ADAM17 inhibitors show promise in blocking SARS-CoV-2 virus entry

Medical News: Researchers from the University of Ferrara and University of Pisa in Italy have discovered a new antiviral approach using ADAM17 inhibitors to hinder the spread of SARS-CoV-2, the virus responsible for COVID-19.
 
The Role of ADAM17 in SARS-CoV-2 Infection
A groundbreaking study has identified ADAM17, also known as tumor necrosis factor-α-converting enzyme (TACE), as a key player in the process by which the SARS-CoV-2 virus enters human cells. ADAM17 is a transmembrane zinc metalloproteinase responsible for shedding certain proteins from the cell surface, including angiotensin-converting enzyme 2 (ACE2). ACE2 is the primary receptor that allows the SARS-CoV-2 virus to bind and penetrate human cells, leading to infection.
 
This Medical News report sheds light on how inhibiting ADAM17 could reduce ACE2 shedding, limiting the virus’s ability to infect new cells. The discovery opens new avenues for developing antiviral treatments that could both prevent the spread of the virus and reduce inflammation in severe COVID-19 cases.
 
The Study: Examining JG26 and Its Derivatives
Researchers at the University of Ferrara and University of Pisa focused on the potential of JG26, an ADAM17 inhibitor, along with its two derivatives, compound 1 and compound 2. These compounds were tested in human lung cells (Calu-3), which are often used to study respiratory viruses like SARS-CoV-2.
 
The researchers wanted to see if these ADAM17 inhibitors could prevent ACE2 from being shed from the cell surface, thereby reducing the virus’s ability to spread. To their delight, none of the tested compounds showed toxic effects at concentrations up to 25 µM, making them safe for further investigation. This was a major positive outcome for future applications, especially in clinical settings.
 
In terms of effectiveness, JG26 was found to partially inhibit the shedding of ACE2 and reduce SARS-CoV-2 infection in the lung cells. While compounds 1 and 2 also showed some promise, JG26 was the most potent in both inhibiting ACE2 receptor shedding and controlling virus replication.
 
How the Inhibitors Work
SARS-CoV-2 typically enters cells by binding its spike (S) protein to ACE2 receptors on the surface of human cells. Once the virus binds to ACE2, it can infect the cell and reproduce. ADAM17 is involved in the process of cleaving ACE2 from the cell surface, which releases a soluble form of ACE2 (sACE2). This soluble form can also bind to the virus and contribute to viral spread, especially in tissues with low ACE2 expression.
 
By inhibiting ADAM17 with compounds like JG26, researchers aim to reduce the shedding of ACE2, which would mean fewer binding sites for the virus and lower levels of sACE2 to help the virus spread. In essence, blocking ADAM17 could reduce the ability of SARS-CoV-2 to infect new cells and propagate within the body.
 
Key Findings of the Study
The most significant findings of the study are:
 
-Safety and non-toxicity: None of the tested compounds, including JG26, compound 1, and compound 2, showed cytotoxic effects at concentrations up to 25 µM, making them safe for use in further testing.
 
-Inhibition of ACE2 s hedding: Treatment with JG26 led to a significant reduction in the shedding of the ACE2 receptor. This suggests that the virus has fewer opportunities to bind to and infect new cells.
 
-Antiviral efficacy: JG26 was the most effective compound in reducing the spread of SARS-CoV-2, followed by compound 1. JG26’s inhibition of both ACE2 shedding and viral infection marks it as a promising candidate for future antiviral therapies.

-Reduced viral replication: By maintaining ACE2 on the cell surface, the inhibitors limited the virus's ability to infect new cells, as confirmed by plaque assays and real-time PCR tests.
 
These findings demonstrate the potential of ADAM17 inhibitors as an innovative way to treat or even prevent COVID-19. The researchers believe that by preventing the virus from accessing its main receptor, we can reduce its ability to spread and ultimately stop the infection from taking hold.
 
Implications for COVID-19 Treatment
The implications of this research are wide-reaching. Since ADAM17 is also involved in the immune response and inflammation, inhibiting it may offer dual benefits for COVID-19 patients. On one hand, it can block the virus from spreading by reducing the availability of ACE2 receptors, and on the other hand, it can help to reduce the so-called “cytokine storm” that contributes to severe cases of COVID-19.
 
By reducing ACE2 shedding and controlling the inflammatory response, JG26 and other ADAM17 inhibitors may offer a more comprehensive approach to treating COVID-19 than antiviral drugs that only target the virus itself. This could be especially important for patients with severe disease who suffer from both high viral loads and excessive inflammation.
 
The Next Steps in Research
While the results of this study are promising, more research is needed before ADAM17 inhibitors can be used in clinical settings. Future studies will need to investigate the long-term effects of JG26 and its derivatives, particularly in living organisms. Although the results from in vitro studies (in cell cultures) are encouraging, researchers must confirm that these compounds are both safe and effective in animals and humans.
 
Additionally, there is potential for combining ADAM17 inhibitors with other antiviral drugs to improve their effectiveness. For example, inhibitors of another key enzyme, TMPRSS2, have shown promise in blocking virus entry. Combining TMPRSS2 and ADAM17 inhibitors may provide even greater protection against the virus by targeting multiple steps in the infection process.
 
Conclusion
This study represents a significant step forward in the fight against COVID-19. The discovery that ADAM17 inhibitors like JG26 can block viral entry and limit the spread of SARS-CoV-2 provides new hope for developing effective treatments. Unlike many existing antiviral drugs that target the virus directly, ADAM17 inhibitors work by targeting the host's cellular machinery, which reduces the likelihood of the virus developing resistance.
 
The researchers concluded that JG26 and its derivatives are promising candidates for further research and potential clinical development. By inhibiting both viral entry and the inflammatory response, these compounds could provide a powerful new tool in the fight against COVID-19, particularly for patients at risk of severe illness.
 
The study findings were published in the peer-reviewed journal: Pharmacological Reports.
https://link.springer.com/article/10.1007/s43440-024-00650-0
 
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