Dengue virus (DENV) causes ~96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue 1,2 . There are no antivirals available to prevent or treat dengue. We describe a highly potent DENV inhibitor (JNJ-A07) that exerts nano-to picomolar activity against a panel of 21 clinical isolates, representing the natural genetic diversity of known geno-and serotypes. The molecule has a high barrier to resistance and prevents the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), thus unveiling an entirely novel mechanism of antiviral action. JNJ-A07 has an excellent pharmacokinetic profile that results in outstanding efficacy against DENV infection in mouse infection models. Delaying start of treatment until peak viremia results in a rapid and significant reduction in viral load. An analogue is currently in further development. MAIN TEXTDengue is currently considered one of the top10 global health threats 1 . Annually, an estimated 96 million develop dengue disease 2 , which is likely an underestimation [3][4][5] . The incidence has increased ~30-fold over the past 50 years. The virus is endemic in 128 countries in (sub-)tropical regions, with an estimated 3.9 billion people at risk of infection. A recent study predicts an increase to 6.1 billion people at risk by 2080 6 . The upsurge is driven by factors such as rapid urbanization and the sustained spread of the mosquito vectors [6][7][8] . DENV has four serotypes (further classified into genotypes), which are increasingly co-circulating in endemic regions. A second infection with a different serotype increases the risk of severe dengue 9,10 . The vaccine Dengvaxia ® , which is approved in a number of countries for those aged ≥9 years, is only recommended for those with previous dengue exposure 11,12,13 . There are no antivirals for the prevention or treatment of dengue; the development of pan-serotype DENV inhibitors has proven challenging 14,15 .

Respiratory syncytial virus is a major cause of acute lower respiratory tract infection in young children, immunocompromised adults, and the elderly. Intervention with small-molecule antivirals specific for respiratory syncytial virus presents an important therapeutic opportunity, but no such compounds are approved today. Here we report the structure of JNJ-53718678 bound to respiratory syncytial virus fusion (F) protein in its prefusion conformation, and we show that the potent nanomolar activity of JNJ-53718678, as well as the preliminary structure–activity relationship and the pharmaceutical optimization strategy of the series, are consistent with the binding mode of JNJ-53718678 and other respiratory syncytial virus fusion inhibitors. Oral treatment of neonatal lambs with JNJ-53718678, or with an equally active close analog, efficiently inhibits established acute lower respiratory tract infection in the animals, even when treatment is delayed until external signs of respiratory syncytial virus illness have become visible. Together, these data suggest that JNJ-53718678 is a promising candidate for further development as a potential therapeutic in patients at risk to develop respiratory syncytial virus acute lower respiratory tract infection.

Dengue is a major health threat and the number of symptomatic infections caused by the four dengue serotypes is estimated to be 96 million1 with annually around 10,000 deaths2. However, no antiviral drugs are available for the treatment or prophylaxis of dengue. We recently described the interaction between non-structural proteins NS3 and NS4B as a promising target for the development of pan-serotype dengue virus (DENV) inhibitors3. Here we present JNJ-1802—a highly potent DENV inhibitor that blocks the NS3–NS4B interaction within the viral replication complex. JNJ-1802 exerts picomolar to low nanomolar in vitro antiviral activity, a high barrier to resistance and potent in vivo efficacy in mice against infection with any of the four DENV serotypes. Finally, we demonstrate that the small-molecule inhibitor JNJ-1802 is highly effective against viral infection with DENV-1 or DENV-2 in non-human primates. JNJ-1802 has successfully completed a phase I first-in-human clinical study in healthy volunteers and was found to be safe and well tolerated4. These findings support the further clinical development of JNJ-1802, a first-in-class antiviral agent against dengue, which is now progressing in clinical studies for the prevention and treatment of dengue.

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