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A G-protein-coupled receptor-based sensor design platform for high throughput drug screening

基于 G 蛋白偶联受体的传感器设计平台，用于高通量药物筛选

基本信息

批准号：
10577416
负责人：
Kayla Elizabeth Kroning
金额：
$ 2.03万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10577416
关键词：
Address Adrenergic Receptor Agonist Binding Biological Assay Cell Culture Techniques Chemicals Collaborations Coupled Cyclic AMP Directed Molecular Evolution Dopamine D1 Receptor Drug Screening Drug Targeting Engineering Event FDA approved Family G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Genomics Goals Human body Ligand Binding Ligands Mammalian Cell Measures Membrane Methods Michigan Modeling Molecular Conformation Monitor Noise Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Physiological Processes Play Protein Engineering Radiolabeled Reagent Receptor Activation Research Role Signal Transduction Techniques Therapeutic Therapeutic Uses Universities Work antagonist beta-2 Adrenergic Receptors cost cost effective design drug use screening high throughput screening high-throughput drug screening improved kappa opioid receptors mu opioid receptors neuronal excitability novel novel therapeutics receptor recruit screening sensor therapeutic target

项目摘要

PROPOSAL SUMMARY G-protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors, comprising over 800 receptor types in the human body. GPCRs play crucial roles in various physiological processes. Consequently, GPCRs are the target of 34% of all FDA approved pharmaceuticals. Despite this significant number, more than half of GPCRs remain untargeted by FDA approved drugs. This is partially due to the lack of a cost-effective, high-throughput drug screening platform for monitoring the immediate signaling events following GPCR activation. To further explore the therapeutic potential of both the FDA drug-targeted and untargeted GPCRs, it is necessary to develop a new high-throughput GPCR drug screening platform with a high signal-to-noise. GPCR-based fluorescent sensors are advantageous for high-throughput drug screening because they do not require expensive reagents or substrates, enabling the screening of hundreds of compounds at low costs. I aim to engineer GPCR-based fluorescent sensors that can be used to screen drugs for both Gαi/o-coupled and Gαs- coupled GPCRs. To design and optimize this platform, I will engineer sensors for the kappa opioid receptor, mu opioid receptor, beta-2-adrenergic receptor, and the dopamine D1 receptor. I will use a combination of rational protein design and directed evolution to optimize these sensors. Then, I will perform a proof of principle drug screening with these sensors in collaboration with the Center of Chemical Genomics at the University of Michigan. I expect this platform to cost less and be easier to use than the current GPCR ligand drug screening platforms. The completion of this proposal will allow the engineering of a wide array of sensors for high throughput GPCR drug screening. This new fluorescent sensor design platform will enable the screening of novel drugs for GPCRs that can be used for therapeutic purposes.

建议总结

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Modular Fluorescent Sensor Motif Used to Detect Opioids, Protein-Protein Interactions, and Protease Activity.

DOI：
10.1021/acschembio.2c00364
发表时间：
2022-08-19
期刊：
ACS CHEMICAL BIOLOGY
影响因子：
4
作者：
Kroning, Kayla E.;Li, Mingcheng;Shen, Jiaqi;Fiel, Hailey;Nassar, Manon;Wang, Wenjing
通讯作者：
Wang, Wenjing