Role of RNA as a Drug Target

The central dogma of molecular biology is that DNA encodes RNA and RNA encodes protein. RNA was essentially viewed as a carrier of genetic information from DNA to protein. Therefore, when drug targets were considered, the primary focus was DNA or proteins in this paradigm. While ~85% of the human genome is transcribed into RNA, only ~3% of those RNA transcripts encode proteins, suggesting that the vast majority are non-coding RNAs (ncRNAs).

DNA/RNA Concept

DNA/RNA Concept. Image Credit: ktsdesign/

The last two decades have seen an explosion of research in the area of RNA biology, including RNA diversity, structural and functional information. This has unraveled the critical roles of RNA, including regulation of transcription and translation, catalysis, protein function, protein transport, peptide bond formation, and RNA splicing. RNA malfunction causes a multitude of diseases including bacterial/viral infections as well as cancer.

RNA is now front and center as a therapeutic drug target

Conventional therapeutics targeting DNA or proteins have many challenges. For DNA therapeutics, toxicity is a major concern (eg; anti-cancer reagents and CRISPR-Cas9 therapy).  In the case of proteins, only a small fraction of the genome is encoded by proteins, and amongst these the disease-related and druggable targets are relatively few. RNA as a drug target provides many more potential targets that constitute a much larger fraction of the genome, with very diverse functions.

Both coding, as well as ncRNAs, can be used as drug targets. RNA molecules such as antisense oligonucleotides (ASO), aptamers, small interfering RNAs (siRNA), and messenger RNAs (mRNAs), have emerged as a new class of compounds for the treatment of several diseases.

Antisense oligonucleotides

ASOs are synthetic single-stranded DNA oligonucleotides that selectively inhibit target gene expression via complementary base pairings with targeted mRNA. The ASO-mediated knockdown of target gene expression involves both RNase-dependent cleavage of mRNAs and precursor mRNAs (RNase H and RNase P) and RNase-independent suppression of protein synthesis. ASOs can also be employed to modulate RNA splicing.

In 1998, the first ASO approved for the treatment of cytomegalovirus retinitis was produced. Since then many ASOs have been prescribed clinically for the treatment of various diseases like Duchenne’s muscular dystrophy, spinal muscular atrophy, and hereditary transthyretin-mediated amyloidosis.


Aptamers are highly structured, single-stranded DNA or RNA oligonucleotides. Aptamers can bind to various molecular targets like proteins, peptides, DNAs, RNAs, small molecules, and ions, with high affinity and specificity. RNA aptamer binds to the target protein and behaves like a nucleic acid antibody or chemical inhibitor thus modulating protein function.  

Small interfering RNAs

siRNAs are 18-22bp double-stranded RNA molecules that have been routinely used for selective and effective knockdown of target genes.

Almost 20 years after the discovery of siRNA-based gene silencing, the first siRNA drug was approved for clinical use in 2018 for the treatment of polyneuropathy of hATTR amyloidosis in adults. The second siRNA drug approved was for the treatment of adults with acute hepatic porphyria. More than 21 siRNA-based therapeutics have now been developed for more than a dozen of diseases including various cancers, viruses, and genetic disorders.


miRNAs are evolutionarily conserved small ncRNAs that regulate gene expression by degrading mRNA or by suppressing mRNA translation. The small size of the miRNAs makes it a challenging prospect as a drug target.

Hitherto, several methods have been employed to target miRNA including the use of anti-sense agents that lead to silencing by mimicking, binding to the target miRNA directly causing a translational arrest, or by targeting Argonaute 2 protein which is a primary executor of the miRNA function.

Messenger RNAs

mRNAs as a drug target has great potential in vaccination, protein replacement therapy, and antibody therapy. The principal advantage of mRNA drugs are a) high sensitivity of immune cells in recognizing antigens that can be coded by exogenous mRNAs, b) their intrinsic immune-stimulatory effects and 3) that they can be translated into target proteins by the cellular machinery without interference with the genome.

Managing infectious diseases through mRNA vaccines is a very promising area of research. There are many mRNA therapeutics currently used in clinical practice. In fact, the coronavirus mRNA vaccine encoding the SARS-CoV-2 spike protein with the native furin cleavage site has been fast-tracked for general use to combat the current pandemic.

Small molecule-based targeting of the RNA

Small molecule-based targeting of RNAs opens up opportunities to therapeutically modulate numerous cellular processes, including those with undruggable protein targets. There are currently three biologically effective small molecules that target RNA.

  1. Linezolid is a broad-spectrum antibacterial agent that binds to the large RNA subunit of the ribosome and interferes with the positioning of the tRNA.
  2. Ribocil binds to riboflavin riboswitches (RNA-mediated regulators of gene expression in bacteria) in an interesting manner because it binds in the same pocket as the natural flavin mononucleotide ligand, and predisposing the RNA to bind a small molecule.
  3. Branaplam and chemotypically similar SMA-C5 both appear to bind at the RNA duplex formed between the U1 RNA and the target (SMN2) pre-mRNA and are likely stabilized by the U1 small nuclear ribonucleoprotein particle (snRNP). These molecules are proof-of-concept for RNA as a drug target.

Modern innovations in screening strategies such as small molecule microarrays, phenotypic assays, high throughput screening, fragment-based screening, and structure-function-based approaches will lead to the discovery of many such therapeutic small molecules.

In conclusion, RNAs have developed into a promising drug target for the treatment of various diseases and infections including bacterial and viral infections, cancer, inherited genetic disorders, cardiovascular as well as rheumatic diseases. While the possibility of design and identification of small molecules that modulate RNA seems promising, many challenges such as specificity and selectivity remain. The question of whether RNAs are druggable is only beginning to be addressed.


  • CONNELLY, C. M., MOON, M. H. & SCHNEEKLOTH, J. S., JR. 2016. The Emerging Role of RNA as a Therapeutic Target for Small Molecules. Cell Chem Biol, 23, 1077-1090.
  • ILINSKAYA, O., HAUSENLOY, D. J., CABRERA-FUENTES, H. A. & ZENKOVA, M. 2020. Editorial: New Advances in RNA Targeting. Front Pharmacol, 11, 468.
  • WARNER, K. D., HAJDIN, C. E. & WEEKS, K. M. 2018. Principles for targeting RNA with drug-like small molecules. Nat Rev Drug Discov, 17, 547-558.
  • SHAO, Y. & ZHANG, Q. C. 2020. Targeting RNA structures in diseases with small molecules. Essays Biochem, 64, 955-966.

Further Reading

Last Updated: Aug 24, 2021

Dr. Poornima Balaji

Written by

Dr. Poornima Balaji

Poonam is passionate about all things science and medicine. She has over 20 years of experience in research in cardiovascular physiology, biochemistry, and molecular biology. Poonam has worked as an independent scientist both in the United States and in Australia and has several publications in high-impact journals. (11 publications with ~700 citations; h index of 11).


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