第470次 SKLBE学术论坛（美国南佛罗里达大学助理教授叶立斌）

题目：How to design a biased drug?

报告人：美国南佛罗里达大学助理教授叶立斌

时间：2019-5-29  10：00

地点：实验18楼513室  

主持人：赵黎明教授

 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 receptor 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 Libin Ye et al, J. Biol. NMR, 2015 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 Libin Ye et al., Nature, 2016. 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 Libin Ye et al., to be submitted. The allosteric modulation of cations was also revisited at the dissected conformational state level Libin et al., Nature Commun, 2018. 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.

 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。2018年11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，特别是对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。

近年来，叶博士在对毕氏酵母表达系统，19F标记探针（Libin Ye et al, J. Biol. NMR, 2015）和GPCR分离纯化平台优化基础上，成功高效异源表达了人体腺苷A2A受体，使液体核磁共振对GPCR—A2AR的构象转化和动力学的研究成为了可能。叶博士的研究首次揭示了腺苷A2AR受体是通过构象选择而非诱导契合的方式激活的 (Libin Ye et al., Nature，2016，该研究成果获得了Faculty 1000推荐) 。与此同时，他的研究发现了另一个与信号转导相关的受体激活态，其可能与受体的部分激动机制(partial agonism)相关，此激活态的发现可能改变人们对部分激动机制的重新认识(Libin Ye et al., to be submitted) 。此外，虽然阳离子(Na+， Mg2+，Ca2+等)对受体激活过程的影响被广泛的认识，叶博士研究首次清淅地展示这些离子对不同受体活性态的动态变构效应(Libin Ye et al., Nature Communications, 2018) 。 受体构象和药物的直接响应关系的揭示，将极大的推动更加高效专一的药物开发。