Targeting RNA vs proteins in drug discovery

In search of new therapeutic solutions, the exploration of RNA and protein targeting has emerged as a pivotal frontier, offering new avenues for the development of medications to treat a wide range of diseases. Both RNA and proteins are fundamental players in cellular processes (Fig. 1), thus representing intricate and diverse prospects for drug development. Their manipulation presents unique opportunities to modulate disease pathways with precision and efficacy. Moreover, the complex interplay between the two approaches of RNA and protein targeting, with their distinct roles, advantages, challenges, and future perspectives, ultimately shapes the landscape of therapeutic innovation.

Fig. 1. a. Key biological processes regulated by RNAs and their functions driven by their structures.
b. Comparison of RNA and protein as therapeutic targets. (Adopted from [1]).

Once considered a mere intermediary in the flow of genetic information, RNA is now recognized as a versatile molecule with various regulatory functions. The ability to target RNA opens up possibilities for modulating gene expression, splicing, and translation, offering unlimited opportunities for therapeutic intervention. Multiple methods and technologies [1-4], such as antisense oligonucleotides, small interfering RNAs, and CRISPR-based approaches, enable precise targeting of RNA molecules implicated in diseases. Notable examples of RNA-targeted drugs include those targeting microRNAs in cancer [5] and antisense oligonucleotides in neurodegenerative disorders [6].

Another vast and diverse class of drug targets represents proteins, the “workhorses” of cellular function. From enzymes and receptors to structural proteins, the therapeutic potential of targeting proteins spans across various disease areas. Traditional approaches, such as small-molecule inhibitors and monoclonal antibodies, have been augmented by advances in protein engineering and computational biology, enabling the design of highly specific and potent protein-targeted drugs [7-8]. Examples are plentiful, including kinase inhibitors in cancer therapy and monoclonal antibodies in autoimmune diseases.

Comparing the two approaches in question, RNA and protein targeting, reveals distinct molecular mechanisms, therapeutic applications, and clinical development pathways. While RNA targeting offers the advantage of modulating gene expression at the pre-transcriptional or post-transcriptional level through various mechanisms such as degradation, splicing modulation, or translation inhibition (Fig. 2), protein targeting allows for the inhibition or modulation of specific protein functions through interactions with ligands, inhibitors, or antibodies. In terms of therapeutic applications, RNA targeting is particularly suited for diseases with dysregulated gene expression, including genetic disorders, cancer, and neurodegenerative diseases [9]. Protein targeting, on the other hand, holds promise for diseases driven by aberrant protein activity, such as enzyme deficiencies, receptor overexpression, or signaling pathway dysregulation. Considering the clinical development, RNA-targeted drugs often face challenges in delivery, stability, and off-target effects, necessitating innovative delivery systems and chemical modifications for clinical translation. At the same time, protein-targeted drugs may encounter issues such as immunogenicity, on-target/off-target toxicity, and drug resistance, requiring optimization of drug design and dosing regimens for clinical efficacy. All in all, the choice between RNA and protein targeting depends on factors such as target druggability, delivery requirements, and desired therapeutic outcomes.

Fig. 2. Inhibition of RNA-binding proteins with small molecules.

The future of both RNA and protein targeting in drug discovery undoubtedly have excellent prospects for continued growth and innovation. Advances in technology, such as CRISPR-based gene editing, RNA-targeted nanoparticles, and protein engineering, will enhance the specificity, efficacy, and safety of targeted therapies. Integration of multi-omic data and computational modeling will facilitate the identification of novel targets and the prediction of drug responses. Furthermore, the development of personalized medicine approaches based on genomic, transcriptomic, and proteomic profiling will enable tailored therapeutic interventions for individual patients. Overall, the synergistic combination of RNA and protein targeting strategies holds immense potential for addressing unmet medical needs and advancing precision medicine in the future.

With this in mind, Life Chemicals has developed proprietary collections of RNA-targeting Screening Compound Libraries, including:

RNA libraries

• RNA Screening Library by 2D Similarity Search (22,300 compounds)
• RNA Screening Subset by Bayesian Modeling (1,000 compounds)
• RNA Screening Subset by Exact Match (900 compounds)
• Human RNA Focused Library (5,500 compounds)
• RNA Diversity Screening Sets (5,120, 3,200, and 1,600 compounds)

Pre-plated sets

• Pre-plated RNA Diversity Screening Sets (1,600, 3,200, and 5,120 compounds)
• Pre-plated RNA Focused Sets (960, 3,300 and 5,120 compounds)

In order to diversify and expand your research toolbox, we also offer several related screening libraries:

• RNA-associated Protein Screening Library (6,500 compounds)
• Transcription-related Screening Library (9,200 compounds)
• DNA and RNA Polymerase Screening Libraries (29,000 compounds)
• Helicase Screening Libraries (7,000 compounds)
• Nuclear Receptor Screening Libraries (44,000 compounds)
• Anticancer Screening Compound Libraries
• Anti-inflammatory Screening Compound Library
• Protein-Protein Interactions (PPI) Screening Libraries

Order your custom compound selections and enjoy the most convenient terms and competitive pricing.

Please, contact us at marketing@lifechemicals.com for any additional information and price quotations.

Download SD files with compound structures directly from our Downloads section

References     

1. Childs-Disney, J.L., Yang, X., Gibaut, Q.M.R. et al. (2022). Targeting RNA structures with small molecules. Nat Rev Drug Discov 21: 736–762. DOI: 10.1038/s41573-022-00521-4

2. Warner, K., Hajdin, C. & Weeks, K. (2018). Principles for targeting RNA with drug-like small molecules. Nat Rev Drug Discov 17: 547–558. DOI: 10.1038/nrd.2018.93

3. Yu A.M., Choi Y.H., Tu M.J. (2020). RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges. Pharmacol Rev. 72(4):862-898. DOI: 10.1124/pr.120.019554

4. Shao Y, Zhang Q.C. (2020). Targeting RNA structures in diseases with small molecules. Essays Biochem. 64(6):955-966. DOI: 10.1042/EBC20200011

5. Shah, V., Shah, J. (2020). Recent trends in targeting miRNAs for cancer therapy. Journal of Pharmacy and Pharmacology, 72 (12):1732–1749. DOI:10.1111/jphp.13351

6. Leavitt, B.R., Tabrizi, S.J. (2020). Antisense oligonucleotides for neurodegeneration. Science 367:1428-1429. DOI: 10.1126/science.aba4624

7. Ha J., Park H., Park J., Park S.B. (2021). Recent advances in identifying protein targets in drug discovery. Cell Chem Biol. 28(3):394-423. DOI: 10.1016/j.chembiol.2020.12.001 

8. Rosell, M., & Fernández-Recio, J. (2018). Hot-spot analysis for drug discovery targeting protein-protein interactions. Expert Opin. Drug Discov, 13(4): 327–338. DOI: 10.1080/17460441.2018.1430763

9. Zhu, Y., Zhu, L., Wang, X. et al. (2022). RNA-based therapeutics: an overview and prospectus. Cell Death Dis 13: 644. DOI: 10.1038/s41419-022-05075-2