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JG26 attenuates ADAM17 metalloproteinase-mediated ACE2 receptor processing and SARS-CoV-2 infection in vitro
Valentina Gentili1, Silvia Beltrami1, Doretta Cuffaro2
1Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, Ferrara, 44121, Italy.
Background:
ADAM17 is a metalloprotease implicated in the proteolysis of angiotensin-converting enzyme 2 (ACE2), known to play a critical role in the entry and spread of SARS-CoV-2. In this context, ADAM17 results as a potential novel target for controlling SARS-CoV-2 infection.
Methods:
In this study, we investigated the impact on ACE2 surface expression and the antiviral efficacy against SARS-CoV-2 infection of the selective ADAM17 inhibitor JG26 and its dimeric (compound 1) and glycoconjugate (compound 2) derivatives using Calu-3 human lung cells.
Results:
None of the compounds exhibited cytotoxic effects on Calu-3 cells up to a concentration of 25 µM. Treatment with JG26 resulted in partial inhibition of both ACE2 receptor shedding and SARS-CoV-2 infection, followed by compound 1.
Conclusion:
JG26, an ADAM17 inhibitor, demonstrated promising antiviral activity against SARS-CoV-2 infection, likely attributed to reduced sACE2 availability, thus limiting viral dissemination.
Insights
ADAM17 inhibitors show promise against SARS-CoV-2. JG26 reduced angiotensin-converting enzyme 2 (ACE2) shedding and viral infection in lung cells, limiting virus spread.
Area of Science:
- Biochemistry
- Virology
- Pharmacology
Background:
- ADAM17 is a metalloprotease involved in angiotensin-converting enzyme 2 (ACE2) proteolysis.
- ACE2 is critical for SARS-CoV-2 entry and spread.
- ADAM17 inhibition is a potential strategy to control SARS-CoV-2 infection.
Purpose of the Study:
- To evaluate the antiviral efficacy of the ADAM17 inhibitor JG26 and its derivatives against SARS-CoV-2.
- To assess the impact of these compounds on ACE2 surface expression.
Main Methods:
- Calu-3 human lung cells were treated with JG26, compound 1 (dimeric derivative), and compound 2 (glycoconjugate derivative).
- Cytotoxicity was assessed.
- ACE2 shedding and SARS-CoV-2 infection inhibition were measured.
Main Results:
- No cytotoxic effects were observed for any compound up to 25 µM.
- JG26 partially inhibited ACE2 receptor shedding and SARS-CoV-2 infection.
- Compound 1 also showed inhibitory effects.
Conclusions:
- JG26, an ADAM17 inhibitor, exhibits promising antiviral activity against SARS-CoV-2.
- This activity is likely due to reduced soluble ACE2 (sACE2) availability, which limits viral dissemination.
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