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

Suzanne J. F. Kaptein, Olivia Goethals, Dominik Kiemel, Arnaud Marchand, Bart Kesteleyn, Jean-François Bonfanti, Dorothée Bardiot, Bart Stoops, Tim H. M. Jonckers, Kai Dallmeier, Peggy Geluykens, Kim Thys, Marjolein Crabbe, Laurent Chatel-Chaix, Max Münster, Gilles Querat, Franck Touret, Xavier Lamballerie, Pierre Raboisson, Kenny Simmen, Patrick Chaltin, Ralf Bartenschlager, Marnix Loock () and Johan Neyts ()
Additional contact information
Suzanne J. F. Kaptein: KU Leuven
Olivia Goethals: Janssen Pharmaceutica
Dominik Kiemel: Heidelberg University
Arnaud Marchand: Cistim Leuven
Bart Kesteleyn: Janssen Pharmaceutica
Jean-François Bonfanti: Janssen-Cilag
Dorothée Bardiot: Cistim Leuven
Bart Stoops: Janssen Pharmaceutica
Tim H. M. Jonckers: Janssen Pharmaceutica
Kai Dallmeier: KU Leuven
Peggy Geluykens: Janssen Pharmaceutica
Kim Thys: Janssen Pharmaceutica
Marjolein Crabbe: Janssen Pharmaceutica
Laurent Chatel-Chaix: Heidelberg University
Max Münster: Heidelberg University
Gilles Querat: Unité des Virus Émergents (UVE), Aix-Marseille Univ, IRD 190 Inserm 1207, IHU Méditerranée Infection
Franck Touret: Unité des Virus Émergents (UVE), Aix-Marseille Univ, IRD 190 Inserm 1207, IHU Méditerranée Infection
Xavier Lamballerie: Unité des Virus Émergents (UVE), Aix-Marseille Univ, IRD 190 Inserm 1207, IHU Méditerranée Infection
Pierre Raboisson: Janssen Pharmaceutica
Kenny Simmen: Janssen Pharmaceutica
Patrick Chaltin: Cistim Leuven
Ralf Bartenschlager: Heidelberg University
Marnix Loock: Janssen Pharmaceutica
Johan Neyts: KU Leuven

Nature, 2021, vol. 598, issue 7881, 504-509

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03990-6

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