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

Author

Listed:
  • 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
    Galapagos)

  • Dorothée Bardiot

    (Cistim Leuven)

  • Bart Stoops

    (Janssen Pharmaceutica)

  • Tim H. M. Jonckers

    (Janssen Pharmaceutica)

  • Kai Dallmeier

    (KU Leuven)

  • Peggy Geluykens

    (Janssen Pharmaceutica
    Charles River Beerse, Discovery)

  • Kim Thys

    (Janssen Pharmaceutica)

  • Marjolein Crabbe

    (Janssen Pharmaceutica)

  • Laurent Chatel-Chaix

    (Heidelberg University
    Institut National de la Recherche Scientifique, Centre Armand-Frappier Santé Biotechnologie)

  • 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
    Aligos)

  • Kenny Simmen

    (Janssen Pharmaceutica)

  • Patrick Chaltin

    (Cistim Leuven
    KU Leuven)

  • Ralf Bartenschlager

    (Heidelberg University
    Heidelberg Partner Site)

  • Marnix Loock

    (Janssen Pharmaceutica)

  • Johan Neyts

    (KU Leuven
    Global Virus Network (GVN))

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.

Suggested Citation

  • 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 Geluy, 2021. "A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction," Nature, Nature, vol. 598(7881), pages 504-509, October.
    • Handle: RePEc:nat:nature:v:598:y:2021:i:7881:d:10.1038_s41586-021-03990-6
    DOI: 10.1038/s41586-021-03990-6
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