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Nikhil Prasad  Fact checked by:Thailand Medical News Team Jan 20, 2025  3 hours, 43 minutes ago

U.S. NIH Discovers New Potential Antivirals Against SARS-CoV-2 Involving p97 Inhibitors

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U.S. NIH Discovers New Potential Antivirals Against SARS-CoV-2 Involving p97 Inhibitors
Nikhil Prasad  Fact checked by:Thailand Medical News Team Jan 20, 2025  3 hours, 43 minutes ago
Medical News: A team of researchers from the University of Minnesota’s Center for Drug Design-USA and the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health-USA have unveiled groundbreaking findings regarding the antiviral potential of p97 inhibitors against SARS-CoV-2. The study sheds light on how these inhibitors may not only provide significant antiviral activity but also do so with minimal cytotoxicity.


U.S. NIH Discovers New Potential Antivirals Against SARS-CoV-2 Involving p97 Inhibitors

p97, scientifically known as valosin-containing protein (VCP), belongs to the AAA+ ATPase family. This group of proteins is essential in various cellular activities, particularly those linked to protein quality control and homeostasis. For years, scientists have focused on p97 inhibitors as a potential anticancer strategy. However, recent developments have revealed p97’s critical role as a pro-viral host factor, paving the way for its evaluation as a target for antiviral drugs.
 
This Medical News report highlights that the study team, led by researchers including Rui Ding, Tiffany C. Edwards, and Liqiang Chen, explored structural modifications to existing p97 inhibitors. These modifications aimed to enhance their efficacy against SARS-CoV-2, the virus responsible for the COVID-19 pandemic.
 
A Novel Approach to Antiviral Development
The study introduced structurally novel inhibitors by reconfiguring the central fused ring in their predecessors. Compounds designed under this approach were tested for three critical attributes: inhibition of p97 ATPase activity, cytotoxicity, and antiviral efficacy against SARS-CoV-2.
 
Two specific compounds emerged as standouts, demonstrating superior anti-p97 activity compared to their predecessors. Even more remarkable was their pronounced antiviral activity against SARS-CoV-2, achieved at dosages that exhibited negligible cytotoxic effects on host cells. The reduced cytotoxicity sets these inhibitors apart from traditional antiviral agents, which often face limitations due to adverse effects on non-targeted cells.
 
Key Findings from the Study
-Enhanced p97 Inhibition: Compounds 8a, 9a, and 10a were among the most effective, inhibiting p97 ATPase activity by more than 90% even at low concentrations of 0.10 μM. This performance was notably better than established inhibitors like CB-5083 and NMS-873.
 
-Low Cytotoxicity: The cytotoxicity of the new inhibitors was markedly lower than their predecessors. For instance, compound 10a demonstrated a CC50 (50% cytotoxic concentration) exceeding 100 μM in A549/ACE2/TMPRSS2 cells, indicating high tolerability.
 
-Potent Antiviral Activity: Using in vitro assays, these compounds effectively inhibited SARS-CoV-2 replication. For instance, compound 9a demonstrated an impressive inhibition of 98% at concentrations of 30 μM. This efficacy was comparable to remdesivir, a widely used antiviral, albeit with a different mechanism of action.
 
-Molecular Docking Insights: Advanced molecular docking studies revealed that the new inhibitors maintained binding modes consistent with their parent compounds. This consistency underscores the rational design strategy employed by the research team.
 
Broader Implications for Drug Development
The implications of these findings extend beyond SARS-CoV-2. p97 inhibitors have already shown promise against a range of viruses, including Zika, dengue, and respiratory syncytial virus. The structural modifications achieved in this study could serve as a template for the development of broad-spectrum antiviral agents.
 
Moreover, the low cytotoxicity profile suggests that these compounds might be suitable for long-term therapeutic use, a critical requirement for treating chronic viral infections. The ability to selectively target p97 without disrupting cellular homeostasis opens doors for further applications in immunology and oncology.
 
Conclusion and Future Directions
The findings of this study underscore the potential of p97 inhibitors as a new class of antiviral agents. Their ability to disrupt key viral replication processes while maintaining low toxicity makes them a compelling candidate for further clinical evaluation.
 
In conclusion, the structural innovations in p97 inhibitors represent a significant stride in antiviral research. These compounds not only offer hope for combating SARS-CoV-2 but also hold promise for addressing other viral pathogens that rely on host cell mechanisms for replication. Continued exploration and optimization of these inhibitors could revolutionize therapeutic strategies for viral infections.
 
The study findings were published in the peer-reviewed journal: Pharmaceuticals.
https://www.mdpi.com/1424-8247/18/1/131
 
For the latest COVID-19 News, keep on logging to Thailand Medical News.
 
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