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由于 非特异性反应以及与密切相关的交叉反应 靶受体和受体亚型。在这方面，芋螺毒素是 特别的兴趣。它们是由有毒的锥形蜗牛产生的， 比如鱼类。捕食者和猎物的移动性差异 所以蜗牛的毒素必须迅速发挥作用这 意味着一旦注入猎物体内毒素分子必须非常 集中注意力，而不是在通往目标的路上“分心”。换句话说， 毒素必须以高选择性起作用。此外，蜗牛是 它能释放的毒液量有限，所以毒素必须与 也是高亲和力。锥螺有五千万年的时间来进化 我们现在已经认识到是非常有效的药物。在这 项目，我们希望解开锥形蜗牛如何产生的秘密， 具有如此高的药理学属性的毒素。 在锥毒液的成分中有一个大家族的肽， 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 该提案探讨了赋予阿尔法的结构特征， 芋螺毒素，他们的迷人的特点。为此将 通过系统地改变它们的结构， 后果预计这项研究将提供新的 关于药物-靶标相互作用的信息，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.