A dual‐acting dengue inhibitor targeting NS5 RdRp-3′UTR interaction while restoring endoplasmic reticulum homeostasis

Dengue virus (DENV) poses a major global health threat with millions of infections annually, yet no specific antiviral therapy has been approved. Although Remdesivir shows moderate anti-DENV activity, its injectable administration and liver-restricted distribution limit systemic efficacy. To address this issue, we developed a dual-target strategy and identified compound A051 , integrating antiviral activity with the anti-inflammatory effects of sEH inhibition. A051 potently inhibited all four DENV serotypes in vitro (EC 50 = 0.32‒1.66 μmol/L, CC 50 > 800 μmol/L) by targeting NS5 RdRp and reducing viral replication, and produced ∼3log viral load reduction in a DENV-2 mouse model. It also suppressed NF- κ B signaling, restored ER homeostasis, and reduced inflammatory cytokine production. Pharmacokinetic studies showed A051 acts as a dual-action prodrug with 55.53% oral bioavailability in rats. Toxicity evaluation demonstrated favorable safety, supporting A051 as a promising oral anti-DENV candidate.