BACKGROUND: Dengue virus (DENV) is estimated to cause 390 million infections each year, but there is no licensed vaccine or therapeutic currently available. METHODS: We describe a novel, high-throughput screen to identify compounds inhibiting the interaction between DENV non-structural protein 5 and host nuclear transport proteins. We document the antiviral properties of a lead compound against all 4 serotypes of DENV, antibody-dependent enhanced infection (ADE), ex vivo and in vivo DENV infections. In addition we use qRT-PCR to examine cellular effects upon compound addition. RESULTS: We identify N-(4-hydroxyphenyl) retinamide (4-HPR) as effective in protecting against DENV-1-4 and DENV-1-ADE infections, with 50 effective concentrations (EC50s) in the low muM range. 4-HPR, but not closely related N-(4-methoxyphenyl) retinamide (4-MPR), could reduce viral RNA levels and titres when applied to an established infection. 4-HPR, but not 4-MPR, was found to specifically up-regulate the PKR-like ER kinase (PERK) arm of the unfolded protein response (UPR). Strikingly, 4-HPR but not 4-MPR restricted infection in peripheral blood mononuclear cells, and in a lethal ADE mouse model. CONCLUSIONS: 4HPR is a novel antiviral that modulates the UPR, effective against DENV1-4 at concentrations achievable in the plasma in a clinical setting, and provides protection in a lethal mouse model.