![]() A focus is placed on small molecules targeting miRNA biogenesis, lncRNAs, mRNAs encoding intrinsically disordered proteins (IDPs), and repeat expansion disorders. This review provides a general overview of recently developed RNA-targeting small molecules, highlighting advances in the field that continue to push towards the development of potent and selective small molecule lead therapeutics. ![]() ![]() Small molecule binding of an RNA target can modulate disease biology, thus creating avenues to further explore RNA-disease biology and potential therapeutics against RNA-associated disorders. 19 Conversely, small molecules are designed to target RNA structure instead of sequence, much like how small molecules are designed to target proteins via structure-based recognition. 19 RNase H recognizes the RNA–DNA heteroduplex and hydrolyzes the phosphodiester bonds of the RNA strand, cleaving it. ASOs, which often contain modified phosphate backbones and sugar motifs to protect against cellular degradation, either repress translation by sterically blocking ribosomal loading onto the RNA or induce degradation of the target RNA via Ribonuclease H (RNase H). 18 ASOs are single-stranded nucleotide sequences designed to complementarily base pair a target RNA's primary sequence. To date, two main therapeutic strategies have been employed to target disease-causing RNAs: antisense oligonucleotides (ASOs) and small molecules. 17 The biological consequences of these repeat expansions will be reviewed in detail below. This class of disorders is responsible for over 30 human diseases including Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), fragile X-associated tremor and ataxia syndrome (FXTAS), and myotonic dystrophies type 1 and 2 (DM1 and DM2). 7, 15, 16 Additionally, structured RNAs have been implicated in several neurological disorders, as reviewed in Bernat et al., 17 a well-known example being RNA repeat expansion/microsatellite disorders. For example, dysregulation of miRNAs, short regulatory RNAs that modulate gene expression via the RNA-induced silencing complex (RISC), 7 have been associated with, among others, cardiovascular disease, inflammatory disorders, and cancer. Predictably, disruption of RNA structure via mutation, formation of unnatural RNA structures, e.g., by insertions or expansions, or aberrant expression, leads to dysregulation of cellular processes, resulting in disease. As these topics will not be reviewed in depth here, we direct the reader to the references cited above for additional detail. 5 In the context of human biology, structured RNAs influence translational regulation, 6- 8 alternative splicing, 9, 10 and even enzymatic catalysis, 11- 14 further demonstrating their intimate involvement in maintaining healthy biology. The influence of these structures has been explored in the context of bacterial gene expression and riboswitches 4 and in viral replication and infection. The variability and complexity of RNA structures has been widely explored, leading to the appreciation that RNAs range from being largely disordered (dynamic) to adopting simple structures such as loops and bulges (secondary structure) to creating highly intricate pseudoknots, G-quadruplexes, and coaxial stacking (tertiary structure). ![]() The Central Dogma of biology, showcasing the numerous types of structured RNAs that have been identified to date. The compounds discussed in this review have proven efficacious in human cell lines, patient-derived cells, and pre-clinical animal models, with one compound currently undergoing a Phase II clinical trial and another that recently garnered FDA-approval, indicating a bright future for targeted small molecule therapeutics that affect RNA function. Additionally, we explore emerging RNA-target strategies, such as bleomycin A5 conjugates and ribonuclease targeting chimeras (RIBOTACs), that allow for the targeted degradation of RNAs with impressive potency and selectivity. This review highlights recent advances in this area, with a focus on the design of small molecule probes that selectively engage structures within disease-causing RNAs, with micromolar to nanomolar affinity. Although the bacterial ribosome has historically been the most well exploited RNA target, advances in RNA sequencing technologies and a growing understanding of RNA structure have led to an explosion of interest in the direct targeting of human pathological RNAs. The rich structural diversity of folded RNAs offers a nearly unlimited reservoir of targets for small molecules to bind, similar to small molecule occupancy of protein binding pockets, thus creating the potential to modulate human biology. Targeting RNAs with small molecules represents a new frontier in drug discovery and development.
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