Helicases, often called molecular motors of the cell, are dynamic enzymes crucial for unwinding DNA and RNA duplexes. They have been known to play pivotal roles in fundamental cellular processes like replication, repair, transcription, and translation [1-3]. Being involved in these essential pathways, helicases are promising targets for drug discovery and therapeutic intervention. They come in diverse flavors and are classified on the basis of their structure, mechanism, and cellular localization (Fig. 1). Ranging from the ubiquitous superfamily 2 (Sf2) helicases to the specialized DEAD-box and RecQ helicases, each helicase family exhibits unique functional characteristics tailored to specific cellular tasks. For instance, Sf2 helicases, like the well-known Pif1 helicase in yeast, are essential for DNA replication, while RecQ helicases, like RECQL4, are crucial for maintaining genome stability [4].
Fig. 1. Helicases in DNA replication (left, art by Armin Mortazavi [5]) and helicase superfamilies (right)
Due to their already described roles in critical cellular processes and, thus, predictable involvement in various diseases, helicases have garnered significant attention as potential therapeutic targets. In fact, their indispensable functions in DNA and RNA metabolism make them attractive candidates for intervention in diseases characterized by dysregulated nucleic acid processes. Modulating helicase activity enables disruption of key cellular pathways involved in disease progression, hence, offering a novel approach to therapeutic intervention.
Recent advancements in drug discovery have unveiled a plethora of small-molecule inhibitors targeting helicases; promising candidates have emerged, showing efficacy in preclinical models and paving the way for clinical translation [6-10]. The mechanism of action of helicase inhibitors varies depending on the specific target and disease context. In cancer, for example, helicase inhibitors can disrupt DNA replication and repair pathways, leading to DNA damage accumulation and cancer cell death. Similarly, in viral infections, helicase inhibitors can hinder viral replication by targeting viral helicases essential for viral genome replication and transcription.
However, targeting helicases still poses some difficult tasks to be solved. One of them is associated with achieving selectivity, as many helicases share structural and functional similarities, creating the demand for the development of inhibitors with high specificity for the target helicase. Additionally, helicases often exhibit complex mechanisms of action involving ATP hydrolysis, nucleic acid binding, and protein-protein interactions, further complicating inhibitor design and optimization.
To overcome these challenges, a combination of computational and experimental approaches has been employed. Computational methods such as virtual screening techniques, molecular docking, and molecular dynamics simulations are helpful in identifying lead compounds with high binding affinity and selectivity for target helicases (Fig. 2). Experimental validation through biochemical assays, and structural studies give proof of the efficacy and specificity of helicase inhibitors, guiding the rational design of next-generation therapeutics. Thus, it has been concluded that this integration does enable accelerating the development of potential helicase inhibitors.
Figure 2. Spatial structure binding site of the complex of SARS-CoV-2 helicase (NSP13) with the lead docking molecule F6548-3989, obtained by the Life Chemicals chemoinformatics team using in silico molecular docking
Driving innovative drug development technologies through targeting helicases, Life Chemicals has designed dedicated Screening Sets of potential helicase inhibitors:
- Helicase Focused Library (3,800 compounds) (Fig. 3)
- Helicase Targeted Library (3,200compounds)
- Pre-plated Helicase Screening Sets
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
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Fig. 3. Representative screening compounds from the Life Chemicals Helicase Focused Library.
References
1. Brosh, R. M. Jr.; Matson, S. W. (2020). History of DNA Helicases. Genes 11 (3): 255. DOI: 10.3390/genes11030255
2. Tuteja, N, Tuteja, R. (2006). Helicases as molecular motors: An insight. Physica A. 372(1):70-83. DOI: 10.1016/j.physa.2006.05.014
3. Frick, D. N., Lam, A. M. (2006) Understanding helicases as a means of virus control. Curr Pharm Des. 12(11):1315-1338. DOI: 10.2174/138161206776361147
4. Datta, A.; Brosh, R. M. (2018). New Insights Into DNA Helicases as Druggable Targets for Cancer Therapy. Frontiers in Molecular Biosciences, 5:59. DOI: 10.3389/fmolb.2018.00059
5. https://www.scq.ubc.ca/dna-replication-not-your-office-photocopier/
6. Shadrick, W. R., Ndjomou, J., Kolli, R., Mukherjee, S., Hanson, A. M., & Frick, D. N. (2013). Discovering new medicines targeting helicases: challenges and recent progress. Journal of biomolecular screening, 18(7): 761-781. DOI: 10.1177/1087057113482586
7. Kwong, A. D., Rao, B. G., & Jeang, K. T. (2005). Viral and cellular RNA helicases as antiviral targets. Nature reviews Drug discovery, 4(10): 845-853. DOI: 10.1038/nrd1853
8. Guang Xi, X. (2007). Helicases as antiviral and anticancer drug targets. Current medicinal chemistry, 14(8): 883-915. DOI: 10.2174/092986707780362998
9. Cai, W., Xiong Chen, Z., Rane, G., Satendra Singh, S., Choo, Z. E., Wang, C., et al.. (2017). Wanted DEAD/H or alive: helicases winding up in cancers. JNCI: Journal of the National Cancer Institute, 109(6): djw278. DOI: 10.1093/jnci/djw278
10. Newman, J. A., & Gileadi, O. (2020). RecQ helicases in DNA repair and cancer targets. Essays in biochemistry, 64(5): 819-830. DOI: 10.1042/EBC20200012
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