RNA folds into functional structures that can be recognized by small molecules. Engaging those structures can redirect stability, splicing or RNA surveillance.
RNA is not only a message. Its sequence folds into stems, loops and higher-order motifs that create addressable surfaces, and the same transcript is assembled through splice decisions that set which isoform a cell makes. Those are two targets, not one. We hold both to the same three questions: is the target addressable, does engaging it change biology, and can it be told apart from everything nearby.
RNA forms folded higher-order structures through intramolecular interactions. They contain bulges, internal loops and junctions, and present characteristic binding pockets that small molecules can recognize.
Functional RNA structural elements control the cell through decay, translation and localization. When a small molecule binds one of them, it is not a single RNA–molecule interaction: the fate of the entire transcript changes.
Short motifs recur throughout the transcriptome, and become a source of off-target toxicity. We add structural constraints to select promising targets and achieve selective interactions with RNA.
Splice sites, branch points and the regulatory elements around them are discrete, and many are already identified. We use our own database to identify the sites that small molecules can control.
Control of exon inclusion is read directly as a quantitative isoform ratio.
For splicing-control drugs, avoiding off-target effects is the key to avoiding toxicity. Using toxicity-related splicing as the readout, we improve selectivity exponentially through a SAR cycle.
The diagrams below illustrate mechanism classes. They do not depict a specific target, compound, development program or quantitative result.
The initial recognition event can be similar. What changes is the regulatory process being influenced, and therefore the biological output.
Structured regions of RNA can recruit or exclude regulatory proteins that influence transcript stability. Small-molecule engagement can reshape that local interaction environment, shifting the balance between RNA maintenance and decay.
Pre-mRNA offers multiple splice choices. By engaging a structured regulatory region, a small molecule can influence splice-site recognition or the activity of splicing factors, favoring one mature isoform over another.
A poison exon is a normally regulated exon that can introduce a premature termination codon when included in the mature transcript. Promoting its inclusion can engage nonsense-mediated mRNA decay, reducing productive mRNA and downstream protein output.