Molecular Imaging of G-Protein-Coupled Receptors for Drug Development

描述（由申请人提供）：G蛋白偶联受体（GPCR）通过与小分子及其替代物（药物）结合，将来自细胞外部的信号传递到细胞内部，在细胞内部它们触发从与G蛋白相互作用开始的级联事件。人类基因组中有1000个不同的GPCR，其中约450个是潜在的药物靶点。目前可用的药物中有一半以上与GPCR相互作用。由于GPCR参与了广泛的生物学活动，例如血压、疼痛、癌症生长等，新药的开发有可能治愈或改善许多疾病的症状。为了加快药物的合理设计，我们建议开发用于确定GPCR的三维结构的方法。这是一项重大的任务。在结构测定的道路上，我们将采用NMR方法筛选已成功应用于其他类别受体的候选药物。这项研究将是多学科的，涉及合成有机化学，分子生物学，结构生物学，核磁共振光谱学和计算机计算。这项研究将推进蛋白质表达和NMR光谱学的基本概念。它将非常有效地培训能够跨边界互动的科学家。它需要最高水平的技术;因此，它涉及加州大学圣地亚哥分校和两家领先的生物技术公司（前景Pharma，Inc.，哥伦比亚，MD和m-phasys GmbH，德国）。前景Pharma的关键技术是同位素标记的生长培养基，他们的工作由Jonathan Miles Brown博士领导，首席运营官M-phasys GmbH开发了在细菌中表达GPCR的方法，该方法可以利用前景Pharma的培养基，并将蛋白质重折叠成其生物活性形式;他们的工作由Hans基弗博士领导，CSO和Stefan Prytulla博士GPCR在许多人类疾病中发挥作用，因为它们在维持活细胞的正常功能方面很重要。阐明GPCR的三维结构将使我们能够在原子水平上观察这个蛋白质家族，有助于理解它们如何发挥作用以及它们如何与各自的配体相互作用。因此，这是帮助设计针对GPCR相关疾病的药物的非常重要的一步，这些疾病影响了大量的人，包括癌症，心脏病和肥胖症。

DESCRIPTION (provided by applicant): G-protein coupled receptors (GPCRs) transduce signals from the outside of cells, by binding to small molecules and their surrogates (drugs), to the inside where they trigger a cascade of events starting with interactions with G-proteins. There are 1000 different GPCRs in human genome, about 450 of which are potential drug targets. More than half of the currently available drugs interact with GPCRs. And since GPCRs are involved in a wide range of biological activities, e.g. blood pressure, pain, cancer growth, etc., the development of new drugs have the potential to cure or ameliorate the symptoms of many diseases. In order to accelerate the rational design of drugs, we propose to develop methods for determining the three dimensional structures of GPCRs. This is a substantial undertaking. On the path towards structure determination we will adapt NMR methods for screening for drug candidates that have been successfully applied to other classes of receptors. This research will be multidisciplinary, involving synthetic organic chemistry, molecular biology, structural biology, NMR spectroscopy, and computer calculations. This research will advance fundamental concepts of protein expression and NMR spectroscopy. It will be highly effective in training scientists that can interact across boundries. It requires the highest levels of technology available; as a result it, involves the University of California, San Diego and two leading biotechnology companies (ProSpect Pharma, Inc., Columbia, MD and m-phasys GmbH, Germany). ProSpect Pharma's key technology is isotopically labeled growth media and their effort is led by Jonathan Miles Brown, Ph.D., COO. M-phasys GmbH has developed methods for expressing GPCRs in bacteria that can utilize ProSpect Pharma's media, and refolding the proteins into their biologically active forms; their effort is led by Hans Kiefer Ph.D., CSO and Stefan Prytulla, Ph.D. GPCRs play a role in a number of human diseases due to their importance in maintaining proper function of living cells. Elucidation of the three-dimensional structures of GPCRs would enable us to look at this family of proteins at the atomic level, aiding in the understanding of how they function as well as how they interact with their respective ligands. This is therefore a very important step in helping to design drugs to target GPCR-related disorders that affect a large number of people including cancer, heart disease and obesity.