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

ABSTRACT: 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 proinflammatory 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310111 | GEO | 2026/04/03

REPOSITORIES: GEO

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Project description:Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade (1) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective treatment strategies. Here, we characterize the antiviral activity of GS-5245, Obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-related Bat-CoV RsSHC014, Middle East Respiratory Syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (Mpro) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. We also evalulate the effect of antiviral therapy on host gene expression using RNAseq and show that therapeutic intervention reduces host inflammatory response as compared to vehicle controls during acute SARS-CoV-2 infection. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions.

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

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