Multi-target mode of action of Sulfodyne(R), a stabilized Sulforaphane, against pathogenic effects of SARS-CoV-2 infection

Romeo, P.-H.; Conquet, L.; Messiaen, S.; Pascal, Q.; Moreno, S. G.; Bravard, A.; Bernardino-Sgherri, J.; Dereuddre-Bosquet, N.; Montagutelli, X.; Le Grand, R.; Petit, V.; Ferri, F.

doi:10.1101/2023.12.18.572126

bioRxiv · 10.1101/2023.12.18.572126

Multi-target mode of action of Sulfodyne(R), a stabilized Sulforaphane, against pathogenic effects of SARS-CoV-2 infection

Romeo, P.-H.·Conquet, L.·Messiaen, S.·Pascal, Q.·Moreno, S. G.·Bravard, A.·Bernardino-Sgherri, J.·Dereuddre-Bosquet, N.·Montagutelli, X.·Le Grand, R.·Petit, V.·Ferri, F.

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Abstract

The coronavirus disease 2019 (COVID-19) due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown that, except vaccination, few therapeutics options for its treatment or prevention are available. Among the pathways that can be targeted for COVID-19 treatment, the Keap1/Nrf2 pathway seems of high interest as it regulates redox homeostasis and inflammation that are altered during SARS-CoV-2 infection. Here, we use three potent activators of the Keap1/Nrf2 pathway and showed that Sulfodyne(R), a stabilized natural Sulforaphane preparation with optimal bioavailability, had the highest antiviral activity in pulmonary or colonic epithelial cell lines even when added late after SARS-CoV-2 infection. This antiviral activity was not dependent on NRF2 activity but associated with action on ER stress and mTOR signaling that are activated during SARS-CoV-2 infection. Sulfodyne(R) also decreased the inflammatory response of epithelial cell lines infected by SARS-CoV-2 independently of SARS-CoV-2 replication and reduced the activation of human monocytes that are recruited after infection of epithelial cells by SARS-CoV-2. Administration of Sulfodyne(R) had little effects on SARS-CoV-2 replication in mice and hamsters infected with SARS-CoV-2 but significantly reduced weight loss and disease severity. Altogether, these results pinpoint the natural compound Sulfodyne(R) as a potent therapeutic agent of COVID-19 symptomatology. Author SummaryAccumulating evidence shows that oxidative stress coupled with the systemic inflammation contribute to COVID-19 pathogenesis. As the Keap1/Nrf2 pathway is the major regulator of redox homeostasis and promotes resolution of inflammation and as lung biopsies from COVID-19 patients showed a decreased NRF2 target gene signature, pharmacological agents that are known to activate NRF2 are good candidates for COVID-19 treatment. We show herein that Sulfodyne(R), an NRF2 activator that consists in a stabilized Sulforaphane preparation with optimal bioavailability, impairs SARS-CoV-2 replication in colonic or pulmonary epithelial cells. We show that this antiviral activity of Sulfodyne(R) is not dependent of NRF2 activation, characterize the pathways associated with the Sulfodyne(R) antiviral activity and show that Sulfodyne(R) displays multiple actions that result in a decrease of the inflammation associated with SARS-CoV-2 infection. Finally, we show that Sulfodyne(R) decreases the pathogenesis of mice or hamster infected with SARS-CoV-2. Overall, this study provides mechanistic explanations of the action of Sulfodyne(R) during SARS-CoV-2 infection and suggests that Sulfodyne(R) is a potential therapeutic agent of COVID-19 pathogenesis.

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Romeo, P.-H., Conquet, L., Messiaen, S., Pascal, Q., Moreno, S. G., Bravard, A., Bernardino-Sgherri, J., Dereuddre-Bosquet, N., Montagutelli, X., Le Grand, R., Petit, V., Ferri, F.. 2023-12-19. Multi-target mode of action of Sulfodyne(R), a stabilized Sulforaphane, against pathogenic effects of SARS-CoV-2 infection. https://doi.org/10.1101/2023.12.18.572126

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