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

  • Pharmacol Rep. 2025 Feb;77(1):260-273. doi: 10.1007/s43440-024-00650-0.
Valentina Gentili  #  1 ,  Silvia Beltrami  #  1 ,  Doretta Cuffaro  2 ,  Giorgia Cianci  1 ,  Gloria Maini  1 ,  Roberta Rizzo  1  3 ,  Marco Macchia  2 ,  Armando Rossello  2 ,  Daria Bortolotti  #  4 ,  Elisa Nuti  #  5
Affiliations
  • 1. Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, Ferrara, 44121, Italy.
  • 2. Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa, 56126, Italy.
  • 3. Clinical Research Center, LTTA, University of Ferrara, Ferrara, Italy.
  • 4. Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, Ferrara, 44121, Italy. [email protected].
  • 5. Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa, 56126, Italy. [email protected].
  • # Contributed equally.
PMID: 39292373 DOI: 10.1007/s43440-024-00650-0
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.

Keywords
ADAM17; Antiviral activity; Arylsulfonamido-based hydroxamic acid; SARS-CoV-2; sACE2.
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