Can a novel PKR inhibitor help lead to new treatments for viral infections? – While the human immune response is astounding and works hard to keep us alive in the face of the many germs we encounter daily, it is exceedingly complex. Unlike the adaptive immune response, the innate response acts quickly. It is considered the first line of defense against pathogens and foreign DNA, including cancerous cells and double-stranded RNA (dsRNA). Viruses activate the innate immune response since 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.
Viral replication results in dsRNA that the host cell recognizes via numerous antiviral proteins. This activates several signaling pathways to perform functions to kill the infected cell or diminish viral replication. Protein kinase RNA-activated (PKR) is one of these proteins activated by the viral dsRNA. Kinases are essential players in cellular functions such as cell signaling, cellular transport, and protein regulation. Regulation is performed via substrate phosphorylation; thus, understanding kinase activity is ideal when studying a particular cellular pathway.
The activated PKR dimerizes and ultimately leads to phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α), which diminishes its ability to synthesize protein. 2 Not only does PKR regulate eIF2α, play a role in translation, it also activates nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB); thereby, activating antiviral interferon cytokines. 2 Additionally, PKR induces apoptosis limiting the spread of viral infection. With the various pathways in which PKR demonstrates antiviral activity, it’s no surprise that scientists have been studying the protein for decades to discover antiviral therapies.
PKR Inhibitor Assay
Although PKR works through different cellular pathways to reduce viral activity, viruses have found ways to continue replicating. 2 This phenomenon keeps scientists on their toes and in an ongoing search for solutions. SARS-CoV was interestingly found to activate PKR as many viruses do. Still, Krahling et al. show that a PKR inhibitor doesn’t decrease replication compared to studies done on hepatitis C virus (HCV).1,3
The Transcreener® ADP² Kinase Assay is an ideal tool capable of detecting the enzymatic activity of Kinases, ATPases, or any other enzyme that produces ADP. The assay provides an excellent tool for researchers examining the antiviral effects of PKR.
The human immune response is multifaceted, and researchers continue to discover pathways and proteins involved that add to the complexity. Researchers likewise persist in finding solutions and increased understanding to the inconstancies and pathogen resistance.
- Krähling, V., Stein, D. A., Spiegel, M., Weber, F., & Mühlberger, E. (2009). Severe Acute Respiratory Syndrome Coronavirus Triggers Apoptosis via Protein Kinase R but Is Resistant to Its Antiviral Activity. Journal of Virology, 83(5), 2298–2309. https://doi.org/10.1128/jvi.01245-08
- Christopher, A. M. L. S. (2016). HHS Public Access. Physiology & Behavior, 176(1), 100–106. https://doi.org/10.1111/nyas.14000.Species-specific
- Watanabe, T., Imamura, T., & Hiasa, Y. (2018). Roles of protein kinase R in cancer: Potential as a therapeutic target. Cancer Science, 109(4), 919–925. https://doi.org/10.1111/cas.13551
- Wikipedia contributors. (2020, December 4). Protein kinase R. In Wikipedia, The Free Encyclopedia. Retrieved 08:23, March 28, 2021, from https://en.wikipedia.org/w/index.php?title=Protein_kinase_R&oldid=992208570