G蛋白偶联受体
异三聚体G蛋白
功能选择性
痛苦
效应器
药理学
生物
药物发现
G蛋白偶联受体激酶
计算生物学
神经科学
信号转导
G蛋白
生物信息学
医学
细胞生物学
法学
政治
政治学
作者
Dylan Eiger,Uyen Pham,Julia Gardner,Chloe Hicks,Sudarshan Rajagopal
出处
期刊:American Journal of Physiology-cell Physiology
[American Physiological Society]
日期:2022-05-01
卷期号:322 (5): C887-C895
被引量:13
标识
DOI:10.1152/ajpcell.00449.2021
摘要
G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and are the target of approximately one-third of all Food and Drug Administration (FDA)-approved pharmaceutical drugs. GPCRs interact with many transducers, such as heterotrimeric G proteins, GPCR kinases (GRKs), and β-arrestins. Recent experiments have demonstrated that some ligands can activate distinct effector proteins over others, a phenomenon termed “biased agonism.” These discoveries have raised the potential of developing drugs which preferentially activate therapeutic signaling pathways over those that lead to deleterious side effects. However, to date, only one biased GPCR therapeutic has received FDA approval and many others have either failed to meet their specified primary end points and or demonstrate superiority over currently available treatments. In addition, there is a lack of understanding regarding how biased agonism measured at a GPCR leads to specific downstream physiological responses. Here, we briefly summarize the history and current status of biased agonism at GPCRs and suggest adoption of a “systems pharmacology” approach upon which to develop GPCR-targeted drugs that demonstrate heightened therapeutic efficacy with improved side effect profiles.
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