Pharmacological induction of the Nrf2 pathway as immunomodulatory, cytoprotective, and antiviral intervention for COVID-19 (COVID-PROTECT)

A hallmark of infection with the highly pathogenic coronaviruses SARS-CoV, SARS-CoV-2, and MERS-CoV is that systemic inflammation and hyperinflammation-related airway damage (including acute respiratory distress syndrome, ARDS) are main determinants of severe morbidity and mortality. Modulating the host immune response might therefore constitute a highly effective addition to treatment regimens based on antiviral agents. The Nrf2 pathway constitutes a particularly attractive therapeutic target because (1) it has a variety of well-documented cytoprotective and anti-inflammatory properties and (2) its pharmacological induction protects mice from LPS-induced ARDS. Indeed, in our ongoing screen of anti-SARS-CoV-2 compounds we have found that the Nrf2 activator bardoxolone strongly reduces cytopathic effect and SARS-CoV-2 infectivity. We therefore hypothesize that Nrf2 inducers may prove useful to treat COVID-19. To test this hypothesis, we will assess anti-inflammatory, cytoprotective and anti-SARS-CoV-2 activity of bardoxolone and other Nrf2 activators using a pipeline based on human primary airway epithelial cells (both iPSC-derived and obtained from human lung) and immortalized cells and ex vivo cultured airway explants, also assessing protective effects in a model of airway epithelial barrier disruption as a proxy for ARDS. Considering that bardoxolone has already advanced in clinical trials to Phase III for other human disorders, further translation into clinical proof-of-concept studies for COVID-19 should be relatively straight forward and will be sought early on.