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

靶向 α-芋螺毒素 MII 抑制 CNS 神经元烟碱乙酰胆碱 α3β2 受体

• 批准号: nhmrc : 102477
• 负责人: Prof Istvan Toth
• 金额: $ 14.56万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2000
• 资助国家: 澳大利亚
• 起止时间: 2000-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/targeting-alpha-conotoxin-receptors-cns/100824
• 关键词: Targeting; alpha; conotoxin; MII; inhibit

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.

烟碱型乙酰胆碱受体(NAChRs)在神经信号传递、轴突生长发育中发挥重要作用，是配体门控离子通道超家族的代表模型。最近的研究，包括刘易斯博士和A-Alewood教授的实验室的研究，已经鉴定出可以区分不同nAChR的α-芋螺毒素多肽，显然是通过与不同亚基组合形成的特定界面结合来实现的。因此，α-芋螺毒素是一种独特的工具，可以用来识别和确定不同的天然神经元nAChRs所发挥的生理作用。此外，它们是非常稳定的多肽，可以经受酶和酸的处理。这些发现鼓励我们追求α-芋螺毒素MII作为与尼古丁成瘾有关的神经元尼古丁受体α3β2的一种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有效地输送到大脑中。托斯教授开发了一种新的药物和多肽口服给药系统，这些药物和多肽未经修饰的形式很难被吸收或生物不稳定。在这个项目中，α-芋螺毒素MII将与专门设计的脂多糖输送系统相结合。该递送系统可以特别定制，以通过不同的生物屏障运输各种各样的多肽。多肽可以以这样的方式连接到递送系统，以在其被吸收(前药)后释放多肽，或者形成生物稳定和具有活性的新分子。这项工作的成果将包括尼古丁拮抗剂的第一个大脑递送系统，以及关于神经元尼古丁受体α3β2在尼古丁成瘾中的重要性的新知识。