Most conventional antiviral strategies target proteins—such as the enzymes the virus needs to replicate its genome or the surface proteins required for cell entry. However, viral RNA is not merely a passive strand of instructions; it forms complex three-dimensional structures, regulates protein synthesis, and can serve as a template for new genomic copies. That is why researchers are increasingly viewing it as a distinct pharmacological target.
This does not mean that any viral RNA can already be “switched off” using an existing drug. The approach encompasses several very different technologies: antisense oligonucleotides, RNA interference, small molecules that bind to folded RNA regions, and experimental Cas13 systems. Their stages of development range from a previously approved drug to experiments in cells and animal models.
In many viruses, RNA performs multiple functions simultaneously. It stores genetic information, serves as a template for protein synthesis, and forms hairpins, loops, and pseudoknots that interact with viral and cellular molecules. If a region is critically important and sufficiently conserved, blocking it could potentially halt a part of the virus’s life cycle.
At the same time, it is important to distinguish between direct and indirect targeting. Nucleoside analogues can be incorporated into nascent viral RNA or disrupt its synthesis, yet the viral polymerase often remains their key protein target. In contrast, an antisense oligonucleotide recognizes a specific RNA sequence, whereas a small molecule can bind to a three-dimensional pocket within it.
An antisense oligonucleotide is a short synthetic strand with a sequence complementary to a target RNA. Upon binding, it can interfere with RNA reading or promote its degradation by cellular enzymes.
The idea has a clinical precedent. In 1998, the FDA approved fomivirsen for the treatment of cytomegalovirus retinitis; the drug was complementary to viral mRNA and was administered directly into the eye. An official FDA review designated fomivirsen as the first approved antisense antiviral agent; it was later withdrawn by the sponsor. This example validated the principle but also demonstrated the extent to which its application depended on the delivery method and the specific clinical need (FDA, antiviral drug review; FDA, list of oligonucleotide drugs).
A more modern example is bepirovirsen, an antisense oligonucleotide targeting hepatitis B virus transcripts. Although HBV has a DNA genome, its life cycle involves critical RNA transcripts, including pregenomic RNA. In two Phase III B-Well trials, protocol-defined functional cure at week 72 was observed in 20% and 19% of participants receiving bepirovirsen, compared to 0% in the placebo groups. However, grade 3 or higher adverse events during treatment were more frequent with bepirovirsen (16% vs. 3%), with elevated alanine aminotransferase levels being the most common. This is a significant result, but it is not a universal effect and does not constitute a basis for independent medical decisions (Hou et al., NEJM, 2026; PubMed; B-Well 1 registry, ClinicalTrials.gov).
Small molecules are easier to manufacture and can potentially penetrate tissues better than large oligonucleotides. The challenge is that RNA was long considered a target that was too flexible and uniformly charged. Now, however, structural methods and compound library screening are helping to identify local “pockets” within stable RNA elements.
One of the most well-documented laboratory cases involves the SARS-CoV-2 RNA frameshifting element. This pseudoknot helps the ribosome shift its reading frame to synthesize the proteins required for replication. Researchers identified aminoquinazoline compounds that bound to this RNA and altered frameshifting in biophysical, cell-free, and cellular assays. However, the binding affinity of the top candidates was only in the micromolar range, and some of the compounds also affected general translation. This illustrates the typical gap between a compound interacting with a target and a candidate being suitable for therapeutic use (primary study, *ACS Chemical Biology*, 2023).
Another study combined an RNA-binding molecule with a RIBOTAC module that recruits a cellular ribonuclease to degrade viral RNA. The authors demonstrated direct binding, an effect on frameshifting, and selectivity in cellular systems. However, this remained a preclinical proof-of-concept rather than a trial in humans (Haniff et al., ACS Central Science, 2020; PubMed).
Cas13 systems use a guide RNA to recognize and cleave target RNA. In 2021, researchers reported that mRNA-encoded Cas13a reduced signs of influenza A infection in mice and SARS-CoV-2 infection in hamsters. While this represents a step beyond cell culture, it still involves an animal model. Clinical application requires the safe delivery of Cas13 and the guide RNA to the target cells, control over the duration of activity, and an assessment of off-target effects (Murray et al., Nature Biotechnology, 2021).
RNA adds a new level of design to classical pharmacology. Its sequence allows for the programming of oligonucleotides, while its three-dimensional structure enables the identification of pockets for small molecules. This can be particularly useful when a suitable protein target is unavailable or when it is important to simultaneously suppress multiple viral products.
However, the main lesson is no longer that “RNA can be targeted,” but rather how to demonstrate the quality of a candidate: confirming direct binding, showing an effect in infected cells, testing delivery and toxicity in animals, and then proceeding through controlled clinical trials.
No. The sequences, RNA structures, target tissues, and modes of replication differ. Even a conserved element requires separate confirmation for each virus.
No. It is being studied in a specific group of people with chronic hepatitis B based on defined criteria. The results cannot be extrapolated to other infections or used as a treatment recommendation.
Cell cultures do not fully replicate drug distribution among organs, immune responses, metabolism, or long-term toxicity. A positive result in a cell culture marks the beginning of testing rather than proof of clinical benefit.
Viral RNA has moved beyond being merely a target for diagnostics; its sequence and structure are becoming viable targets for antisense molecules, small compounds, and programmable RNases. Clinical results with bepirovirsen demonstrate the potential of this approach, while research into pseudoknots and Cas13 is expanding the available toolkit. At the same time, efficacy, delivery, and safety remain distinct challenges for each technology. It is advisable to track developments in this field through peer-reviewed publications and clinical trial registries, and to discuss treatment decisions exclusively with a qualified physician.
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