Targeting post-transcriptional control for drug discovery

Post-transcriptional regulatory mechanisms, dependent on specific RNA:RNA, RNA:protein, or protein:protein interactions that generate large numbers of different RNP constellations, can have sizeable effects on the expression of any given gene. At the mRNA-specific level, these mechanisms also provide numerous novel targets for small molecule drugs capable of enhancing or inhibiting the accumulation of specific proteins. Here, we describe two drug screening technologies that target the post-transcriptional regulation of specific mRNAs with specific small molecules. In one case the GEMSTM technology utilizes mRNA-specific 5'- and 3'-UTR pairs to identify compounds that reduce protein production as a consequence of the UTRs. The second example utilizes nonsense-containing mRNAs to identify compounds capable of promoting therapeutic nonsense suppression. Both programs have yielded drug candidates that are presently in clinical testing for human diseases with high unmet clinical needs, thus illustrating the therapeutic potential of targeting post-transcriptional control.