Leveraging structure and function studies of thromboxane A2 receptors for drugs targeting cardiovascular and inflammatory diseases

利用血栓素 A2 受体的结构和功能研究开发针对心血管和炎症疾病的药物

• 批准号: 327066363
• 负责人: Dr. Dietmar Weichert
• 金额: --
• 依托单位: Biomedical Sciences Institute
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/327066363?language=en
• 关键词: Leveraging; structure; function; studies; thromboxane

This proposal outlines a multifaceted approach to solving the atomic resolution structure of the thromboxane A2 prostanoid (TP) receptor in complex with a potential drug candidate using X-ray crystallography to inform the development of drugs targeting cardiovascular and inflammatory diseases. TP receptors are medically important G protein-coupled receptors (GPCRs) that are activated by the endogenous prostanoid thromboxane A2 (TXA). The TXA-TP receptor transmembrane signaling system has been implicated in a range of cardiovascular as well as inflammatory and proliferatory conditions, like asthma and Alzheimer's disease and certain cancers, making it an attractive target for the development of therapeutics. In the absence of a high-resolution structure, however, the TP receptor has remained an elusive drug target. A structural understanding of the molecular basis underlying TP function and ligand-recognition will not only inform the rational design of drugs inhibiting TP receptors, it will also serve as a molecular blueprint for the eight cognate prostanoid receptor subtypes that are increasingly recognized as targets for therapeutic drug development. This project will therefore open avenues for the structure-based design of inhibitors targeting TP receptors and the wider prostanoid system. The methodological approach to achieving this aim comprises state-of-the-art protein expression and purification techniques, supported by protein engineering and thorough biochemical characterization of the TP receptor constructs. This will ensure the production of high-quality protein in quantities suitable for crystallization trials. The full range of traditional and innovative approaches for crystallizing membrane proteins will be tested to solve the co-crystal structure of the TP receptor in complex with a potential drug candidate. Collectively, this project bridges the disciplines of biochemistry, structural biology and medicinal chemistry. It will be hosted by Professor Martin Caffrey at Trinity College Dublin (one of the foremost scientists in the field of membrane protein structural biology) and will be undertaken in collaboration with a multidisciplinary team of international experts, including Professor Brian Kobilka of Stanford University (2012 winner of the Nobel Prize for Chemistry for his research on GPCRs) and Professor B. Therese Kinsella of University College Dublin (thromboxane A2 receptor pharmacologist and Chief Scientific Officer of ATXA Therapeutics Ltd., a company dedicated to the development of drugs targeting TP receptors). Each member will provide specialized advice and a resourceful environment to support the accomplishment of the Applicant's research program goals and overall professional development.

该提案概述了一种多方面的方法来解决血栓烷A2前列腺素（TP）受体与潜在候选药物的复合物的原子分辨率结构，使用X射线晶体学来告知靶向心血管和炎症性疾病的药物的开发。TP受体是医学上重要的G蛋白偶联受体（GPCR），其由内源性前列腺素类血栓烷A2（TXA）激活。TXA-TP受体跨膜信号传导系统与一系列心血管疾病以及炎症和增殖性疾病有关，如哮喘和阿尔茨海默病以及某些癌症，使其成为开发治疗方法的有吸引力的靶标。然而，在缺乏高分辨率结构的情况下，TP受体仍然是一个难以捉摸的药物靶标。对TP功能和配体识别的分子基础的结构理解不仅可以为抑制TP受体的药物的合理设计提供信息，还可以作为八种同源前列腺素受体亚型的分子蓝图，这些亚型越来越多地被认为是治疗药物开发的靶点。因此，该项目将为靶向TP受体和更广泛的前列腺素系统的抑制剂的基于结构的设计开辟道路。实现这一目标的方法学途径包括最先进的蛋白表达和纯化技术，由蛋白工程和TP受体构建体的彻底生物化学表征支持。这将确保以适合结晶试验的数量生产高质量的蛋白质。将测试用于结晶膜蛋白的全部传统和创新方法，以解决TP受体与潜在候选药物复合物的共晶结构。总的来说，这个项目是生物化学、结构生物学和药物化学学科的桥梁。会议将由都柏林Trinity学院的Martin Caffrey教授（膜蛋白结构生物学领域最重要的科学家之一）主持，并将与包括斯坦福大学的Brian Kobilka教授（因其对GPCR的研究而赢家2012年诺贝尔化学奖）和B教授在内的多学科国际专家团队合作进行。都柏林大学学院的Therese Kinsella（血栓烷A2受体药理学家和ATXA治疗有限公司的首席科学官，一家致力于开发靶向TP受体的药物的公司）。每个成员将提供专业的建议和资源丰富的环境，以支持申请人的研究计划目标和整体专业发展的实现。