须与 也有很高的亲和力。锥形蜗牛已经有5000万年的进化了吗 我们现在开始意识到它们是非常有效的药物。在这 项目，我们希望解开锥形蜗牛是如何产生的秘密 毒素具有如此令人向往的药理属性。 在锥形蛇毒的成分中有一大家族的多肽， 与烟碱型乙酰胆碱相互作用的α-芋螺毒素 受体(NAChR)，具有极高的选择性。这 提案探讨了赋予阿尔法的结构特征- 芋螺毒素具有诱人的药理特性。这件事会做到的 通过系统地改变它们的结构和检查功能 后果。预计这项研究将提供新的 关于药物-靶相互作用的信息，这将有助于设计 更有效的药物。

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.