Modulation of pre-mRNA splicing by small molecules

Alternative splicing of mRNA precursors is an important mechanism of gene regulation, which is frequently altered in a variety of pathologies. Recent advances demonstrate that modulating splice-site selection can offer new therapeutic options for unmet medical needs. Here, we review structural and functional data that help explain basic principles of splice site selection and their modulation by small molecules. These include selective effects of inhibitors of branch point recognition, as well as the effects of intercalating compounds that serve to repair imperfect base-pairing interactions important for 5' splice site recognition. The remarkable complexity and versatility of the spliceosome, which removes introns with high precision despite the diversity of splice-site sequences, can offer unique opportunities to selectively modulate splice-site selection for gene regulation and therapeutic applications.