Can DDX3 Inhibitors Lead to the Discovery of Antiviral Therapies?
DDX3 inhibitors could unlock new treatments for viral diseases. The human immune response is extraordinary and incredibly complex. As the first line of defense against pathogens and foreign DNA, the innate response acts quickly. Viruses activate innate immunity as the host has proteins that recognize viral components. The innate immune response relies on several cell types of proteins such as interferons (INFs) to be effective. This group of cytokines facilitates the removal of viral pathogens. Other types of cytokines include chemokines, interleukins, lymphokines, and tumor necrosis factors (TNF).
While the viral host has cellular proteins that detect, activate, and fight viruses, various proteins allow the virus to thrive and replicate. DEAD-box helicase 3 (DDX3) is an ATP-dependent RNA helicase that can unwind double-stranded nucleic acid, a necessary step in replication, transcription, and translation. Interestingly, it’s also associated with viral entry into the host cell and viral metabolism. As such, DDX3 is essential for the replication and assembly of several viruses, making it an ideal target for potential antiviral therapies. Researchers have found that knocking down DDX3 blocks the replication of several types of viruses.1
Along with the range of viruses that DDX3 could provide relief, scientists believe that DDX3 has potential therapeutic ability towards SARS-CoV-2 (the virus that causes COVID-19). DDX5, which binds to DDX3, has been shown to participate in SARS-CoV replication.2 Furthermore, due to the multifunctional ability, especially in areas of replication, cell adhesion, increased cell migration, and overall enhanced tumor progression functionality, it’s no surprise that DDX3 is also targeted to combat an assortment of cancers.1 DDX3 is increasingly becoming an important antiviral and anticancer therapeutic target.
Finding DDX3 Inhibitors
Researchers have already started discovering hundreds of DDX3 inhibitors; however, there is much to learn as DDX3 plays a role in the activation of the innate immune response in addition to its role in viral replication. The goal would be to decrease or stop viral replication without limiting the positive aspects of DDX3. Targeting specific domains of the multifunctional protein could be the answer.
The Transcreener® ADP² Assay can detect the enzymatic activity of Kinases, ATPases, and any enzyme that produces ADP; consequently, it is ideal for the continued research into DDX3.
The easy-to-use universal ADP assay limits the need for specific reagents. Since DDX3 hydrolyzes ATP forming ADP as a product, measuring the ADP formed can effectively determine DDX3’s ATPase activity with precision. The assay has different formats (fluorescence polarization (FP), time-resolved FRET (TR-FRET), and fluorescence intensity (FI)), enabling a variety of methods as preferred by the researcher.
As we learn more about the role of DDX3, we will continue to add to our growing repertoire of antiviral and anticancer therapies, including DDX3 inhibitors.
References
- Kukhanova, M. K., Karpenko, I. L., & Ivanov, A. V. (2020). Antiviral and Anticancer Drugs. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070539/
- Winnard, P. T., Vesuna, F., & Raman, V. (2021). Targeting host DEAD-box RNA helicase DDX3X for treating viral infections. Antiviral Research, 185(November 2020), 104994. https://doi.org/10.1016/j.antiviral.2020.104994
