Publication date: Jul 29, 2026
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.
| Concepts | Keywords |
|---|---|
| 152sdac | antiviral agents |
| Health | inflammation |
| Mercaptoethylamine | innate immunity |
| Pathogenesis | oxidative stress |
| Viral | SARS-CoV-2 |
| thiol compounds |
Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | infection |
| pathway | REACTOME | Release |
| disease | MESH | lung injury |
| pathway | KEGG | Viral replication |
| drug | DRUGBANK | Glutathione |
| disease | MESH | GSH |
| drug | DRUGBANK | L-Cysteine |
| drug | DRUGBANK | Acetylcysteine |
| drug | DRUGBANK | Cysteamine |
| drug | DRUGBANK | Isoxaflutole |
| disease | MESH | inflammation |
| disease | MESH | SARS-CoV-2 infection |
| pathway | REACTOME | SARS-CoV-2 Infection |
| disease | MESH | CHAC |