Non-coding RNA structures called riboswitches are known to regulate gene expression. As opposed to proteins and nucleic acids, riboswitches have remained a largely underdeveloped class of drug targets. A team from Merck recently reported the discovery of ribocil, a compound that selectively modulates bacterial riboflavin riboswitches. The small molecule was identified as part of a phenotypic screen. Ribocin was found to inhibit bacterial cell growth by repressing ribB gene expression. Specifically, this new molecule competitively mimics the natural ligand of a bacterial riboswitch, namely flavin mononucleotide (on the right hand side of the graphic below is a representative riboswitch complexed with flavin mononucleotide). I think it is exciting that small molecules can now target non-coding RNA structural elements. One cannot help but notice structural similarities between ribocin and a number of well known kinase inhibitors, which begs a question about the possibility of repurposing some of those “usual suspects”.
Indeed, many kinase inhibitors, especially with purine and pyrimidine core interact pretty well with secondary structures of RNA. I wonder if the structural similarity to nucleobases have something to do with it.
I think this is exactly what happens. Someone should figure out the rules of engagement there… As an aside, Peter Dervan has done some great stuff in the area of DNA/oligoheterocycle interaction. There must be a good and rational way of treating RNA in the same way.