Nikhil Prasad Fact checked by:Thailand Medical News Team Oct 25, 2024 16 hours, 9 minutes ago
Medical News: Researchers from several leading institutions have discovered a promising new target for COVID-19 treatments - p70S6K. This protein kinase could play a key role in mitigating the severe inflammatory responses seen in COVID-19 patients, opening doors to new therapies.
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SARS-CoV-2 PI3K/mTOR binding to toll-like receptor (TLR) pathway activation. TLR recognizes viral proteins and causes phosphorylation of many kinases, including p70S6K, which can control various cellular functions. Arrows indicate activation, and blocks indicate inhibition. CRS = cytokine release syndrome. LY2584702, an ATP-competitive p70S6K, tested in phase I clinical trials as an anti-cancer agent, but trials were terminated prematurely (ClinicalTrials.gov NCT01394003). PF–4708671 is used as a specific p70S6K research tool that has not been evaluated in clinical trials.
Key Findings from the Study
In a study conducted by scientists from the University of Massachusetts Lowell (USA), Psivant Therapeutics (USA), and the MIGAL Galilee Research Institute (Israel), researchers explored the molecular mechanisms underlying COVID-19 infections. They specifically examined the role of a protein known as p70S6K, which is involved in regulating cellular processes related to inflammation and viral replication. The results were striking, as they found significant changes in the activity of this kinase in COVID-19-infected cells, suggesting it could be a crucial element in the body's response to the virus.
This
Medical News report will dive deeper into how the discovery was made and what it could mean for the future of COVID-19 treatment. The research focused on understanding the interactions between p70S6K and other molecular pathways that become hyperactive during COVID-19 infections, contributing to what is known as the cytokine storm.
What is p70S6K and Why is it Important?
p70S6K (short for p70 ribosomal S6 kinase) is an enzyme involved in controlling cell growth, protein synthesis, and metabolism. It’s activated by a key signaling pathway in the body - the mTOR pathway, which plays a central role in cell survival and immune responses.
During a COVID-19 infection, the body’s immune system sometimes goes into overdrive, triggering what’s known as a cytokine storm. This overwhelming inflammatory response can cause damage to various organs, including the lungs, heart, and kidneys, and is a major cause of death in severe COVID-19 cases.
The Study Design and Findings
In this groundbreaking study, researchers conducted both lab-based and computational experiments to investigate the behavior of p70S6K in cells infected with COVID-19. Using a macrophage cell line (RAW264.7), they tracked changes in the phosphorylation (activation) of various kinases after transfecting the cells with the spike protein from SARS-CoV-2.
One of the most remarkable findings was that p70S6K showed a 3.5-fold increase in phosphorylation at a specific site (S418), indicating that this protein plays a
significant role in the immune response to the virus. This change in activity led the researchers to focus on p70S6K as a potential therapeutic target.
In addition to the wet-lab experiments, the team employed advanced computational methods to further explore how p70S6K could be targeted by drugs. They used molecular docking simulations to identify compounds that could inhibit p70S6K without affecting other important proteins like Akt2, which is known to cause adverse side effects when targeted.
The Role of In Silico Studies
The team’s in silico (computer-based) investigations played a crucial role in advancing their understanding of how to inhibit p70S6K. They identified a drug known as M2698, which had previously been tested in clinical trials for cancer treatment, as a potent inhibitor of both p70S6K and Akt2. However, M2698 was found to cause psychosis in some patients due to its interaction with Akt2.
To address this, the researchers developed a modified version of M2698, called S34, which showed improved specificity for p70S6K. Their computer simulations suggested that S34 had a 2-fold stronger binding affinity for p70S6K compared to Akt2, meaning it could effectively target the desired protein without causing harmful side effects. This discovery represents a major step forward in the quest for safe and effective COVID-19 treatments.
How This Discovery Could Shape Future Treatments
The findings from this study are promising because they offer a potential new strategy for combating severe cases of COVID-19. By targeting p70S6K, future therapies could reduce the hyperinflammatory response associated with the disease, preventing the life-threatening complications that arise in many patients.
What makes this approach particularly exciting is that it addresses a fundamental aspect of how the body responds to the virus. Instead of focusing solely on antiviral therapies, which aim to stop the virus itself, targeting p70S6K could help modulate the body's immune response, reducing damage to vital organs and improving patient outcomes.
Conclusions and Future Directions
The discovery of p70S6K as a potential target for COVID-19 therapies represents a significant breakthrough. The research team’s combination of wet-lab experiments and computational modeling has paved the way for new treatments that could mitigate the deadly cytokine storms seen in severe COVID-19 cases.
While this study focused primarily on understanding the molecular mechanisms of COVID-19, the implications extend beyond this single disease. The mTOR signaling pathway, in which p70S6K plays a key role, is involved in various other diseases, including cancer and inflammatory disorders. Therefore, the knowledge gained from this research could be applied to a broader range of medical conditions.
However, it’s important to note that more research is needed before these findings can be translated into clinical practice. While the computational models show great promise, the next steps will involve testing the safety and efficacy of S34 in animal models and eventually in human trials.
The study findings were published in the peer-reviewed journal: Cells.
https://www.mdpi.com/2073-4409/13/21/1760
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