key: cord-263754-iv21q46l authors: Cuadrado, Antonio; Pajares, Marta; Benito, Cristina; Jiménez-Villegas, José; Escoll, Maribel; Fernández-Ginés, Raquel; Garcia Yagüe, Angel J.; Lastra, Diego; Manda, Gina; Rojo, Ana I.; Dinkova-Kostova, Albena T. title: Can activation of NRF2 be a strategy against COVID-19? date: 2020-07-14 journal: Trends Pharmacol Sci DOI: 10.1016/j.tips.2020.07.003 sha: doc_id: 263754 cord_uid: iv21q46l Acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2 is largely the result of a dysregulated host response, followed by damage to alveolar cells and lung fibrosis. Exacerbated pro-inflammatory cytokines release (cytokine storm) and loss of T-lymphocytes (leucopenia) characterize the most aggressive presentation. Here we propose that a multi-faceted anti-inflammatory strategy based on pharmacological activation of nuclear factor erythroid 2 p45-related factor 2 (NRF2), can be deployed against the virus. The strategy provides robust cytoprotection by restoring the redox and protein homeostasis, promoting resolution of inflammation, and facilitating repair. NRF2 activators such as sulforaphane and bardoxolone methyl are already in clinical trials. The safety and efficacy information of these modulators in humans, together with their well-documented cytoprotective and anti-inflammatory effects in preclinical models, highlight the potential of this armamentarium for deployment to the battlefield against COVID-19. J o u r n a l P r e -p r o o f NRF2 for promote the resolution of COVID-19 associated inflammation whilst in parallel, restore redox homeostasis and facilitate tissue repair. It should be noted that the protein under discussion is distinctly separate from the identically abbreviated Nuclear Respiratory Factor 2 (also known as GA Binding Protein Transcription Factor Subunit Beta, gene name GABPB1), which is a completely different transcription factor involved in mitochondrial biogenesis [8] . NRF2 is a cap´n´collar (CNC) transcription factor that heterodimerizes with small musculoaponeurotic fibrosarcoma (sMAF) proteins, K, G or F [9] , or with reported in animal models of a number of lung disorders, including respiratory infections and ARDS [18] . Moreover, single nucleotide polymorphisms (SNPs) located in the promoter region of NFE2L2 (encoding NRF2) have been implicated in lung disease susceptibility in humans, hence reinforcing NRF2 as therapeutic target for pulmonary diseases [19, 20] . NRF2 also plays a role in both the execution and the resolution of inflammation DMF is used in the treatment of multiple sclerosis (MS) and psoriasis and may have beneficial effect in lung diseases [73] . Consistent with its role in prevention of de- occurs in a subset of MS patients [75] . Considering that leukopenia is a hallmark of severe cases of COVID-19, the potential use of DMF in this setting should be considered with caution. The isothiocyanate sulforaphane (SFN), originally isolated from broccoli, a cruciferous vegetable, as an inducer of the classical NRF2 target, NAD(P)H:quinone oxidoreductase 1 (NQO1) [76] , is the most potent naturally occurring NRF2 activator, with well-documented antioxidant and anti-inflammatory effects [77] . The high bioavailability of SFN and its stabilised α-cyclodextrin encapsulated version sulforadex (SFX-01), makes it an excellent candidate for alleviating excessive anti-inflammatory responses and protecting the lungs. SFN has been found to be protective in animal models of respiratory disease, including an ARDS model in rabbits [78] , and a hyperoxia-induced pulmonary injury model in mice [79] . It also limits RSV replication Table 1 ). The clinical trials provide extensive pharmacokinetics, pharmacodynamics, safety and efficacy information [77] that can be extrapolated to COVID-19. Notably, most of these trials have recommended cruciferous-free diets during the study period in order to minimize baseline noise and be able to detect accurately the plasma and urinary levels of sulforaphane and its metabolites [86] . Semi-synthetic pentacyclic triterpenoids derived from the natural product oleanolic acid represent the most potent NRF2 activators known to date, with activities in the sub-to low-nanomolar concentration range [87] . An early study highlighted that the anti-inflammatory and NRF2 inducer potencies among 18 triterpenoids were linearly correlated over 6 orders of magnitude of concentration, suggesting that the two processes were mechanistically linked [88] . Some triterpenoids isolated from Ganoderma lucidum have been found to be potential inhibitors of the NS2B-NS3 protease of DENV [89] . A study conducted in 2003 after the SARS outbreak [90] found activate NRF2 in other settings [77, 91] , and it is plausible that at least part of the observed antiviral effect was due to NRF2 activation. In the past few months, COVID-19, a disease caused by a novel coronavirus SARS-CoV-2, has had a tremendous health and socio-economic impact on a global scale. Here we propose a potential anti-inflammatory therapy based on pharmacological targeting of transcription factor NRF2. We envision that the benefits of pharmacological activation of NRF2 in the context of SARS-Cov-2 infection will be three-fold: 1) increasing fitness and providing protection to the host cell; 2) promoting the antiinflammatory phenotype during macrophage activation and thus preventing uncontrolled production of proinflammatory cytokines and pyroptosis; 3) inhibiting viral propagation. Notably, unlike direct antioxidants, such as vitamin C, which are short-lived (minutes to hours) and consumed in the process of ROS-scavenging, the antioxidant and cytoprotective effects of NRF2 activation are long-lasting and persist for several days after inducer elimination [110, 111] . This is because they are mediated by enzymes, which in contrast to small molecules, have long half-lives [11] and are not consumed, but are regenerated during the reactions which they catalyze [112] . 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