Antiviral Strategies Against Dengue Virus: Recent Insights into Compounds Targeting Viral and Host Factors

Dengue virus (DENV), the most prevalent arbovirus worldwide, continues to pose a major public health threat with no approved antiviral therapy to date. Despite decades of research, therapeutic development remains stalled at the preclinical stage, hindered by the virus's genetic variability, narrow therapeutic window, and complex interplay with the host immune system. This review offers a comprehensive overview of current antiviral strategies, covering both direct-acting antivirals (DAAs) targeting viral proteins (E, prM/M, C, NS2B/NS3, NS4A/B, and NS5) and host-targeting antivirals (HTAs) interfering with viral entry, replication, assembly, and immune modulation. Across 11 mechanistic categories, we observe a strong prevalence of natural products with in vitro efficacy, but limited advancement to in vivo or clinical testing. This translational gap reflects key limitations: restricted compound availability, lack of pharmacokinetic data, and insufficient collaboration between pharmacognosy, virology, and medicinal chemistry. We highlight the urgent need for integrated efforts to optimize promising leads and promote their clinical development. This review outlines the main challenges and perspectives to reinvigorate antiviral discovery against DENV.