Recent discoveries implicating RNA in the pathogenesis of several forms of cancer and neuromuscular diseases have created a paradigm shift in drug discovery. This work combined with advances in structural characterization techniques such as NMR spectroscopy and X-ray crystallography together with computational modeling, has pushed forward the realization that RNA is a dynamic yet viable drug target. Traditionally, RNA was thought to be a mediator between DNA sequence-encoded instructions and functional protein. However, recent reports have shown that there are a large number of non-coding RNAs (ncRNAs) that are not translated into protein. Whereas 85% of the human genome is transcribed into RNA only 3% of the transcripts code for functional protein. Although, ncRNAs do affect gene expression levels by a variety of mechanisms. Further, RNA can adopt discrete secondary or tertiary structures which play a pivotal role in many biological processes and disease pathology. For these reasons, RNA is being recognized as an attractive drug target for small molecules.
The earliest attempts to target RNA led to the discovery that aminoglycosides could bind to human RNA. In an early report, Noller discovered that several classes of antibiotics (streptomycin, tetracycline, spectinomycin, edeine, hygromycin, and the neomycins) could "protect" nucleotides in 16S ribosomal RNA by binding to this RNA. Subsequent studies by Schroeder and Green began to plant the seed that RNA could be targeted. Schroeder uncovered that aminoglycosides could inhibit protein synthesis by interacting with the ribosome through interactions with the 3’ end of the 16S RNA of E. coli taking advantage of RNA conformational changes. Green and coworkers further confirmed this idea, discovering that aminoglycosides blocked the interaction of HIV-1 Rev protein and its viral RNA-binding site.
David Wilson and David Draper were the first to suggest that RNA structures could be targeted by small molecules. They hypothesized that RNA could be "druggable" by targeting the 3D structure in the same way as protein 3D structures are used as drug targets and furthered the idea that targeting RNA could be used to treat diseases. Czarnik and co-workers at Parke-Davis completed a screen on HIV Tat. They found multiple small molecule inhibitors of the HIV-1 Tat—TAR system that recognized the bulge, lower stem, or loop region of the TAR RNA. One of the compounds discovered, 2,4,5,6-tetraaminoquinozaline, binds to the loop region of TAR, downregulates cellular Tat transactivation, and ultimately inhibits HIV-1 replication.
The use of aminoglycosides, while an early start to RNA-targeting, came with some challenges. These molecules were only modestly selective and showed unfavorable toxicity levels at relevant therapeutic concentrations. As another strategy for targeting RNA, antisense oligonucleotides were developed which have been pushed forward through the clinic for several diseases. By this principle, if one can identify an RNA involved in disease then the sequence can be used to design a complementary antisense oligonucleotide, and that agent can be introduced into cells to treat the disease. But, this approach in its basic form has been met with several challenges. The most obvious are their large size and propensity to degradation by nucleases. In order for cellular RNA to be effective it must enter the cells intact. While backbone modifications to antisense oligonucleotides in order to prevent nuclease degradation have been shown to work, this approach is still somewhat limited. Small molecules may present a better way to target RNA and subsequently DNA because they can be designed to be more "drug-like" and have a better chance of reaching their target, most by oral administration. For this reason, there is an emerging interest in designing and discovering small molecules to target RNA secondary and tertiary structures to ultimately treat new diseases.