Discovery of 10-Shogaol from Zingiber officinale with Broad Antiviral and Anti-inflammatory Activity against Dengue and Zika Viruses Using Activity-Guided Molecular Networking

The bioactive constituents of ginger ( Zingiber officinale Roscoe) display well-documented immunomodulatory and antimicrobial effects; however, the role of these components in combating dengue virus (DENV) and other flaviviruses infection remains unknown. Here, activity-guided molecular networking and antiviral screening identified 10-shogaol as the primary antiviral phytochemical in ginger, with a half-maximal inhibitory concentration (IC 50 ) value of 2.502 μM. Mechanistically, 10-shogaol bound the n -octyl-β- d -glucopyranoside (β-OG) pocket of viral envelope protein (E), interfering with viral attachment and conferring broad antiviral properties against DENV and Zika virus (ZIKV). Additionally, 10-shogaol suppressed proinflammatory cytokines and mitigated tissue damage in mice by acting as a novel Nrf2 activator by inhibiting Keap1-mediated ubiquitination and proteasome degradation. Activation of Nrf2 by 10-shogaol induced antioxidant gene expression and inhibited inflammatory NF-κB signaling. Collectively, our study suggests that 10-shogaol acts as a broad-spectrum entry inhibitor against DENV and ZIKV as well as confers anti-inflammatory benefits for mitigating virus-induced inflammatory tissue damage.