JG26 attenuates ADAM17 metalloproteinase-mediated ACE2 receptor processing and SARS-CoV-2 infection in vitro

IF 3.6 3区医学 Q2 PHARMACOLOGY & PHARMACY Pharmacological Reports Pub Date : 2024-09-18 DOI:10.1007/s43440-024-00650-0

Valentina Gentili, Silvia Beltrami, Doretta Cuffaro, Giorgia Cianci, Gloria Maini, Roberta Rizzo, Marco Macchia, Armando Rossello, Daria Bortolotti, Elisa Nuti

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Abstract

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.

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JG26 可减轻 ADAM17 金属蛋白酶介导的 ACE2 受体处理和体外 SARS-CoV-2 感染

背景ADAM17是一种金属蛋白酶，与血管紧张素转换酶2（ACE2）的蛋白水解有关，已知ACE2在SARS-CoV-2的进入和传播中起着关键作用。方法在这项研究中，我们使用 Calu-3 人肺部细胞研究了选择性 ADAM17 抑制剂 JG26 及其二聚体（化合物 1）和糖结合体（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。结论JG26 是一种 ADAM17 抑制剂，对 SARS-CoV-2 感染具有良好的抗病毒活性，这可能是由于 sACE2 的可用性降低，从而限制了病毒的传播。

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来源期刊

Pharmacological Reports 医学-药学

CiteScore

8.40

自引率

0.00%

发文量

审稿时长

6 months

期刊介绍： Pharmacological Reports publishes articles concerning all aspects of pharmacology, dealing with the action of drugs at a cellular and molecular level, and papers on the relationship between molecular structure and biological activity as well as reports on compounds with well-defined chemical structures. Pharmacological Reports is an open forum to disseminate recent developments in: pharmacology, behavioural brain research, evidence-based complementary biochemical pharmacology, medicinal chemistry and biochemistry, drug discovery, neuro-psychopharmacology and biological psychiatry, neuroscience and neuropharmacology, cellular and molecular neuroscience, molecular biology, cell biology, toxicology. Studies of plant extracts are not suitable for Pharmacological Reports.