Chinese researchers discover host protein ACTN4 as a promising new target in the fight against SARS-CoV-2
Nikhil Prasad Fact checked by:Thailand Medical News Team Sep 18, 2024 1 day, 8 hours, 42 minutes ago
Medical News: The constant mutations of the SARS-CoV-2 virus have posed an immense challenge for researchers around the world. This ongoing battle has led to the discovery of potential new targets that could help combat the virus. One such target is a host factor called ACTN4 (Alpha-actinin-4). A recent study, led by researchers from the Wuhan Institute of Virology, University of Chinese Academy of Sciences, and Hubei Jiangxia Laboratory, explored the relationship between ACTN4 and SARS-CoV-2. This
Medical News report will delve into how the suppression of ACTN4 impacts the virus and the potential for this discovery to lead to new antiviral drugs.
Host protein ACTN4 as a promising new target in the fight against SARS-CoV-2
The model of intricate interplay between host factor ACTN4 and SARS-CoV-2. (Left half part) SARS-CoV-2 infection decreases the m6A related factors and global m6A modification levels in cells, which correlates with reduction of ACTN4 expression. (Right half part) ACTN4 targets viral protein nsp12 for binding to block the viral RdRp complex formation, which causes inhibition of SARS-CoV-2 replication. Two ACTN4 agonists, YS-49 and demethyl-coclaurine, are identified to inhibit viral replication.
Understanding the Role of ACTN4
SARS-CoV-2, the virus that causes COVID-19, is a single-stranded RNA virus. It replicates in host cells by hijacking various proteins and enzymes. Researchers have discovered that ACTN4, a protein involved in maintaining cell structure and stability, plays a crucial role in viral replication. The study highlighted that ACTN4 interacts with the virus's RNA polymerase complex (nsp12), which is essential for the virus's ability to replicate its RNA. By binding to this complex, ACTN4 can disrupt the viral replication process.
One of the key findings of this study was that the SARS-CoV-2 virus reduces the m6A modification on ACTN4 mRNA, leading to decreased stability and expression of ACTN4. This reduction in ACTN4 levels allows the virus to replicate more efficiently. The researchers conducted several experiments using cells and animal models to demonstrate the effect of ACTN4 suppression on viral replication.
How SARS-CoV-2 Affects ACTN4 Expression
The researchers discovered that SARS-CoV-2 significantly downregulates ACTN4 expression by modifying m6A levels, a process that involves adding methyl groups to the RNA. This change reduces the stability of ACTN4 mRNA and its ability to translate into the ACTN4 protein. The study shows how the reduction of ACTN4 creates an environment that allows the virus to multiply more easily.
The researchers utilized high-throughput sequencing to identify differentially expressed genes in infected and non-infected cells. They found that ACTN4 was one of the proteins most affected by the virus. ACTN4, which normally helps maintain cell structure, was found to be downregulated in cells infected with SARS
-CoV-2.
ACTN4’s Role in Viral Inhibition
Interestingly, while the virus tries to suppress ACTN4, the protein itself has antiviral properties. When the researchers overexpressed ACTN4 in cells, they found that it inhibited viral replication. ACTN4 competes with the virus’s RNA polymerase complex, preventing the virus from efficiently replicating its genetic material.
To explore this further, the researchers tested two compounds, YS-49 and demethyl-coclaurine, which act as agonists for ACTN4. They found that both compounds significantly reduced viral replication in lab-grown cells and in mice infected with SARS-CoV-2. These findings suggest that activating ACTN4 could be a promising strategy for developing new antiviral treatments.
Testing in Mice
The next step in the research was to test whether these compounds could work in animal models. The researchers used transgenic mice that expressed human ACE2, the receptor the virus uses to enter cells. After infecting the mice with the Omicron variant of SARS-CoV-2, they treated the animals with either YS-49 or demethyl-coclaurine. The results were encouraging. Both compounds reduced the viral load in the mice's lungs and brains. This suggests that these ACTN4 agonists could potentially be developed into effective treatments for COVID-19.
In addition to reducing viral load, the treated mice showed fewer signs of inflammation. The researchers measured several inflammatory markers, such as IL-1β, IL-6, and TNF-α, and found that they were significantly lower in the treated animals compared to untreated controls. This reduction in inflammation is crucial because severe COVID-19 is often characterized by a hyper-inflammatory response, sometimes referred to as a cytokine storm.
Potential for Drug Development
The discovery that ACTN4 plays a role in inhibiting SARS-CoV-2 replication opens the door to new possibilities for drug development. Unlike many antiviral drugs that target the virus directly, targeting host factors like ACTN4 may reduce the likelihood of the virus developing resistance. Since ACTN4 is a host protein, mutations in the virus are less likely to render the treatment ineffective.
Moreover, the two ACTN4 agonists, YS-49 and demethyl-coclaurine, are promising candidates for further drug development. Demethyl-coclaurine, in particular, showed lower toxicity and higher efficacy compared to YS-49. This compound is derived from traditional Chinese medicine and has been used for its anti-inflammatory and pain-relieving properties. Its potential to reduce inflammation and inhibit viral replication makes it a strong candidate for further clinical testing.
Conclusion
The study's findings suggest that targeting ACTN4 could be a valuable strategy in the fight against COVID-19. By activating ACTN4 with compounds like YS-49 and demethyl-coclaurine, it may be possible to reduce viral replication and alleviate the severe inflammatory responses seen in many COVID-19 patients.
Further research is needed to better understand the precise mechanisms by which ACTN4 inhibits the virus and to develop these compounds into safe and effective treatments. However, the study represents a significant step forward in understanding how host factors can be manipulated to combat viral infections.
The study findings were published in the peer-reviewed journal: Signal Transduction and Targeted Therapy.
https://www.nature.com/articles/s41392-024-01956-4
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