Binding to RNA is not enough—changing its shape is what makes a drug work, study reveals

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Ribonucleic acids (RNAs) serve as messengers between DNA and protein production, and perform a wide variety of regulatory functions across different cellular processes. This makes them an interesting target for drug designers. Molecular genetics researcher Danny Incarnato (University of Groningen) studies how small-molecule drugs could interfere with RNA structure and function. In a new paper published on March 23 in the journal Nature Communications, he shows that small molecules that bind to RNA only rarely affect its function, while molecules that change RNA structure have a bigger effect.

RNA is a single-stranded nucleic acid molecule that can fold back on itself and is found in all living cells. Many small molecules bind to RNA and, in doing so, could change its regulatory functions. However, to date, despite billion-dollar investments in this domain, only one mRNA-targeting small molecule drug (risdiplam, for the treatment of spinal muscular atrophy) has made it to the market. This shows that a huge gap still exists in our understanding of what makes a good RNA-targeting drug.

Design new molecules to control RNA shapes

In previous works, Incarnato's team has shown that one RNA molecule can often take on several different shapes. In the new study, they show how the FDA-approved cancer drug mitoxantrone changes the way RNA folds back on itself. "RNA molecules have not just one shape," explains Incarnato. "They can adopt and interconvert between different shapes. Mitoxantrone stabilizes a specific shape of the RNA molecule." Incarnato's team shows that this modulation of RNA folding has functional consequences.

He concludes that, in the search for drugs that act on RNA, scientists should not just look at molecules that bind to it, but also for signs that a molecule can change an RNA's structure.

In the new paper, his team describes a framework that could identify and characterize such RNA structure-changing small molecule drugs. To realize this goal, more studies must be carried out to understand how different drugs influence RNA structures across the whole cell. "Then, we could even design new molecules specifically to control RNA shapes." The long-term goal of this project is to develop better drugs that target RNA directly.

Publication details

Chundan Zhang et al, RNA functional modulation by Mitoxantrone via RNA structural ensemble repartitioning, Nature Communications (2026). DOI: 10.1038/s41467-026-70801-9

Journal information: Nature Communications

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molecular biology

Provided by University of Groningen