Dengue Virus Molecular Targets and Antiviral Drug Development: Advances, Challenges and Therapeutic Perspectives
Dengue is the most prevalent arboviral disease in tropical and subtropical regions, with over 13 million cases recorded in the Americas in 2024. Despite its enormous public health impact, no specific antiviral therapy is currently approved for dengue virus (DENV). In this context, this narrative review critically analyses the principal molecular targets of DENV, including structural proteins (C, prM/M and E), nonstructural proteins (NS1–NS5) and host factors, with emphasis on the development of small‐molecule antivirals and an evaluation of their progress in pre‐clinical and clinical studies. The NS2B–NS3 protease complex and NS5 (both RdRp and MTase domains) remain the most extensively explored targets, owing to the availability of high‐resolution crystal structures and higher inter‐serotype conservation. NS4B has emerged as the most clinically advanced target. Among direct‐acting antivirals, AT‐752 was also discontinued due to low viraemia at enrolment, while NITD‐688 remains among the most advanced pipeline molecules. Host‐directed therapies including anakinra and baricitinib are under clinical investigation for severe dengue. Key translational challenges include viral serotype diversity, pharmacokinetic limitations, cytotoxicity, and the timing of treatment initiation relative to viral kinetics. Advances in rational drug design, drug repurposing, allosteric inhibition, and targeted protein degradation (PROTACs) offer renewed perspectives for effective dengue therapeutics.