Targeting alpha-conotoxin MII to inhibit neuronal nicotinic acetylcholine alpha3beta2 receptors of the CNS

烟碱型乙酰胆碱受体（nAChRs）是配体门控离子通道超家族的代表性成员，在神经信号传递、神经突起生长发育等方面发挥重要作用。最近的研究，包括来自刘易斯博士和阿-教授Alewood的实验室的研究，已经确定了α-芋螺毒素肽，其可以区分不同的nAChR，显然是通过结合到由不同亚基组合形成的特定界面。因此，α-芋螺毒素是鉴定和确定不同天然神经元nAChR发挥的生理作用的独特工具。此外，它们是异常稳定的肽，可以承受酶和酸处理。这些发现鼓励我们追求α-芋螺毒素MII作为参与尼古丁成瘾的神经元烟碱受体α 3 β 2的新的选择性拮抗剂的可行性。该项目的挑战和主要目标是将α-芋螺毒素MII有效地递送到大脑中。Toth教授开发了一种新型的药物递送系统，用于口服药物和肽，这些药物和肽在未修饰的形式下吸收不良或生物不稳定。在该项目中，α-芋螺毒素MII将与专门设计的脂多糖递送系统相结合。递送系统可以被特别定制以运输多种肽通过不同的生物屏障。肽可以以这样的方式与递送系统缀合，即在肽被吸收后释放肽（前药），或形成生物学稳定和活性的新分子。这项工作的成果将包括尼古丁拮抗剂的第一个交付系统的大脑和新的知识的重要性，神经nictotinic受体α 3 β 2尼古丁成瘾。

Nicotinic acetylcholine receptors (nAChRs) play a central role in nerve signal transmission, neurite growth and development and are the representative model of the ligand-gated ion channel superfamily. Recent studies, including those from Dr Lewis' and A-Prof Alewood's laboratories, have identified alpha-conotoxin peptides which can discriminate among the different nAChRs, apparently by binding to the specific interfaces formed by different subunit combinations. Thus alpha-conotoxins are unique tools with which to identify and determine the physiological role, played by the different native neuronal nAChRs. Moreover, they are unusually stable peptides and can withstand enzyme and acid treatment. These findings have encouraged us to pursue the viability of alpha-conotoxin MII as a new and selective antagonist for the neuronal nictotinic receptor alpha3 beta2 which is involved in nicotine addiction. The challenge and major goal of this project is to deliver alpha-conotoxin MII efficiently into the brain. A-Prof Toth has developed a novel drug-delivery system for the oral administration of drugs and peptides, which in their unmodified form are poorly absorbed or biologically unstable. In this project alpha-conotoxin MII will be combined with a specifically designed lipopolysaccharide delivery system . The delivery system can be specifically tailored to transport a wide variety of peptides through the different biological barriers. The peptides can be conjugated to the delivery system in such a way as to release the peptide after it has been absorbed (prodrug), or to form a biologically stable and active novel molecule. The outcomes of this work will include the first delivery system of nicotinic antagonists to the brain and new knowledge concerning the importance of the neuronal nictotinic receptor alpha3 beta2 in nicotine addiction.