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

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, Pietro Scaturro, Johan Neyts, Marnix Loock, Olivia Goethals and Ralf Bartenschlager ()
Additional contact information
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
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

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50437-3

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