SULFORAPHANE

SULFORAPHANE

Following exploratory experiments using the in vitro CPE inhibition assay, Sulforaphane (SFN) was identified as a promising candidate to target the host cellular response, given that it is orally bioavailable, commercially available at low cost, and has limited side effects. We observed that SFN has dual antiviral and anti-inflammatory properties against coronaviruses. We determined that SFN has potent antiviral activity against HCoV-OC43 and multiple strains of SARS-CoV-2, including Delta and Omicron, with limited toxicity in cell culture. The similar results observed between the coronaviruses evaluated suggest that SFN could have broad activity against coronaviruses, a feature that may prove invaluable as new strains of pathogenic coronaviruses enter the human population.

The pathogenesis of many viral infections is associated with increased production of reactive oxygen species (ROS), which leads to cell death. Conversely, SFN increases antioxidant, anti-inflammatory, and antiviral defenses through multiple mechanisms, including the activation of the cap’n’collar transcription factor NRF2. Under normal conditions, NRF2 remains in an inactive state by association with its inhibitor protein Kelch-like ECH-associated protein 1 (KEAP1) [38]. In response to oxidative stress, KEAP1 is inactivated, and NRF2 is released to induce NRF2-responsive genes that subsequently protect against stress-induced cell death.

The dual antiviral and anti-inflammatory properties of SFN have also been previously described for other viral infections. In vitro antiviral activity has been reported against influenza virus, and SFN treatment significantly limited lung viral replication and virus-induced inflammation in respiratory syncytial virus-infected mice.

As a potent NRF2 activator, SFN can modulate the host’s immune response while also providing direct, NRF2-independent antiviral effects. Targeting the NRF2 pathway has been considered a promising approach to develop therapeutics for COVID-19 for multiple reasons. NRF2 deficiency is known to upregulate the angiotensin-converting enzyme 2 (ACE2), the primary mechanism of cell entry for SARS-CoV-2. The NRF2 activator oltipraz reduces ACE2 levels, suggesting that NRF2 activation might reduce the availability of ACE2 for SARS-CoV-2 entry into the cell49. Increased NRF2 activity also reportedly inhibits IL-6 and IL-1β gene expression, two cytokines known to play key roles in promoting the hyperactive immune response in severely ill COVID-19 patients. Conversely, NRF2 activity is dysregulated in disease states that have been associated with increased severity of COVID-19 (e.g., diabetes). Further, NRF2 activity declines in older patients who are more susceptible to severe COVID-19. Recent reports suggest that NRF2-dependent genes are suppressed in SARS-CoV-2 infected cells and lung biopsies from COVID-19 patients. Similarly, treatment of cells with NRF2 agonists 4-octyl-itaconate and dimethyl fumarate inhibited replication of SARS-CoV-2 in vitro. (Ordonez, 2022).

Reference:

(Ordonez, 2022). Ordonez AA, Bullen CK, Villabona-Rueda AF, et al. Sulforaphane exhibits antiviral activity against pandemic SARS-CoV-2 and seasonal HCoV-OC43 coronaviruses in vitro and in mice. Communications Biology. 2022 Mar;5(1):242. DOI: 10.1038/s42003-022-03189-z. PMID: 35304580; PMCID: PMC8933402.