GPCRs: Chemical-Scale Studies with Unnatural Amino Acids

描述（由申请人提供）：大约40%的人用药物靶向G蛋白偶联受体（GPCR），整个制药行业正在进行的研究都集中在这些普遍存在的蛋白质上。有数百种不同的GPCR，尽管做出了相当大的努力，但我们对其结构和作用方式的了解有限。在过去的十年中，我们的实验室已经开发出一种强大的方法来揭示药物-受体相互作用。该方法结合了有机化学，分子生物学和电生理学，将非天然氨基酸纳入受体。我们已经将这种方法应用于许多神经受体和离子通道，并获得了信息丰富和重要的结果。在目前的工作中，我们建议应用非天然氨基酸的方法来研究GPCR。我们最初的目标将是一个多巴胺受体家族，它与包括帕金森病和精神分裂症在内的许多神经系统疾病的治疗有关。从这项工作中获得的见解将对开发更安全，更有效的药物，特别是针对多巴胺受体和一般的GPCR的努力具有重要价值。公共卫生相关性对药物如何与靶受体相互作用的深入了解极大地帮助了开发更安全、更有效的药物的努力。目前的工作将为制药行业最普遍的目标提供这样的信息。研究结果将有助于开发帕金森病、精神分裂症和注意力缺陷多动障碍的新疗法。

DESCRIPTION (provided by applicant): Roughly 40% of human medicines target G protein-coupled receptors (GPCRs), and ongoing research throughout the pharmaceutical industry is focused on these ubiquitous proteins. There are hundreds of different GPCRs, and despite considerable efforts, our knowledge of their structures and modes of action is limited. Over the past decade, our laboratory has developed a powerful methodology for revealing drug- receptor interactions. The method combines organic chemistry, molecular biology, and electrophysiology to incorporate unnatural amino acids into receptors. We have applied the approach to many neuroreceptors and ion channels, with informative and important results. In the present work we propose to apply the unnatural amino acid methodology to the study of GPCRs. Our initial target will be a family of dopamine receptors, which are implicated in treatments for a number of neurological disorders including Parkinson's disease and schizophrenia. The insights gained from this work will be of great value to efforts to develop safer, more efficacious pharmaceuticals that target dopamine receptors in particular, and GPCRs in general. PUBLIC HEALTH RELEVANCE Efforts to develop safer, more efficacious pharmaceuticals are greatly aided by insights into precisely how drugs interact with their target receptors. The present work will provide just such information for the most ubiquitous targets of the pharmaceutical industry. The results will aid in the development of new treatments for Parkinson's disease, schizophrenia, and attention-deficit hyperactivity disorder.