Targeting dengue virus infection through a translation-modulator small-molecule screen

Dengue virus (DENV), a mosquito-borne RNA virus, poses a significant global health concern due to the lack of effective antivirals and the limitations of current vaccines. To uncover host-targeted vulnerabilities, we performed a functional screen of small-molecule translation modulators. Elongation inhibitors consistently produced the most potent antiviral effects, markedly reducing viral RNA levels, nonstructural protein 3 (NS3) levels, and infectious virus production. Compounds targeting cap-dependent initiation were largely ineffective, except for eIF4E:eIF4G inhibitors, which exerted moderate suppression. This may likely be due to the internal ribosome entry site (IRES)-like activity reported in the DENV 5' untranslated region (UTR). Rocaglamide A strongly suppressed DENV, consistent with an eIF4A helicase-specific vulnerability. Two clinically relevant inhibitors, homoharringtonine (HHT) and bruceantin (BCT), blocked DENV propagation at low nanomolar doses in cell lines and reduced viral RNA and titers in primary human macrophages, underscoring their translational potential. Similar effects were observed with the related Zika virus (ZIKV) in cell lines. These pharmacological data suggest that translation elongation and eIF4A helicase activity are candidate host dependencies for orthoflaviviruses, motivating stage-resolved and in vivo evaluation studies.