In Situ Synthesis Of GPCR Ligands

GPCR 配体的原位合成

基本信息

批准号：
8620213
负责人：
Vadim Cherezov
金额：
$ 20.61万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8620213
关键词：
Adverse effects Affinity Antineoplastic Agents Basal cell carcinoma Behavior Binding Binding Sites Biological CXCR4 Receptors Chemistry Clinical Trials Complex Crystallization Crystallography Detergents Development Drug Targeting Family Funding Future G Protein-Coupled Receptor Genes G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Goals Human Human Genome In Situ Joints Knowledge Ligand Binding Ligands Lipids Malignant Neoplasms Malignant neoplasm of pancreas Membrane Membrane Proteins Metastatic Prostate Cancer Methods Molecular Conformation Myeloid Leukemia Non-Small-Cell Lung Carcinoma Opioid Receptor Orphan Pathway interactions Pharmaceutical Preparations Proteins Protocols documentation Route Signal Transduction Solid Neoplasm Structure System Technology Therapeutic Time Transducers Work anti-cancer therapeutic antitumor agent antitumor drug base chemical reaction design drug discovery drug market flexibility human SMO protein innovation member novel novel therapeutics pharmacophore public health relevance receptor serotonin 5 receptor small molecule smoothened signaling pathway therapeutic target three dimensional structure tool transmission process

项目摘要

DESCRIPTION (provided by applicant): G-protein coupled receptors (GPCRs) constitute the largest family of membrane proteins in the human genome with approximately 800 members. GPCR signaling through multiple effector pathways has profound therapeutic implications, making these receptors the targets of ~40% of currently marketed drugs. Modulation of GPCR activity by small molecule ligands is emerging as a new strategy for development of anticancer therapeutics. However, design of new drugs with higher efficacy and lower side effects, and detailed understanding of GPCR mechanism of action are hampered by the limited structural information. Structural studies of many GPCRs are in turn limited by a scarcity of high-affinity ligands that stabilize GPCRs and enable their crystallization. The project attempts to develop a new platform using the in situ click chemistry approach to discover novel ligands that bind GPCRs to serve as tool compounds for structural and functional studies or as starting point for drug discovery. Target-guided synthesis approaches including in situ click chemistry, by which reactive fragments are joined in the binding sites of a biological target, have shown great promise in drug discovery but have not been applied to GPCRs. The challenges lie in the GPCRs' membrane disposition, their high conformational dynamics, low stability and low expression levels. The proposed platform is being developed targeting all GPCRs, with initial focus primarily on those known to be cancer targets. In the two years of this study, we will focus on smoothened (SMO) receptor which is an orphan receptor and a key signal transducer in the Hedgehog (Hh) signaling pathway activated during development, and thus is a target of a number of antitumor drugs in clinical trials. Our goal will be attained by achieving the following two aims: (1) Establish an in situ click chemistry platform to generate high-affinity GPCR ligands, (2) Characterize the interaction between selected ligands from Aim 1 and SMO by crystallography. The study will be supported by a team that had developed the GPCR Structure Determination Pipeline as well as its underlying technologies which have led to the structure determination of 12 GPCR structures since 2007.

描述（由申请人提供）：G蛋白偶联受体（GPCR）构成了人类基因组中最大的膜蛋白家族，约有800个成员。通过多种效应器途径的 GPCR 信号传导具有深远的治疗意义，使这些受体成为目前上市药物约 40% 的靶标。通过小分子配体调节 GPCR 活性正在成为抗癌疗法开发的新策略。然而，有限的结构信息阻碍了疗效更高、副作用更低的新药的设计以及对GPCR作用机制的详细了解。许多 GPCR 的结构研究反过来又受到缺乏稳定 GPCR 并使其结晶的高亲和力配体的限制。该项目试图开发一个新平台，利用原位点击化学方法来发现结合 GPCR 的新型配体，作为结构和功能研究的工具化合物或作为药物发现的起点。靶标引导合成方法，包括原位点击化学，通过将反应性片段连接到生物靶标的结合位点，在药物发现方面显示出巨大的前景，但尚未应用于 GPCR。挑战在于 GPCR 的膜配置、高构象动力学、低稳定性和低表达水平。拟议的平台正在针对所有 GPCR 进行开发，最初的重点主要是那些已知的癌症靶标。在这项研究的两年中，我们将重点关注平滑（SMO）受体，它是一种孤儿受体，也是发育过程中激活的刺猬（Hh）信号通路中的关键信号转导器，因此是许多抗肿瘤药物的靶点在临床试验中。我们的目标将通过实现以下两个目标来实现：(1) 建立原位点击化学平台以生成高亲和力 GPCR 配体，(2) 通过晶体学表征 Aim 1 和 SMO 中选定配体之间的相互作用。该研究将得到开发 GPCR 结构测定管道及其基础技术的团队的支持，自 2007 年以来，该技术已导致 12 个 GPCR 结构的结构测定。