Dual antiviral and anti-inflammatory effects of BAY 11-7082 in SARS-CoV-2 infection via inhibition of the canonical NF-κB signaling pathway

The continued emergence of SARS-CoV-2 variants and persistent inflammatory complications of COVID-19 highlight the urgent need for therapeutics with both antiviral and anti-inflammatory properties. Despite intensive global efforts, no approved antiviral therapy with these dual functions has yet been developed, representing a significant gap in current COVID-19 treatment strategies. In this study, we identify BAY 11-7082 (BAY) as a dual-action compound that inhibits SARS-CoV-2 replication and the production of virus-induced pro-inflammatory cytokines and chemokines, including IL-6, IL-8, CXCL1, and CXCL2. BAY predominantly exerts its antiviral activity at the post-entry stage of the viral life cycle. Mechanistically, BAY potentially interacts with SARS-CoV-2 NSP14 and inhibits virus-induced phosphorylation and degradation of IκBα, suppressing NF-κB activation through the IKK-IκBα signaling axis. Furthermore, BAY exhibits potent antiviral activity against multiple SARS-CoV-2 variants of concern (VOCs). Collectively, these findings support the potential of BAY as a dual-action therapeutic candidate, combining antiviral and anti-inflammatory effects, against SARS-CoV-2 and its emerging variants.