ZINC-592 Ameliorates IgE-Mediated Chronic Inflammatory Responses of Viral Infections via Keap1/Nrf2 Signaling.

Chronic inflammation triggered by viral infections poses significant challenges to human health. This study aims to evaluate the potential of ZINC-592, a novel Keap1 inhibitor, in mitigating chronic inflammation associated with viral infections mediated by IgE. High-throughput screening, molecular docking studies, and molecular dynamics simulations were employed. RBL-2H3 cells and human whole blood basophils were used to evaluate the IgE-mediated anti-inflammatory effects. Molecular docking analysis revealed favorable binding interactions between the lead compound ZINC-592 and Keap1, suggesting its potential as a Keap1 inhibitor. Molecular dynamics simulations confirmed the stability of the ZINC-592-Keap1 complex over time. In vitro assays demonstrated that ZINC-592 effectively suppressed IgE-sensitized RBL-2H3 degranulation and proinflammatory cytokine production in these cells. The compound dose-dependently inhibited CD63 in IgE-FcεRI-stimulated basophils. Keap1 and Nrf2-positive populations were decreased upon ZINC-592 treatment in IgE-stimulated RBL-2H3 cells. The findings of this study highlight the promising therapeutic potential of ZINC-592 as a Keap1 inhibitor for mitigating chronic inflammation associated with viral infections, including those exacerbated by IgE-mediated immune responses. Further preclinical and clinical investigations are warranted to develop ZINC-592 as a novel therapeutic agent for viral infection-induced inflammation, particularly in the context of IgE-mediated immune responses.