Multiple Mechanisms of Action of Sulfodyne<sup>®</sup>, a Natural Antioxidant, against Pathogenic Effects of SARS-CoV-2 Infection
Paul-Henri Romeo,
Laurine Conquet,
Sébastien Messiaen,
Quentin Pascal,
Stéphanie G. Moreno,
Anne Bravard,
Jacqueline Bernardino-Sgherri,
Nathalie Dereuddre-Bosquet,
Xavier Montagutelli,
Roger Le Grand,
Vanessa Petit,
Federica Ferri
Affiliations
Paul-Henri Romeo
Laboratory on Repair and Transcription in Hematopoietic Stem Cells (LRTS/IRCM), Université Paris Cité, Inserm, CEA, 92265 Fontenay-aux-Roses, France
Laurine Conquet
Mouse Genetics Laboratory, Université Paris Cité, Institut Pasteur, 75724 Paris, France
Sébastien Messiaen
Laboratory on Development of the Gonads (LDG/IRCM), Université Paris Cité, Inserm, CEA, 92265 Fontenay-aux-Roses, France
Quentin Pascal
Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-Saclay, Inserm, CEA, 92265 Fontenay-aux-Roses, France
Stéphanie G. Moreno
Laboratory on Repair and Transcription in Hematopoietic Stem Cells (LRTS/IRCM), Université Paris Cité, Inserm, CEA, 92265 Fontenay-aux-Roses, France
Anne Bravard
Laboratory on Repair and Transcription in Hematopoietic Stem Cells (LRTS/IRCM), Université Paris Cité, Inserm, CEA, 92265 Fontenay-aux-Roses, France
Jacqueline Bernardino-Sgherri
Laboratory on Repair and Transcription in Hematopoietic Stem Cells (LRTS/IRCM), Université Paris Cité, Inserm, CEA, 92265 Fontenay-aux-Roses, France
Nathalie Dereuddre-Bosquet
Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-Saclay, Inserm, CEA, 92265 Fontenay-aux-Roses, France
Xavier Montagutelli
Mouse Genetics Laboratory, Université Paris Cité, Institut Pasteur, 75724 Paris, France
Roger Le Grand
Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-Saclay, Inserm, CEA, 92265 Fontenay-aux-Roses, France
Vanessa Petit
Laboratory on Repair and Transcription in Hematopoietic Stem Cells (LRTS/IRCM), Université Paris Cité, Inserm, CEA, 92265 Fontenay-aux-Roses, France
Federica Ferri
Laboratory on Repair and Transcription in Hematopoietic Stem Cells (LRTS/IRCM), Université Paris Cité, Inserm, CEA, 92265 Fontenay-aux-Roses, France
Few therapeutic options are available to treat COVID-19. The KEAP1/NRF2 pathway, the major redox-responsive pathway, has emerged as a potential therapeutic target for COVID-19 as it regulates redox homeostasis and inflammation that are altered during SARS-CoV-2 infection. Here, we characterized the effects of NRF2-agonist Sulfodyne®, a stabilized natural Sulforaphane, in cellular and animal models of SARS-CoV-2 infection. In pulmonary or colonic epithelial cell lines, Sulfodyne® elicited a more efficient inhibition of SARS-CoV-2 replication than NRF2-agonists DMF and CDDO. This antiviral activity was not dependent on NRF2 but was associated with the regulation of several metabolic pathways, including the inhibition of ER stress and mTOR signaling, which are activated during SARS-CoV-2 infection. Sulfodyne® also decreased SARS-CoV-2 mediated inflammatory responses by inhibiting the delayed induction of IFNB1 and type I IFN-stimulated genes in infected epithelial cell lines and by reducing the activation of human by-stander monocytes recruited after SARS-CoV-2 infection. In K18-hACE2 mice infected with SARS-CoV-2, Sulfodyne® treatment reduced both early lung viral load and disease severity by fine-tuning IFN-beta levels. Altogether, these results provide evidence for multiple mechanisms that underlie the antiviral and anti-inflammatory activities of Sulfodyne® and pinpoint Sulfodyne® as a potent therapeutic agent against pathogenic effects of SARS-CoV-2 infection.