A novel quinoline-based synthetic zinc ionophore regulates Class I HDAC-associated host antiviral response against Newcastle disease virus replication.

Newcastle disease virus (NDV) remains a substantial threat to the worldwide poultry industry. Targeting ion homeostasis is studied as a potential antiviral strategy to prevent viral infection and treat channelopathies. Quinoline derivatives, such as 8-aminoquinolines (AQ), are well-established scaffolds in medicinal chemistry with known antiviral properties. The study introduces a novel series of AQ derivatives and evaluates their transmembrane zinc (Zn²⁺) transport activity. Our results suggested that a potent Zn²⁺ transporter, AQ-CN, effectively suppressed NDV replication post-infection, both in vitro and in ovo, with reduced hemolytic activity and potent inhibitory concentration. Additionally, elevated Zn²⁺ levels affected host epigenetic regulators, downregulating Class I histone deacetylases (HDAC1, HDAC2, HDAC3, HDAC8) and reducing global lysine acetylation. Furthermore, in the presence of Zn2 +, AQ-CN increased type I interferon signaling and upregulated antiviral cytokine genes. Pharmacological inhibition with valproic acid, a class I HDAC inhibitor, largely restored the antiviral phenotype, indicating that HDAC-dependent mechanisms are involved in the observed effect. Overall, our findings point to AQ-CN-mediated transmembrane transport as a viable anti-NDV strategy and support a model in which zinc-regulated host Class I HDAC pathways help combat NDV replication.