Beaulieu Jean Martin
Dept. Psychiatry and Neuroscience, Faculty of Medicine, Laval University, Canada.
Methods. 2016 Jan 1;92:64-71. doi: 10.1016/j.ymeth.2015.08.018. Epub 2015 Aug 28.
The realization that G-protein coupled receptors (GPCR) engage several cell signaling mechanisms simultaneously has led to a multiplication of research aimed at developing biased ligands exerting a selective action on subsets of responses downstream of a given receptor. Several tools have been developed to identify such ligands using recombinant cell systems. However the validation of biased ligand activity in animal models remains a serious challenge. Here we present a general strategy that can be used to validate biased ligand activity in vivo and supports it as a strategy for further drug development. In doing so, we placed special attention on strategies allowing to discriminate between G-protein and beta-arrestin mediated mechanisms. We also underscore differences between in vitro and in vivo systems and suggest avenues for tool development to streamline the translation of biased ligands development to pre-clinical animal models.
G蛋白偶联受体（GPCR）能同时参与多种细胞信号传导机制，这一认识引发了大量研究，旨在开发对特定受体下游反应子集具有选择性作用的偏向性配体。已开发出多种工具，利用重组细胞系统来识别此类配体。然而，在动物模型中验证偏向性配体活性仍然是一项严峻挑战。在此，我们提出一种通用策略，可用于在体内验证偏向性配体活性，并支持将其作为进一步药物开发的策略。在此过程中，我们特别关注能够区分G蛋白和β-抑制蛋白介导机制的策略。我们还强调了体外和体内系统之间的差异，并提出了工具开发的途径，以简化偏向性配体开发向临床前动物模型的转化。
