Probing Receptor Structures with Unnatural Amino Acids

描述(由申请人提供)：目前的工作将提供新的见解，以了解药物如何结合和激活遍布中枢和外周神经系统的受体家族。这些受体被称为Cys-loop受体，它们是阿尔茨海默病、精神分裂症、帕金森病、疼痛、癫痫、ADHD、自闭症、抑郁症、成瘾等疾病的既定治疗靶点。使用在前几年拨款中开发的强大方法，受体的结构可以以精确和微妙的方式进行修改。特别是，构成这些蛋白质受体的氨基酸可以特别地被设计的、非天然的氨基酸所取代。这允许对现有功能进行前所未有的控制。这些修饰如何影响针对受体的药物的有效性，为药物作用机制提供了关键的见解。一个需要解决的关键问题将是受体的选择性--某些药物如何能够仅针对非常密切相关的受体集合中的特定成员。这些研究产生的知识将对努力开发新的药物来解决与Cys-loop受体故障相关的许多神经疾病非常有价值。 公共卫生相关性：根据世界卫生组织全球疾病负担评估，包括单相抑郁障碍、双相情感障碍和精神分裂症在内的神经疾病是发达国家成年人最大的健康危害。目前的工作将为药物如何与中枢和外周神经系统中发现的受体家族结合并激活提供新的见解。这些受体的故障与所有神经疾病有关，这笔赠款产生的知识将对努力开发新的药物来对抗这些可怕的疾病具有重要价值。

DESCRIPTION (provided by applicant): The present work will provide new insights into how drugs bind to and activate a family of receptors that are found throughout the central and peripheral nervous systems. These receptors are called Cys-loop receptors, and they are established therapeutic targets for Alzheimer's disease, schizophrenia, Parkinson's disease, pain, epilepsy, ADHD, autism, depression, addiction and more. Using powerful methodologies developed in previous years of the grant, the structures of the receptors can be modified in precise and subtle ways. In particular, the amino acids that are the building blocks of these protein receptors can be specifically replaced with designed, unnatural amino acids. This allows unprecedented control over the functionality present. How these modifications impact the effectiveness of drugs that target the receptor provides key insights into the mechanism of drug action. A key issue to be addressed will be receptor selectivity - how certain drugs are able to target only specific members of a collection of very closely related receptors. The knowledge generated from these studies will be very valuable to efforts to develop new pharmaceuticals to address the many neurological disorders associated with malfunctions of the Cys-loop receptors. PUBLIC HEALTH RELEVANCE: Neurological disorders, including unipolar depressive disorders, bipolar affective disorder, and schizophrenia, present the greatest health hazard to adults in developed countries, according to the World Health Organization Global Burden of Disease assessment. The present work will provide new insights into how drugs bind to and activate a family of receptors found throughout the central and peripheral nervous systems. Malfunctions of these receptors are associated with the full spectrum of neurological disorders, and knowledge generated by this grant will be of great value to efforts to develop new pharmaceuticals to combat these dreaded diseases.