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Peer-reviewedCC BY 4.0Antimicrobial Agents and Chemotherapy

Redox-sensitive factors as targets of thiol compounds to hinder SARS-CoV-2 replication and inflammatory response

  • Marta De Angelis1,2
  • Gianni Gori Savellini3
  • Elena Piselli1
  • Gabriele Anichini3
  • Giulia Radocchia1
  • Sofia Masini4
  • Francesca Monittola4
  • Francesca Bartoccini4
  • Michela Bruschi4
  • Mauro Magnani4
  • Anna Teresa Palamara1,5
  • Maria Grazia Cusi3
3 more authors
  • Rita Crinelli4
  • Alessandra Fraternale4
  • Lucia Nencioni1
5 affiliations
  1. 1Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, Rome, Italy
  2. 2Laboratory of Virology, Department of Molecular Medicine, Sapienza University, Rome, Lazio, Italy
  3. 3Department of Medical Biotechnologies, Policlinico Santa Maria delle Scotte, University of Siena, Siena, Italy
  4. 4Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy
  5. 5Department of Infectious Diseases, Istituto Superiore Di Sanità, Rome, Italy
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Abstract

SARS-CoV-2 has undergone rapid genetic evolution, leading to the emergence of new variants with distinct mutations impacting global public health. Upon infection, the virus triggers a robust inflammatory response characterized by the release of pro-inflammatory cytokines, which play a central role in lung injury. It also alters the host antioxidant response, causing oxidative stress that supports viral replication and cytokine overproduction. This study investigated key pathogenic effectors in Calu-3 and A549-ACE2/TMPRSS2 cells infected with SARS-CoV-2 variants, focusing on replication kinetics, cellular redox state, and inflammatory cytokine profile. A dramatic redox alteration in terms of glutathione (GSH) and Cysteine (Cys) was observed at 48 h p.i., along with a strong pro-inflammatory cytokine response , likely via activation of the JNK/AP-1 signaling pathway. To counteract these effects, two thiol molecules were tested: I-152, a monothiol conjugate of N-Acetyl-Cysteine (NAC) and β-mercaptoethylamine (MEA) and its dithiol derivative, I-152SdAc. Thiols restored GSH balance by enhancing the expression of Nrf2-mediated genes, such as glutamate-Cys ligase modifier subunit (GCLM), and counteracted AP-1-mediated pathway, resulting in a significant reduction of inflammation and viral replication. Antiviral and anti-inflammatory activities of thiols were confirmed in NHBE cells. These findings highlight that redox imbalance is a key pathogenetic event in SARS-CoV-2 infection. Notably, besides Nrf2 and AP-1, other redox-sensitive factors, such as the CHAC glutathione-specific gamma-glutamyl-cyclotransferase 1 (CHAC1), seem to contribute to the pathogenesis and may represent a new potential therapeutic target of redox active compounds. Therefore, the thiol-derived molecules act as broadly effective compounds by limiting virus replication and inflammation.

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Cite

BibTeXRIS
BibTeX
@article{angelis2026redoxsensitive,
  title = {{Redox-sensitive factors as targets of thiol compounds to hinder SARS-CoV-2 replication and inflammatory response}},
  author = {Marta De Angelis and Gianni Gori Savellini and Elena Piselli and Gabriele Anichini and Giulia Radocchia and Sofia Masini and Francesca Monittola and Francesca Bartoccini and Michela Bruschi and Mauro Magnani and Anna Teresa Palamara and Maria Grazia Cusi and Rita Crinelli and Alessandra Fraternale and Lucia Nencioni},
  journal = {Antimicrobial Agents and Chemotherapy},
  year = {2026},
  month = jul,
  doi = {10.1128/aac.00518-26},
  url = {https://doi.org/10.1128/aac.00518-26},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Redox-sensitive factors as targets of thiol compounds to hinder SARS-CoV-2 replication and inflammatory response
AU  - Marta De Angelis
AU  - Gianni Gori Savellini
AU  - Elena Piselli
AU  - Gabriele Anichini
AU  - Giulia Radocchia
AU  - Sofia Masini
AU  - Francesca Monittola
AU  - Francesca Bartoccini
AU  - Michela Bruschi
AU  - Mauro Magnani
AU  - Anna Teresa Palamara
AU  - Maria Grazia Cusi
AU  - Rita Crinelli
AU  - Alessandra Fraternale
AU  - Lucia Nencioni
PY  - 2026
DA  - 2026/07/29
JO  - Antimicrobial Agents and Chemotherapy
DO  - 10.1128/aac.00518-26
UR  - https://doi.org/10.1128/aac.00518-26
AB  - SARS-CoV-2 has undergone rapid genetic evolution, leading to the emergence of new variants with distinct mutations impacting global public health. Upon infection, the virus triggers a robust inflammatory response characterized by the release of pro-inflammatory cytokines, which play a central role in lung injury. It also alters the host antioxidant response, causing oxidative stress that supports viral replication and cytokine overproduction. This study investigated key pathogenic effectors in Calu-3 and A549-ACE2/TMPRSS2 cells infected with SARS-CoV-2 variants, focusing on replication kinetics, cellular redox state, and inflammatory cytokine profile. A dramatic redox alteration in terms of glutathione (GSH) and Cysteine (Cys) was observed at 48 h p.i., along with a strong pro-inflammatory cytokine response , likely via activation of the JNK/AP-1 signaling pathway. To counteract these effects, two thiol molecules were tested: I-152, a monothiol conjugate of N-Acetyl-Cysteine (NAC) and β-mercaptoethylamine (MEA) and its dithiol derivative, I-152SdAc. Thiols restored GSH balance by enhancing the expression of Nrf2-mediated genes, such as glutamate-Cys ligase modifier subunit (GCLM), and counteracted AP-1-mediated pathway, resulting in a significant reduction of inflammation and viral replication. Antiviral and anti-inflammatory activities of thiols were confirmed in NHBE cells. These findings highlight that redox imbalance is a key pathogenetic event in SARS-CoV-2 infection. Notably, besides Nrf2 and AP-1, other redox-sensitive factors, such as the CHAC glutathione-specific gamma-glutamyl-cyclotransferase 1 (CHAC1), seem to contribute to the pathogenesis and may represent a new potential therapeutic target of redox active compounds. Therefore, the thiol-derived molecules act as broadly effective compounds by limiting virus replication and inflammation.
SN  - 0066-4804
SN  - 1098-6596
ER  -