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

Kaptein, Suzanne JF; Goethals, Olivia; Kiemel, Dominik; Marchand, Arnaud; Kesteleyn, Bart; Bonfanti, Jean-Francois; Bardiot, Dorothee; Stoops, Bart; Jonckers, Tim HM; Dallmeier, Kai; Geluykens, Peggy; Thys, Kim; Crabbe, Marjolein; Chatel-Chaix, Laurent; Muenster, Max; Querat, Gilles; Touret, Franck; de Lamballerie, Xavier; Raboisson, Pierre; Simmen, Kenny; Chaltin, Patrick; Bartenschlager, Ralf; Van Loock, Marnix; Neyts, Johan

doi:10.1038/s41586-021-03990-6

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

Author:

Kaptein, Suzanne JF

Goethals, Olivia ; Kiemel, Dominik ; Marchand, Arnaud ; Kesteleyn, Bart ; Bonfanti, Jean-Francois ; Bardiot, Dorothee ; Stoops, Bart ; Jonckers, Tim HM ; Dallmeier, Kai ; Geluykens, Peggy ; Thys, Kim ; Crabbe, Marjolein ; Chatel-Chaix, Laurent ; Muenster, Max ; Querat, Gilles ; Touret, Franck ; de Lamballerie, Xavier ; Raboisson, Pierre ; Simmen, Kenny ; Chaltin, Patrick ; Bartenschlager, Ralf ; Van Loock, Marnix ; Neyts, Johan

Keywords:

Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, NS4B, REPLICATION, NS3, Animals, Antiviral Agents, Dengue, Dengue Virus, Disease Models, Animal, Female, Male, Membrane Proteins, Mice, RNA Helicases, Serine Endopeptidases, Viral Load, Viral Nonstructural Proteins, Viremia, Virus Replication, General Science & Technology

Abstract:

Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue1,2. 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.