Department of Medical Protein Research, VIB, Ghent, Belgium.
Methods. 2012 Dec;58(4):335-42. doi: 10.1016/j.ymeth.2012.08.003. Epub 2012 Aug 14.
Developing agents that target protein-protein interactions (PPIs) is an emerging field in drug discovery. Although this target class has hitherto remained underexplored, it holds exceptional promise related to the large amount of potential PPI targets compared to single protein targets and it offers important opportunities to increase the specificity of therapeutic molecules. While several PPI modulating therapeutics have recently been reported and a number of these are in clinical trial, progress in the field has been hampered by the lack of efficient screening systems. Recently, a number of cellular approaches have been developed that complement classical in vitro screening methods and which exhibit a number of important assets related to the physiological context they provide. Here we discuss the utility of two-hybrid technologies towards high-throughput screening for PPI inhibitors, in particular those that operate in a mammalian cellular background. We review a number of cases where mammalian two-hybrids have been successfully applied to identify small molecule disruptors of PPIs and zoom in further on the MAPPIT (Mammalian Protein-Protein Interaction Trap) technology platform. The value of this approach for drug discovery is illustrated by recent data from MAPPIT-based screening projects.
开发针对蛋白质-蛋白质相互作用 (PPI) 的药物是药物发现领域的一个新兴领域。尽管这个靶点类别迄今仍未得到充分探索，但与单个蛋白质靶点相比，它具有巨大的潜力，并且为提高治疗分子的特异性提供了重要机会。尽管最近已经报道了几种 PPI 调节剂治疗药物，并且其中一些正在临床试验中，但该领域的进展受到缺乏有效筛选系统的阻碍。最近，已经开发了许多细胞方法来补充经典的体外筛选方法，并具有与它们提供的生理背景相关的许多重要资产。在这里，我们讨论了双杂交技术在高通量筛选 PPI 抑制剂中的应用，特别是那些在哺乳动物细胞背景下运行的抑制剂。我们回顾了一些成功应用哺乳动物双杂交技术来识别小分子 PPI 破坏剂的案例，并进一步关注 MAPPIT（哺乳动物蛋白质-蛋白质相互作用陷阱）技术平台。基于 MAPPIT 的筛选项目的最新数据说明了这种方法在药物发现中的价值。
