The use of mammalian two-hybrid technologies for high-throughput drug screening.
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.
Department of Medical Protein Research, VIB, Ghent, Belgium.
Sam
S
Lievens
Maureen
M
Caligiuri
Niko
N
Kley
Jan
J
Tavernier
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D010446:Peptide Fragments / Q000096:biosynthesis; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping / Q000379:methods; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis; D020798:Two-Hybrid System Techniques
D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors