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Dengue — which can be caused by any of the four Dengue virus (DENV) serotypes (DENV-1–4) — represents the most rapidly spreading mosquito-borne viral disease worldwide, and there are currently no antiviral drugs available for treatment or prophylaxis. Building on findings from a previous anti-DENV-2 screen, Goethals et al. characterize the small-molecule DENV inhibitor JNJ-1802. In vitro, the compound exerted picomolar to nanomolar antiviral potency against a panel of 20 DENV strains that represent the diversity of genotypes within the four serotypes. JNJ-1802 was found to act by blocking the NS3–NS4B interaction within the viral replication complex and exhibited a high barrier to resistance. In mice, JNJ-1802 demonstrated prophylactic activity against DENV-1–4 and was also effective in a therapeutic setting: when treatment was initiated after infection at the time of peak viraemia, DENV RNA was efficiently reduced. Oral JNJ-1802 treatment starting 3 days before infection also showed excellent prophylactic efficacy against DENV-1 and DENV-2 infection in rhesus macaques, with viral RNA remaining undetectable in animals receiving the highest dose. JNJ-1802 has successfully completed a phase I clinical study in healthy volunteers.