JG26在体外可减弱ADAM17金属蛋白酶介导的ACE2受体加工过程及新冠病毒感染。
JG26 attenuates ADAM17 metalloproteinase-mediated ACE2 receptor processing and SARS-CoV-2 infection in vitro.
作者信息
Gentili Valentina, Beltrami Silvia, Cuffaro Doretta, Cianci Giorgia, Maini Gloria, Rizzo Roberta, Macchia Marco, Rossello Armando, Bortolotti Daria, Nuti Elisa
机构信息
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, Ferrara, 44121, Italy.
Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa, 56126, Italy.
出版信息
Pharmacol Rep. 2025 Feb;77(1):260-273. doi: 10.1007/s43440-024-00650-0. Epub 2024 Sep 18.
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.
背景
ADAM17是一种金属蛋白酶，参与血管紧张素转换酶2（ACE2）的蛋白水解，已知其在严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的进入和传播中起关键作用。在此背景下，ADAM17成为控制SARS-CoV-2感染的潜在新靶点。
方法
在本研究中，我们使用Calu-3人肺细胞研究了选择性ADAM17抑制剂JG26及其二聚体（化合物1）和糖缀合物（化合物2）衍生物对ACE2表面表达的影响以及对SARS-CoV-2感染的抗病毒效果。
结果
在浓度高达25 μM时，这些化合物均未对Calu-3细胞表现出细胞毒性作用。用JG26处理导致ACE2受体脱落和SARS-CoV-2感染均受到部分抑制，其次是化合物1。
结论
ADAM17抑制剂JG26对SARS-CoV-2感染表现出有前景的抗病毒活性，这可能归因于可溶性ACE2可用性降低，从而限制了病毒传播。
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