A pan-serotype dengue virus inhibitor targeting the NS3-NS4B interaction

The small molecule JNJ-A07 interferes with the interaction between the NS3 and NS4B proteins of dengue virus and reduces the viral load in mice even when first administered at peak viraemia. Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue(1,2). There are no antiviral agents available to prevent or treat dengue. Here, we describe a highly potent dengue virus inhibitor (JNJ-A07) that exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that represent the natural genetic diversity of known genotypes 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 revealing a previously undescribed mechanism of antiviral action. JNJ-A07 has a favourable pharmacokinetic profile that results in outstanding efficacy against dengue virus infection in mouse infection models. Delaying start of treatment until peak viraemia results in a rapid and significant reduction in viral load. An analogue is currently in further development.

Automated summary

JNJ-A07 is a highly potent inhibitor of dengue virus, showing nanomolar to picomolar activity against a panel of 21 clinical isolates. It prevents the formation of viral replication complex by blocking the interaction between NS3 and NS4B proteins, revealing a previously undescribed mechanism of antiviral action. The molecule has a favorable pharmacokinetic profile and exhibits outstanding efficacy in mouse infection models, even when treatment is initiated at peak viraemia.