Abstract

Dengue virus (DENV) infection remains a major global health threat. Its incidence is increasing, with frequent outbreaks affecting millions of people each year. Although vaccines are available, their limited effectiveness and the absence of targeted antiviral therapies highlight the critical need for alternative treatment approaches. In this study, we investigated the antiviral activity of bidebiline A and heteropsine, two dimeric aporphine alkaloids isolated from Trivalvaria costata, against DENV-infected Huh7 liver cells. Our findings reveal that heteropsine inhibits DENV production and infection in Huh7 cells more effectively than bidebiline A. Heteropsine also exerts antiviral activity in endothelial and lung cell lines. Mechanistic studies, including time-of-addition assays and molecular docking, elucidate that heteropsine targets early steps during cellular infection, possibly by binding to domain III of the dengue virus envelope protein (EDIII). Viral binding and internalization assays confirmed that heteropsine disrupts viral entry. Furthermore, heteropsine suppresses DENV-induced immunopathogenesis by downregulating the expression of cytokine/chemokine genes (TNF-α, IL-6, RANTES, and IP-10) and attenuating nuclear translocation of the p65 subunit of the nuclear factor-kappaB (NF-κB) transcription factor. These findings highlight the importance of heteropsine as a promising antiviral candidate with the potential for further development to address the urgent need for effective dengue therapeutics.