E protein inhibitors and host-directed therapies in dengue virus infection: perspectives on combination and complementary antiviral strategies

This is the authors' abstract. We don't add key points for this paper.

INTRODUCTION: Dengue virus (DENV) remains a significant global health threat, causing millions of infections and substantial morbidity each year. The viral E protein is a key target for neutralizing antibodies and vaccine design; however, antibody-dependent enhancement (ADE) complicates safe immunization. Currently licensed vaccines offer only partial and serotype-dependent protection, highlighting the urgent necessity for additional therapeutic strategies. AREAS COVERED: This review summarizes advances in direct-acting antivirals (DAAs) targeting the E protein and host-directed therapies (HDTs). It discusses DAAs that block E-mediated viral entry and HDTs that modulate lipid metabolism, nucleotide biosynthesis, protein folding, translation, and immune pathways. Promising preclinical candidates and experimental DAAs-HDTs combinations with synergistic activity are highlighted, alongside persistent challenges related to viral diversity, ADE risk, host toxicity, and translational limitations. Relevant literature was identified through PubMed, Scopus, Web of Science, ClinicalTrials.gov, and WHO databases, including recent and foundational studies up to September 2025. EXPERT OPINION: Combining DAAs with HDTs represents a rational strtategy to enhance antiviral efficacy, broaden serotype coverage, reduce resistence, and pontentially limit toxicity. Although clinical evidence remains limited, expandend preclinical and clinical evaluation of these approaches, incorporating serotype-specific testing and sex-based analyses will be essential for advancing effective dengue therapeutics.