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Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates

Author

Listed:
  • Olivia Goethals

    (Janssen Pharmaceutica NV)

  • Suzanne J. F. Kaptein

    (KU Leuven)

  • Bart Kesteleyn

    (Janssen Pharmaceutica NV)

  • Jean-François Bonfanti

    (Janssen-Cilag
    Galapagos)

  • Liesbeth Wesenbeeck

    (Janssen Pharmaceutica NV)

  • Dorothée Bardiot

    (Cistim Leuven vzw)

  • Ernst J. Verschoor

    (Biomedical Primate Research Centre)

  • Babs E. Verstrepen

    (Biomedical Primate Research Centre)

  • Zahra Fagrouch

    (Biomedical Primate Research Centre)

  • J. Robert Putnak

    (Walter Reed Army Institute of Research)

  • Dominik Kiemel

    (Center for Integrative Infectious Diseases Research)

  • Oliver Ackaert

    (Janssen Pharmaceutica NV)

  • Roel Straetemans

    (Janssen Pharmaceutica NV)

  • Sophie Lachau-Durand

    (Janssen Pharmaceutica NV)

  • Peggy Geluykens

    (Janssen Pharmaceutica NV
    Charles River Beerse)

  • Marjolein Crabbe

    (Janssen Pharmaceutica NV)

  • Kim Thys

    (Janssen Pharmaceutica NV)

  • Bart Stoops

    (Janssen Pharmaceutica NV)

  • Oliver Lenz

    (Janssen Pharmaceutica NV)

  • Lotke Tambuyzer

    (Janssen Pharmaceutica NV)

  • Sandra Meyer

    (Janssen Pharmaceutica NV)

  • Kai Dallmeier

    (KU Leuven)

  • Michael K. McCracken

    (Walter Reed Army Institute of Research)

  • Gregory D. Gromowski

    (Walter Reed Army Institute of Research)

  • Wiriya Rutvisuttinunt

    (Walter Reed Army Institute of Research)

  • Richard G. Jarman

    (Walter Reed Army Institute of Research)

  • Nicos Karasavvas

    (Walter Reed Army Institute of Research)

  • Franck Touret

    (Aix-Marseille Université-IRD 190-Inserm 1207)

  • Gilles Querat

    (Aix-Marseille Université-IRD 190-Inserm 1207)

  • Xavier Lamballerie

    (Aix-Marseille Université-IRD 190-Inserm 1207)

  • Laurent Chatel-Chaix

    (Center for Integrative Infectious Diseases Research
    Institut National de la Recherche Scientifique)

  • Gregg N. Milligan

    (The University of Texas Medical Branch Health)

  • David W. C. Beasley

    (The University of Texas Medical Branch Health)

  • Nigel Bourne

    (The University of Texas Medical Branch Health)

  • Alan D. T. Barrett

    (The University of Texas Medical Branch Health)

  • Arnaud Marchand

    (Cistim Leuven vzw)

  • Tim H. M. Jonckers

    (Janssen Pharmaceutica NV)

  • Pierre Raboisson

    (Janssen Pharmaceutica NV
    Galapagos NV)

  • Kenny Simmen

    (Johnson & Johnson Innovation)

  • Patrick Chaltin

    (Cistim Leuven vzw
    KU Leuven)

  • Ralf Bartenschlager

    (Center for Integrative Infectious Diseases Research
    Heidelberg Partner Site)

  • Willy M. Bogers

    (Biomedical Primate Research Centre)

  • Johan Neyts

    (KU Leuven
    Global Virus Network (GVN))

  • Marnix Loock

    (Janssen Pharmaceutica NV)

Abstract

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.

Suggested Citation

  • Olivia Goethals & Suzanne J. F. Kaptein & Bart Kesteleyn & Jean-François Bonfanti & Liesbeth Wesenbeeck & Dorothée Bardiot & Ernst J. Verschoor & Babs E. Verstrepen & Zahra Fagrouch & J. Robert Putnak, 2023. "Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates," Nature, Nature, vol. 615(7953), pages 678-686, March.
    • Handle: RePEc:nat:nature:v:615:y:2023:i:7953:d:10.1038_s41586-023-05790-6
    DOI: 10.1038/s41586-023-05790-6
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    Citations

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    Cited by:

    1. Li-Hsin Li & Winston Chiu & Yun-An Huang & Madina Rasulova & Thomas Vercruysse & Hendrik Jan Thibaut & Sebastiaan ter Horst & Joana Rocha-Pereira & Greet Vanhoof & Doortje Borrenberghs & Olivia Goetha, 2024. "Multiplexed multicolor antiviral assay amenable for high-throughput research," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Dominik Kiemel & Ann-Sophie Helene Kroell & Solène Denolly & Uta Haselmann & Jean-François Bonfanti & Jose Ignacio Andres & Brahma Ghosh & Peggy Geluykens & Suzanne J. F. Kaptein & Lucas Wilken & Piet, 2024. "Pan-serotype dengue virus inhibitor JNJ-A07 targets NS4A-2K-NS4B interaction with NS2B/NS3 and blocks replication organelle formation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. J. Ross Terrell & Thao T. Le & Ananya Paul & Margo A. Brinton & W. David Wilson & Gregory M. K. Poon & Markus W. Germann & Jessica L. Siemer, 2024. "Structure of an RNA G-quadruplex from the West Nile virus genome," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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