Novel Neuronal nAChR-Targeted Peptides

新型神经元 nAChR 靶向肽

• 批准号: 7834868
• 负责人: J MICHAEL MCINTOSH
• 金额: $ 4.37万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7834868
• 关键词: Acetylcholine; Affinity; Binding; Binding Proteins; Biological Assay; Characteristics; Cognition Disorders; Collaborations; Collection; Conotoxin; Conus Venom; Conus genus; DNA; Development; Disease; Drosophila acetylcholine receptor alpha-subunit; Duct (organ) structure; Elements; Generations; Genes; Genomics; Grant; Health; Knockout Mice; Laboratories; Ligand Binding; Ligands; Marines; Mediating; Molecular; Molecular Probes; Mood Disorders; Mutagenesis; Nervous System Physiology; Nervous system structure; Neurologic; Neurons; Nicotine; Nicotinic Receptors; Parkinson Disease; Peptides; Pharmaceutical Preparations; Psyche structure; RNA; Research; Retinal Cone; Role; Snails; Source; Specificity; Structure; Toxin; Venoms; Work; alpha-Conotoxin; base; chronic pain; neurotransmitter release; novel; pressure; presynaptic; protein aminoacid sequence; receptor; receptor binding

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.

描述（由申请人提供）：选择性操纵烟碱乙酰胆碱受体（nAChR）的功能可能有益于治疗影响精神和神经健康的各种障碍，包括情绪障碍、帕金森病、认知障碍和慢性疼痛。目前研究的一个主要目标是确定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亚型的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介导的功能的药物提供平台。芋螺属肉食性海洋蜗牛的毒液是一种非常丰富的化合物（α-芋螺毒素）来源，其有效地和选择性地靶向特定的nAChR亚型。这项建议的目的是确定和表征这些毒液中的化合物，区分不同的乙酰胆碱结合亚基界面的神经元乙酰胆碱受体。这一目标将通过使用基于受体的测定来跟踪活性毒液化合物的纯化来实现。编码α-芋螺毒素的基因也将被克隆以分离新的毒素。通过任一方法鉴定的肽将进行生物化学表征和合成。然后，这些肽将在受体亚型特异性方面进行充分表征。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。使用方法的组合，包括使用选择性芋螺毒素探针，天然受体的分子组成将在功能上和生物化学上被定义。