5月31日 叶立斌:How to design a biased drug?


报告题目:How to design a biased drug?

报告人:Libin Ye, University of South Florida

主持人:张美玲 教授

报告时间:2019531日上午1000(周五上午)

报告地点:生命科学学院534小会议室


报告人简介:

叶立斌博士目前是美国南佛罗里达大学细胞生物学、微生物学和分子生物学系助理教授同时隶属于Moffitt癌症研究中心。叶博士于2008年南京农业大学取得博士学位。2010年到2018年间先后在美国伊利诺伊大学香槟分校、匹兹堡大学医学中心和多伦多大学化学系和生物化学系从事博士后研究。201811月叶博士正式加盟南佛罗里达大学成为独立PI

叶博士的研究主要分两个方向:一是对G蛋白偶联受体的构象转化、动力学和信号转导的研究,特别是那些与神经性疾病和癌症相关的G蛋白偶联受体的研究;实验室同时也从事构象转化和动力学方法学开发的研究。另一个方向是研究致病菌生物膜的合作机制以及开发相关的药物。


报告内容:

G protein-coupled receptor (GPCR) dysfunction causes various diseases, including cancer, cardiac failure, neurological diseases, and obesity. Although only 5% of GPCRs have been subjected to drug discovery, they already represent targets of 33% of FDA-approved medications. More precisely, the occurrence of a disease can be interpreted by a specific conformational state being excessively accumulated or depleted under a certain unnormal physiological environment, consequently leading to a corresponding downstream signaling dysfunction. Most marketed drugs were developed based on a dose-dependent manner rather than a conformation-based manner. As a result, these drugs more or less have undesirable side effects by merely activating or deactivating the receptor rather than rectifying the dysfunctional conformational state. Nuclear magnetic resonance spectroscopy (NMR) is exceptionally suited to the detection of entire ensembles of conformational states associated with a given receptor at once. In my research, upon attaching an optimized sensitive (19F) fluorinated reporter to a judiciously chosen labeling site of a prototypical GPCR—A2A adenosine receptor (A2AR), an ensemble of four conformational states, two inactive and two active states, were quantified. The A2AR activation process was therefore revealed for the first time to be conformational selection rather than induced fit. My research also identified an intermediate active state, potentially in charge of partial agonism. This finding provides a deeper insight into the mechanism of partial agonism. The allosteric modulation of cations was also revisited at the dissected conformational state level. A deeper insight into receptor activation and allostery, based on the delineated conformational states, will have wide-reaching implications for our understanding of GPCR activation and designing conformation-guided biased drugs with a high selectivity and fewer side effects.