Novel Neuronal nAChR-Targeted Peptides

描述（由申请人提供）：选择性操纵尼古丁乙酰胆碱受体（nachr）的功能可能有益于治疗各种影响精神和神经健康的疾病，包括情绪障碍、帕金森病、认知障碍和慢性疼痛。当前研究的一个重点是确定nachr不同功能通道亚型中的亚基，并了解它们在健康和疾病中的作用。nAChR亚型选择性探针的可用性将极大地促进这些努力，并为开发能够调节神经系统中特定nAChR介导功能的药物提供平台。来自Conus属食肉海螺的毒液是一种非常丰富的化合物（α -conotoxins）的来源，它能有效地和选择性地靶向特定的nAChR亚型。本提案的目的是鉴定和表征这些毒液中区分神经元nachr的不同乙酰胆碱结合亚基界面的化合物。这一目标将通过使用基于受体的分析来跟踪活性毒液化合物的纯化来实现。编码α -conotoxins的基因也将被克隆以分离新的毒素。通过这两种方法鉴定的肽将被生物化学表征和合成。这些肽将被充分表征受体亚型特异性。随后，将利用合成策略开发具有精细特异性的第二代配体。结构/功能研究将确定关键的受体结合残基。使用多种方法，包括使用选择性螺毒素探针，天然受体的分子组成将被功能和生物化学定义。

DESCRIPTION (provided by applicant): Selective manipulation of the function of nicotinic acetylcholine receptors (nAChRs) may be beneficial in the treatment of a variety of disorders that impact mental and neurological health, including mood disorders, Parkinson's Disease, cognitive disorders and chronic pain. A major thrust of current research is to identify the subunits in the different functional channel subtypes of nAChRs and to understand their roles in health and disease. The availability of selective probes for the nAChR subtypes will greatly facilitate these efforts, and provide a platform for development of medications capable of modulating specific nAChR-mediated functions in the nervous system. Venoms from carnivorous marine snails of the genus Conus are an extraordinarily rich source of compounds (alpha-conotoxins) that potently and selectively target specific nAChR subtypes. The aim of this proposal is to identify and characterize compounds from these venoms that discriminate among distinct acetylcholine-binding subunit interfaces of neuronal nAChRs. This aim will be accomplished by using receptor-based assays to track the purification of active venom compounds. Genes encoding alpha-conotoxins will also be cloned to isolate new toxins. Peptides identified by either approach will be biochemically characterized and synthesized. These peptides will then be fully characterized with respect to receptor subtype specificity. Subsequently, synthetic strategies will be utilized to develop second-generation ligands with refined specificity. Structure/function studies will determine critical receptor binding residues. Using a combination of approaches, including the use of selective conotoxin probes, the molecular composition of native receptors will be functionally and biochemically defined.