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Pan-serotype dengue virus inhibitor JNJ-A07 targets NS4A-2K-NS4B interaction with NS2B/NS3 and blocks replication organelle formation

Author

Listed:
  • Dominik Kiemel

    (Center for Integrative Infectious Disease Research)

  • Ann-Sophie Helene Kroell

    (Center for Integrative Infectious Disease Research)

  • Solène Denolly

    (Center for Integrative Infectious Disease Research)

  • Uta Haselmann

    (Center for Integrative Infectious Disease Research)

  • Jean-François Bonfanti

    (Janssen-Cilag
    Evotec)

  • Jose Ignacio Andres

    (a Johnson & Johnson company)

  • Brahma Ghosh

    (a Johnson & Johnson company)

  • Peggy Geluykens

    (Charles River Beerse)

  • Suzanne J. F. Kaptein

    (KU Leuven)

  • Lucas Wilken

    (Leibniz Institute of Virology)

  • Pietro Scaturro

    (Leibniz Institute of Virology)

  • Johan Neyts

    (KU Leuven)

  • Marnix Loock

    (a Johnson & Johnson company)

  • Olivia Goethals

    (a Johnson & Johnson company)

  • Ralf Bartenschlager

    (Center for Integrative Infectious Disease Research
    Heidelberg partner site)

Abstract

Dengue fever represents a significant medical and socio-economic burden in (sub)tropical regions, yet antivirals for treatment or prophylaxis are lacking. JNJ-A07 was described as highly active against the different genotypes within each serotype of the disease-causing dengue virus (DENV). Based on clustering of resistance mutations it has been assumed to target DENV non-structural protein 4B (NS4B). Using a photoaffinity labeling compound with high structural similarity to JNJ-A07, here we demonstrate binding to NS4B and its precursor NS4A-2K-NS4B. Consistently, we report recruitment of the compound to intracellular sites enriched for these proteins. We further specify the mechanism-of-action of JNJ-A07, which has virtually no effect on viral polyprotein cleavage, but targets the interaction between the NS2B/NS3 protease/helicase complex and the NS4A-2K-NS4B cleavage intermediate. This interaction is functionally linked to de novo formation of vesicle packets (VPs), the sites of DENV RNA replication. JNJ-A07 blocks VPs biogenesis with little effect on established ones. A similar mechanism-of-action was found for another NS4B inhibitor, NITD-688. In summary, we unravel the antiviral mechanism of these NS4B-targeting molecules and show how DENV employs a short-lived cleavage intermediate to carry out an early step of the viral life cycle.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50437-3
    DOI: 10.1038/s41467-024-50437-3
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    References listed on IDEAS

    as
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